Ashwagandha

Genevieve Guenther Ricart Embree, MD


https://medicine.duke.edu/faculty/genevieve-guenther-ricart-embree-md

Genomics and pro teomics represent a possible pathway to enhanced future drug discovery anxiety or heart attack purchase ashwagandha australia. Despite the size of this flood anxiety symptoms keep coming back buy ashwagandha 60 caps visa, its flow has not filled the drug discovery pipeline with winning candidates anxiety symptoms head ashwagandha 60 caps on line. Determining gene structure and function through genomics definitely does illuminate the path for deciphering human biochemistry and for linking specific genes to specific diseases anxiety lump in throat cheap ashwagandha american express. Although genomics did deliver phenomenal masses of raw information anxiety quotes tumblr discount ashwagandha 60caps on-line, the genomics technologies have so far failed to deliver the more than 10 anxiety symptoms muscle twitches order ashwagandha line,000 anticipated druggable targets predicted by the early hyperbole of the genomics era. Taking genomics one step further for the pur pose of drug discovery will require linking specific proteins to those specific genes. Bridging this gap will ultimately be a daunting task that lies within the domain of proteomics. More concretely, proteomics is the molecular biology discipline that seeks to elucidate the structure and function profiles of all proteins encoded within a specific genome; this collection of proteins is termed the proteome. The proteomes of multicellular organisms present an immense challenge in that more than 75% of the predicted proteins have no apparent cellular function. Furthermore, although the human proteome has more than 100,000 proteins, only a fraction of these proteins are expressed in any individual cell type. If specific dis eases are to be linked to specific proteins, it is imperative that ways be developed to deduce which individual protein is expressed in which individual cell. This is the multiple minima problem (also called the protein folding problem) referred to in chapter 1. The need to solve this problem has given rise to the subdiscipline of structural proteomics, a technology that is based upon the principle that structure underlies function and that endeavors to provide three-dimensional struc tural information for all proteins. These interactions underlie the events of cell-cycle regulation, cellular architecture, intracellular signal transduction, nucleic acid metabolism, lipid metabolism, and carbohydrate metabolism. Even when the technologies of structural proteomics and interaction proteomics have evolved to maturity, the pathway to the awaiting plethora of drugs is still not paved and perfect. Just as pro teomics is a crucial bridge uniting genomics to disease, so too will an equally crucial bridge be needed to unite proteomics with therapeutics. Using databases of compounds and other theoretical mol ecular design techniques, bioinformatics and cheminformatics will attempt to identify novel molecules to alter the function of various proteins defined by the genome-based proteome. Bioinformatics/cheminformatics will apply knowledge-discovery and pattern recognition algorithms to the genome-wide and proteome-wide experimental data, thereby facilitating drug design. If structural proteomics has identified the functional portion of an important protein, cheminformatics will search large databases of drug-like molecules to identify one that has the right shape and properties to dock with the pro tein. Because of the importance of bioinformatics and cheminformatics to the future of drug design, these topics are discussed in greater detail in chapter 1. In conven tional cheminformatics, a single drug is designed for a single protein target; in chemogenomics, multiple drugs will be designed to target multiple-gene families. Data gleaned for one protein can be applied to structurally similar proteins coded by the same gene family. Chemogenomics represents a new conceptual approach to target identifi cation and drug development. Conventional drug design attempts to discover drugs to treat par ticular diseases; pharmacogenomics attempts to design individualized drugs to treat particular people with particular diseases. On the basis of a variety of genetic testing, a physician would be able to predict how an individual patient would respond to a spe cific drug and if this patient will experience any specific side effects. On the basis of person-to-person variability in pharmacokinetics and pharmacodynamics, pharmacoge nomics will study how genetic variations affect the ways in which particular people respond to specific drug molecules. In attempting to achieve this lofty ideal, pharmacogenomics will rely upon genetic data such as single nucleotide polymorphism maps. The emergence of pharmacogenomics will also enhance the interaction of medicinal chemistry as a discipline with other disciplines, including the social sciences, ethics, and economics. Society has a difficult enough time paying for currently available drug therapies. Will this further widen the chasm between have and have-not populations, between developed and developing nations This is the point at which medici nal chemistry overlaps heavily with synthetic organic chemistry. Organic synthesis (from the Greek, synthetikos, to put together) is the preparation of complicated organic molecules from other, simpler, organic compounds. Because of the ability of carbon atoms to form chains, multiple bonds, and rings, an almost unimaginably large number of organic compounds can be conceived and created. A linear synthesis constructs the target molecule from a single starting material and progresses in a sequential step-by step fashion. A convergent synthesis creates multiple subunits through several parallel linear syntheses, and then assembles the subunits in a single final step. Since overall yield is a function of the number of steps performed, convergent syntheses have higher yields and are preferred over linear syntheses. In creating synthetic routes for the development of drug molecules, the synthetic chemist wants to create a molecular entity in which functional groups (carbonyls, amines, etc. The synthetic chemist has ten general classes of reactions available for such synthetic tasks: 1. Oxidations and reductions these ten reactions provide the capacity to construct a molecular framework and then to position functional groups precisely on this framework. Accordingly, these ten reac tions permit two fundamental construction activities: 1. Creation of C-C/C=C/C-H bonds (for the purpose of building a structural framework) 2. Creation of functional groups (to give functionality to the framework) Appendix 3. Detailed discussion and mechanisms for these reactions are not provided, but are available in many textbooks of basic or advanced organic chemistry. The synthesis of a complicated drug molecule from simple starting materials must be approached in a rigorous and sys tematic fashion. This approach is based upon the notion that it is easier to work backwards from the target molecule. In retrosynthetic analysis, a procedure known as disconnection is used to dissect a molecule into progressively smaller and smaller frag ments until readily available starting materials are obtained. Typically, a bond is broken and the electron pair is assigned to one of the fragments, resulting in a positively charged synthon and a negatively charged synthon. The next task is to find readily available starting materials that can actually be used as sources of these synthons. These available materials that are equivalent to a syn thon are referred to as synthetic equivalents, and are generally commercially available compounds that represent the nucleophile and the electrophile that must react. Cyclohexanol may be disconnected to a hydride ion and a hydroxycarbocation (the syn thons). Sodium borohydride and cyclohexanone are the synthetic equivalents of these two synthons. It is apparent that this system of disconnections can be applied to molecules of sig nificant complexity to deduce a synthetic route. At the research level, it is acceptable for a synthetic scheme to employ unusual catalysts or large amounts of organic solvents. If a drug costs $85 per milligram to synthesize and will be administered at 60 mg/day for many months, then it will not be a commercially viable drug. If a drug is to be successful it will have to be produced in large quantities in an industrial setting, necessitating the implementation of syntheses that are scalable, effi cient, and environmentally friendly. A synthetic scheme with fewer steps and employing water as a preferred solvent has distinct advantages over a technically complicated, low yield synthesis that uses large quantities of organic solvents that are difficult to dispose of. Thus, there are some differences between a classical synthetic organic chemist and a synthetic medicinal chemist. The classical synthetic organic chemist is proud of a com plex multistep synthesis which may, regrettably, have a low yield. The synthetic medi cinal chemist is pleased to design a molecule that can be synthesized in as few steps as possible, hopefully with a high yield and few by-products. A number of very important characteristics go into making a biological assay useful. Ideally, the assay should be rapid, cost-effective, efficient, and easy to implement. The alcohol functionality then undergoes a functional group interchange by conversion to a bromide. This is particularly true if one is pursuing lead compound discovery by high throughput screening of millions of compounds. More importantly, the biological model should accurately reflect the human disease for which it is being used as a drug-screening tool. Just because an animal model pro duces a similar disease as is found in humans, there is no guarantee that it will truly reflect the corresponding human disease. For example, occluding the middle cerebral artery in a gerbil will produce a gerbil stroke. A drug that successfully treats strokes in gerbils may not nec essarily treat strokes in humans. Alternatively, there may be diseases that are unique to humans or primates, thereby making it difficult to develop meaningful biological assays in species such as rodents. Biological assays for compound evaluation may be broadly categorized as follows: 1. Consequently, in silico methods are acceptable for preliminary screens, but are completely unacceptable for the advanced assessment of a candidate compound. Radiolabeled competitive binding studies can be used to ascertain whether a drug binds to a receptor. A second equivalent of the p-chloroaniline leads to a six-membered ring with two nitrogens. This is hydrolytically opened to expose a free amino group which reacts with an aminoester to yield a seven-member ring. Functional in vitro assays with a measurable biological outcome are required to tell whether a compound is functioning as an agonist or an antagonist. Regrettably but understandably, this assay is the most labor-intensive and costly. In vivo assays give the highest quality information about the efficacy of a lead compound. Ideally, a candidate drug molecule should not be advanced in the development process unless it demonstrates good to excellent efficacy in an appropriate in vivo model. Nevertheless, the optimization of a lead compound is a lengthy and expensive undertaking, fraught with a frighteningly high rate of failure. It means the application of previously recognized correlations of biological activity with physico chemical characteristics in the broadest sense, in the hope that the pharmacological suc cess of a not yet synthesized compound can be predicted. Although some practicing biologists and pharmacologists still regard efforts at drug design with some condescension and ill-concealed impatience, a slow but promising development gives renewed hope that progress in this area will not be less rapid than in the application of biology and physical chemistry to human and animal pathology. The explosive development of computer-aided drug design and bioinformatics (see chapter 1) promises to lead to the era of true rational drug design. The probabilities of finding a clinically useful drug were not good; it was estimated that anywhere from 3000 to 5000 compounds were synthesized in order to produce one optimized drug. The guiding principle was the paradigm that minor changes in a molecular structure lead to minor, quantitative alterations in its biological effects. Although this may be true in closely related series, it depends on the definition of minor changes. Extension of the side chain of diethazine by only one carbon atom led to the serendipitous discovery of chlorpromazine and the field of modern psychopharmacology.

The primary sulfur-containing constituents are glutamyl-S-alk(en)yl-L-cysteines and S-alk(en)yl-L-cysteine sulfoxides anxiety 7 year old daughter purchase genuine ashwagandha on-line. Considerable varia tion in the S-alk(en)ylcysteine sulfoxide content can occur; alliin (S-allylcysteine sulfoxide) is the largest contributor anxiety symptoms going crazy purchase 60 caps ashwagandha. Alliin concentrations can increase during storage because of the transforma tion of glutamylcysteines anxiety symptoms quotes buy discount ashwagandha online. Although garlic does not typically serve as a major source of essential nutrients anxiety at night buy ashwagandha 60 caps without prescription, it may contribute to several dietary factors with potential health benefts anxiety ulcer order ashwagandha 60 caps fast delivery, including the presence of oligosaccharides anxiety buzzfeed buy ashwagandha visa, arginine-rich proteins and, depending on soil and growing conditions, selenium and favonoids. Preclinical models provide rather compelling evidence that garlic and its associated components can lower the incidence of breast, colon, skin, uterine, esophagus, and lung cancers. Suppression of nitrosamine formation continues to surface as one of the most likely mechanisms by which garlic retards cancer. More recent evidence suggests as little as 1 g of garlic may be suffcient to suppress nitroproline formation (Cope et al. The ability of garlic to inhibit tumors due to different cancer-inducing agents and in different tissues indicates that a generalized cellular event is likely responsible for the change in tumor inci dence and that the response is highly dependent on environmental or other types of biological insults. However, this lack of responsiveness may relate to the amount and duration of exposure, the quantity of carcinogen administered, or the methods used to assess the cytochrome content or activity. Their data demonstrated that the number of sulfur atoms in the allyl compound is inversely related to the depression in these cytochromes. A breakdown of alli cin appears to be necessary for achieving maximum tumor inhibition. Undeniably, not all allyl sulfur compounds from garlic are equally effective in retarding tumor proliferation. Allyl sulfur compounds preferentially suppress neoplastic over non neoplastic cells (Sakamoto, Lawson, and Milner 1997). It is becoming increasingly clear that the response to allyl sulfurs relates to their ability to form free radicals rather than to serve as an anti oxidant (Antosiewicz et al. Allyl sulfurs may bring about changes by infuencing the genomic expression by affecting histone homeostasis. It is sometimes called root ginger to distinguish it from other products that share the name. The principal constituents of ginger include [6]-gingerol, [6]-paradol, [6]-shogaol (dehydration gingerols), and zingerone. Lipid and protein oxidation was inhibited in rats consuming ginger, as evidenced by signifcant decreases (p <. Rats fed with a basal diet supplemented with 1% ginger extract for 26 weeks had signifcantly fewer urothelial lesions compared to the controls or those fed with the diet with 0. To determine whether ginger had antiemetic effects in cisplatin-induced emesis, Manusirivithaya et al. The addition of ginger (1 g/day) to a standard antiemetic regimen has no advantage in reducing nausea or vomiting in the acute phase of cisplatin-induced emesis. In the delayed phase, ginger and metoclopramide have no statistically signifcant difference in effcacy (Manusirivithaya et al. Ginger was determined to be as effective as metoclopramide, but neither was as effective as ondansetron (Sontakke, Thawani, and Naik 2003). Overall, while the anticancer fndings of ginger are intriguing and several processes may be associated with the observed responses, additional studies are needed to clarify the underlying mechanisms and to determine overall benefts to humans (Pan et al. Rosemary is native to the Mediterranean region and possesses a bitter, astringent taste and highly aromatic char acteristics that complement a wide variety of foods. Rosemary is a member of the family Lamiaceae, and it contains a number of potentially biologically active compounds, including antioxidants such as carnosic acid and rosmarinic acid. Other bioactive compounds include camphor (up to 20% in dry rosemary leaves), caffeic acid, ursolic acid, betulinic acid, rosmaridiphenol, and rosmanol. Due to its high antioxidant activity, crude and refned extracts of rosemary are now widely avail able commercially (Ho et al. While the data are diffcult to interpret, when rosemary is added along with other herbs to a balsamic vinegar preparation used in soups and salads, it appears to provide protection again oxidative stress in humans (Dragan et al. Considerable evidence also suggests that rosemary extracts, or its isolated components, can retard chemically induced cancers. Although not extensively studied, such evidence suggests the ability of rosemary to infuence drug-metabolizing enzymes. Although carnosol may be effective, it may also interfere with the actions of some other antitumor agents. Overall, these data suggest that car nosol, and possibly other constituents in rosemary, may block the terminal apoptotic events induced by some chemotherapeutic drugs and therefore may decrease the effectiveness of some standard therapies for leukemia. Signifcant information points to the ability of saffron to inhibit cancer (Abdullaev 2003). Aqueous saffron preparations have been reported to inhibit chemically induced skin carcinogenesis (Das, Chakrabarty, and Das 2004). Both changes in carcinogen bioactivation and tumor prolifera tion appear to occur. Similar to other spices, they appear to suppress cell growth in neoplastic cells to a greater extent than in normal cells (Aung et al. The ability of crocin to decrease cell viability occurs in a concentration and time-dependent manner (Bakshi et al. The response is not limited to cells in culture because pancreatic xenografts are also infuenced by saffron (4 mg/kg diet for 30 days; Dhar et al. The effects of tumor suppression also have an impact on the longevity of the host. The mechanism by which saffron suppresses tumor proliferation has not been adequately explored, but a shift in caspases and an increase in Bax protein are possible (Mousavi et al. Saffron-induced apoptosis was inhibited by pan-caspase inhibitors, indicating the importance of this process in determining the response. Today, common usage refers to any or all members of the plant genus Thymus, also of the Lamiaceae family. Several active agents are reported, includ ing thymol, carvacrol, apigenin, luteolin, tannins, terpinene, and other oils (Aydin, Basaran, and Basaran 2005; Kluth et al. The number of studies on genotoxic effects of thymol and carvacrol are limited, but contradictory. Spices have been consumed for centuries for a variety of purposes, such as favoring agents, colorants, and preservatives. This chapter only scratches the surface of the overall impact of herbs and spices since there are approximately 180 spices com monly being used for culinary purposes. Without question, evidence exists that multiple processes, including proliferation, apoptosis, angiogenesis, and immunocompetence, can be infuenced by one or more spices. While the currently available data are intriguing, considerably more information is needed to determine who will beneft most from exaggerated intake of one or more spices, the effec tive exposures needed to bring about the desired outcome(s), and what interactions (both positive and negative) exist with other components of the diet or with medications that an individual may regularly consume. Targeting infammation-induced obesity and metabolic diseases by curcumin and other neutraceuticals. Antimicrobial property, antioxidant capacity, and cytotoxicity of essential oil from cumin produced in Iran. Effect of coriander seeds on hexachlorocyclohex ane induced lipid peroxidation in rat liver. Role of reactive oxygen interme diates in cellular responses to dietary cancer chemopreventive agents. Role of Cuminum cyminum on ethanol and preheated sun fower oil induced lipid peroxidation. Crocin from Crocus sativus possesses signifcant anti-proliferation effects on human colorectal cancer cells. Infuence of certain essential oils on carcinogen metabolizing enzymes and acid-soluble sulfhydryls in mouse liver. Comparison of different analytical methods for assessing total antioxidant capacity of human serum. Cinnamon polyphenol extract affects immune responses by regulating anti and proinfammatory and glucose transporter gene expression in mouse macrophages. Antiviral activities of extracts and selected pure constituents of Ocimum basilicum. Zingiberis rhizoma: A comprehensive review on the ginger effect and effcacy profles. A gas chromatography mass spectrometry method for the quantitation of N-nitrosoproline and N-acetyl-S-allylcysteine in human urine: Application to a study of the effects of garlic consumption on nitrosation. Chemomodulatory effcacy of basil leaf (Ocimum basilicum) on drug metabolizing and antioxidant enzymes, and on carcinogen-induced skin and forestomach papil lomagenesis. Dose dependent inhibitory effect of dietary caraway on 1,2-dimethylhydrazine induced colonic aberrant crypt foci and bacterial enzyme activity in rats. Crocetin inhibits pancreatic cancer cell proliferation and tumor pro gression in a xenograft mouse model. Anti-oxidant effects of cinnamon (Cinnamomum verum) bark and greater cardamom (Amomum subulatum) seeds in rats fed high fat diet. Effects of selected plant essential oils on the growth and development of mouse preimplantation embryos in vivo. Carnosol-induced apoptosis and downregulation of Bcl-2 in B-lineage leukemia cells. Role of multi-component functional foods in the complex treatment of patients with advanced breast cancer. Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. Inhibition of skin tumorigenesis by rosemary and its constitu ents carnosol and ursolic acid. Chemopreventive prop erty of dietary ginger in rat urinary bladder chemical carcinogenesis. Potential health benefts of Indian spices in the symptoms of the metabolic syndrome: A review. Chemistry and antioxidant activity of essential oil and oleoresins of black caraway (Carum bulbocastanum) fruits. Suppressive effects of mioga ginger and ginger constituents on reactive oxygen and nitrogen species generation, and the expression of inducible pro-infammatory genes in macrophages. Studies on molecular mechanisms of growth inhibitory effects of thymoquinone against prostate cancer cells: Role of reactive oxygen species. Alterations in antioxidant status of rats following intake of ginger through diet. Anti-histone acetyltransferase activity from allspice extracts inhibits androgen receptor-dependent prostate cancer cell growth. In vitro investigation of the potential immunomodulatory and anti cancer activities of black pepper (Piper nigrum) and cardamom (Elettaria cardamomum). Mechanisms by which garlic and allyl sulfur compounds suppress carcinogen bioactivation: Garlic and carcinogenesis. Dietary ginger constituents, galanals A and B, are potent apoptosis inducers in human T lymphoma Jurkat cells. In vitro anti-bacterial activity of sweet basil fractions against Helicobacter pylori. Anti-angiogenesis effcacy of the garlic ingredient alliin and antioxidants: Role of nitric oxide and p53. The genotoxic potential in vitro and in vivo of the allyl benzene etheric oils estragole, basil oil and trans-anethole. Protective effects of propolis and thymoquinone on development of atherosclerosis in cholesterol-fed rabbits. Inhibition of microsomal lipid peroxidation and monooxygenase activities by eugenol. Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfdes: Studies with sulforaphane and garlic organosulfur compounds. Synergistic role of curcumin with current therapeutics in colorectal cancer: Minireview. Dehydrozingerone and isoeugenol as inhibitors of lipid peroxidation and as free radical scavengers. Allyl sulfdes from garlic suppress the in vitro prolifera tion of human A549 lung tumor cells. Ginger as an antiemetic in nausea and vomiting induced by chemotherapy: A randomized, cross-over, double blind study. Toxicity of selected plant volatiles in microbial and mammalian short-term assays. Screening and analysis of spices with ability to suppress verocytotoxin production by Escherichia coli O157. The in vitro anti-tumor activity of some crude and purifed components of blackseed, Nigella sativa L. Differential effects of garlic oil and its three major organosulfur components on the hepatic detoxifcation system in rats. Diallyl trisulfde-induced apoptosis in human cancer cells is linked to checkpoint kinase 1-mediated mitotic arrest. Inhibitory effect of gingerol on the proliferation and invasion of hepatoma cells in culture.

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Also anxiety symptoms ruining my life order ashwagandha in india, health care professionals will be more informed as to what therapies may cause harm for patients anxiety relief techniques 60caps ashwagandha visa, and thus anxiety 5 htp order generic ashwagandha, they can guide patients to avoid these deleterious practices anxiety reduction techniques trusted 60 caps ashwagandha. Patients have a right to choice in treatment anxiety symptoms before sleep order 60caps ashwagandha amex, but this right assumes that their clinicians can pro vide them with enough information about their therapeutic options (conventional anxiety symptoms stomach pain generic ashwagandha 60caps free shipping, complementary, and alternative) for them to do so. To promote full disclosure, clinicians should cultivate respectful rela tionships in which patients know that their preferences, values, and beliefs will be considered when making treatment decisions. With continued research and careful attention to patient-centered care, issues sur rounding the ethical use of herbal medicines will be dealt with in such a way as to promote benef cence, nonmalfeasance, and patient autonomy. Ethical considerations of complementary and alternative medical therapies in conventional medical settings. Management of stimulant medications in children with attention defcit/hyperactivity disorder. Complementary and alternative medicine use among adults and children: United States, 2007. Potential physician malpractice liability associated with comple mentary and integrative medical therapies. American Academy of Pediatrics: Counseling families who choose complementary and alternative medicine for their child with chronic illness or disability. Prescription, over-the-counter, and herbal medicine use in a rural, obstetric population. Task force on complementary and alternative medicine: Provisional section on complementary, holistic, and integrative medicine. Knowledge and attitudes of lay public, pharmacists, and physicians toward the use of herbal products in north Jordan. Biological diversity, indigenous knowledge, drug discovery and intellectual property rights: Creating reciprocity and maintaining relationships. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Herbal therapy use in a pediatric emergency department population: Expect the unexpected. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Effcacy and tolerability of a fxed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. The use of herbal and other non-vitamin, non mineral supplements among pre and post-menopausal women in Ontario. Long-acting propranolol in migraine prophylaxis: Results of a double-blind, placebo-controlled study. Effcacy of an extract of North American ginseng containing poly-furanosyl-pyranosyl-saccharides for preventing upper respiratory tract infections: A randomized controlled trial. A controlled trial of traditional Chinese medicinal plants in wide spread non-exudative atopic eczema. Over-the-counter medication and herbal or dietary supplement use in college: Dose frequency and relationship to self-reported distress. Severe hepatotoxicity fol lowing ingestion of Herbalife nutritional supplements contaminated with Bacillus subtilis. Effcacy and safety of Echinacea in treating upper respiratory tract infections in children: A randomized controlled trial. Medicinal herb use in a population-based survey of adults: Prevalence and frequency of use, reasons for use, and use among their children. A systematic review and meta-analysis of Hypericum perfora tum in depression: A comprehensive clinical review. Saw palmetto extracts for treatment of benign prostatic hyperplasia: A systematic review. Second, it can be practice integrated with modern medicine by individual health care practitioners. Third, traditional and modern practices can be integrated as two branches of medical science, with the ultimate incorporation of elements of both to form a new branch (World 453 454 Herbal Medicine: Biomolecular and Clinical Aspects Health Organization 2000a). However, documentation of its successful integration in clinical practice is lacking (Giordano, Garcia, and Strickland 2004). However, proof of effcacy or safety for the vast majority of herbal medicine has not been fully established through an evidence-based approach. Further, other issues, such as scientifc, cultural, educational, economical, and legal, need to be addressed. In this chapter, we examine the current status and major scientifc issues or factors that affect the integration of herbal medicine into evidence-based medical therapy. Established in 1999, the Consortium of Academic Health Centers for Integrative Medicine represents 44 academic health centers in the United States and Canada. Unfortunately, the quality of the majority of the clini cal studies of herbal medicines reported to date is of great concern due to a number of factors that have rendered the data of dubious value. In these studies, only slightly over a quarter of the trials adequately reported blinding, and one-ffth reported generation of random allocation sequences (Gagnier et al. For example, only 15% of these studies used blinding, the sample size was mostly less than 300 patients, the controls were inadequate, few studies used quantitative outcome measures, and the studies were short term. There have been many nonclinical in vitro and in vivo studies on herbal medicines that have commonly supported the traditional therapeutic claims. However, systematic reviews of the study protocols or the data interpretation and validation are lacking. Further, the translation of an in vitro and/or in vivo biological/pharmacological effect of a herbal medicine to human therapeutic use may not be successful due to species differences or other mitigating circumstances, including the simple attribute of a biological or clinical outcome by the name of the mother herb, while neglecting the type of plant extract, methods of processing, and pharmaceutical formulation, which invariably contain varying content and proportions of active chemical components (Brinker 2009). Herbal medicine quality can be substantially different due to intrinsic and extrinsic factors. Species differences, organ specifcity, and diurnal and seasonal variations are examples of intrinsic fac tors that can affect the qualitative and quantitative accumulation of the biologically or pharmaco logically active chemical constituents produced and/or accumulated in the herb. Extrinsic factors affecting the quality of the herbal medicine include environmental conditions, cultivation and feld collection practices, postharvest handling, storage, manufacturing, inadvertent contamination, sub stitution, and intentional adulteration (Awang 1997; Huang, Wen, and Hsiao 1997; Slifman et al. In the case of single chemical drugs, the quality and properties are well defned and documented in pharmacopoeias or on fle with regulatory agencies or marketing authorities. On the other hand, herbal medicines, be they single herbs or polyherbal products, suffer from a lack of uniformity in their chemical and physical qualities due to various factors as mentioned above. All these factors have contributed to extensive lists of herbal medicines being reported in the scientifc and lay media to be of inferior and questionable quality and authenticity. Another major extrinsic quality problem concerns substitution and/or adulteration. Herbal medicines collected in the wild as well as some cultivated source materials, where more than a single species is grown in a given farm or site, can lead to nontargeted species being harvested by either accidental substitution or intentional adulteration. Substitution of Periploca sepium Bunge for Eleutherococcus senticosus (eleuthero) had been well documented (Awang 1997), and the U. Unintentional in-process adulteration with heavy metals, microbial and chemical agents (pesti cides, herbicides, and heavy metals), as well as with foreign matter such as insects, animals, animal parts, and animal excreta during any of the stages of source plant material production or procure ment can result in unsafe source materials (Fong 2002). Perhaps the most egregious impediment to the integration of herbal medicine into conventional medicine is the intentional adulteration of herbal medicine products with synthetic pharmaceutical drugs. Multicomponent Chinese or Ayurvedic herbal medicines have long been documented to be adulterated with synthetic anti-infammatory drugs such as phenylbutazone, indomethacin, and/or cor ticoid steroids in arthritis remedies (Farnsworth 1993). Unfortunately, reports proved the product to have been adulterated with estrogen, warfarin, and other pharmaceuticals (Blumenthal 2002; Cordell 2002). For dietary supplements, including herbal medi cines, the requirements apply only to the manufacturers of the fnal product and not to the dietary ingredient suppliers, which have been the source of some of the most high-profle problems of adulterated, substituted, or contaminated ingredients associated with herbal dietary supplements. Consequently, product quality may differ from country to country, within the same country from product brand to product brand, and even from batch to batch within the same brand. In the case of single-molecular pharmaceuticals, there is no uncertainty as to which chemical compound is to be used for pharmacokinetic and bioavail ability studies. Herbal medicines are constrained by their unknown and/or unidentifable active chemical constituents (Fong et al. For example, the mechanism of action of a Chinese herbal medicine formula (consisting of seven herbs formulated based on the results of a series of in vitro experiments and a comprehensive literature review) was postulated from a study of its in vitro effect on rat peritoneal mast cells and macrophage cells (Lenon et al. It was found that the formula signifcantly inhibited the release of several infammatory mediators, including histamine and prostaglandins, which led the researchers to conclude that it has multiple mechanisms and that potential synergistic effects of the individual herbal constituents could all have contributed to the actions of the formula. A recent review based on extensive literature search suggested that, when herbs are often administered in combination with drugs, there were only limited clinical observations on the interactions among humans (Hu et al. A recent review concluded that 34 commonly used drugs that interacted with herbal medicines in humans had been identifed. If the defnition of the herbal medicine extended to botanicals including fungi, algae, and other component matters, nearly 80 herbal medicines would be identifed that had clinically signifcant interactions with drugs. For example, Wu Tou (Aconitum rhizome) cannot be used with Ban Xia (Pinellia ternata rhizome; Weng, Nie, and Huang 2004), and Fu Zi (Radix Aconiti) is incompatible with Bei Mu (Bulbus Fritillariae; Xiao et al. It should be noted that evidence of the adverse reactions and/or toxicity of the combined use of these herbs was mainly derived from clinical observations in ancient times. Researchers have attempted to generate more scientifc evidence through modern pharmacological studies, but conclusive recommendations have not yet been possible (Tang et al. With a plausible biologi cal basis, herbal products can be evaluated through double-blinded, placebo-controlled, multicenter trials. Trials with poor outcome measurements can exaggerate the estimates of treatment effects (Schulz et al. Perhaps one obstacle is the holistic concept and approach being emphasized by the unique philosophy of herbal medicine. As a result, negative attitudes and doubtful perceptions of herbal medicine may now only be held by a minority of the conventional medical profession. Nevertheless, it is of critical concern to clinicians that many herbal medicine users take herbal remedies and conventional therapies concurrently without informing their medical doctors. The above-mentioned population study on 2526 Australian adults also indicated that approxi mately half of herbal medicine users took two forms of therapy on the same day (Zhang et al. However, only about half of these users had voluntarily informed their medical practitioners about their herbal medicine use. This fnding was not striking and, in fact, the situation is similar in the United States, with only one-third of the users having informed their medical providers about their use of herbs or supplements (Kennedy, Wang, and Wu 2008). This study also found that nondisclo sure of herb and supplement use was particularly common among racial and ethnic minority groups (Kennedy, Wang, and Wu 2008). Therefore, understanding the reasons for nondisclosure not only can help doctors to provide better clinical care but also to promote safe integration of herbal medi cine into evidence-based medical therapy. The three most important major areas of research can be defned as (1) herbal medicine quality and standardization, (2) preclinical pharmacological assessments and action mechanisms, and (3) clinical effcacy and safety assessments. Each herb should be subjected to purity as well as contaminant tests for the presence of foreign matters, toxic metals, pesticide residues, mycotoxins, and microorganisms. Thus, it has been recommended that quality-certifed standardization be a prerequisite for future laboratory and clinical investigations (Harkey et al. As in the case of single-molecule pharmaceutical drugs, herbal medications being considered for integra tive therapy must frst undergo preclinical pharmacological assessment for safety and effcacy, if possible. However, the biological response to a drug product may not be species transferable, and an active substance in animals may be entirely inactive in humans. On the other hand, acute and/or chronic toxicity manifestations in animal models are reliable indicators of drug safety. In current practice, acute and chronic toxicities are usually determined by experimental studies using animal models. Suitable methods for testing toxicity need to be established so that herbal ingredients and their derived products can be reliably assessed. For herbal medicines, testing for the presence of heavy metals such as lead, mercury, and arsenic should be mandatory, as these toxic substances are environmental contaminants often found accumulated in many herbs. In addition, where feasible, the mechanisms of action or bioavailability of herbal medicines should be determined. However, as noted by Brinker (2009), single-dose pharmacokinetic or phar macodynamic may not yield true data, especially in the cases of herbal preparations exhibiting weak pharmacological effects. Given the long history of the use of herbal medicine and increasing clinical evidence on its effcacy, extensive investigations of the chemical composition of constituent herbs and of the biological activity of the identifed compounds are clearly warranted. In addition to identifying the active compounds and providing information about their mechanisms of action, it seems inevitable that such studies will lead to new and improved therapeutic agents for the treatment of human diseases. In recent years, reviews of the key chemical compounds present in the individual herbs used in the herbal formulae are most useful (Xue et al. For many traditional herbal medicine products, the inherent complexities in their organoleptic proper ties, such as their taste, odor, or appearance, can be distinguished between the clinical preparations and their respective placebos, and thus are more vulnerable as comparison factors for testing their true therapeutic effects. Details of controlling this possible bias must be fully described so that the study can be replicated by other investigators. On the other hand, systematic review and meta-analysis of the existing clinical evidence should be conducted in line with the intrinsic factors of herbal medicines.

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In spite of this set back anxiety or heart problem discount 60caps ashwagandha, his cell division regulators pyruvic aldehyde and thiourea were not disturbed from their normal periodicity separation anxiety cheap 60caps ashwagandha, no bacterial amines were present to disturb them anxiety symptoms centre order ashwagandha us, there was no Clostridium anxiety symptoms sweating buy ashwagandha online. On his last day anxiety symptoms pdf ashwagandha 60caps for sale, the ultrasound showed that his prostate had shrunk to thirty-seven grams and was still quite normal anxiety symptoms of menopause buy cheap ashwagandha 60caps on-line. His bone scan was not repeated since bone density does not change significantly in five weeks. We had missed getting an ultrasound of his prostate on the day he arrived, and by the time it was done, there were no tumors visible. If we do surgery, if he survives, he will be paralyzed from the waist down and his brain will be a vegetable. Beside this was a completely calcified pineal gland; it had turned into stone or calcium deposits and appears black on the print. His whole body test was Positive for lead, vanadium, aluminum, thulium, formaldehyde, asbestos, isopropyl alcohol, benzene, zearalenone, aflatoxin, and all five malonates. His plastic glasses frames seeped vanadium; he was to soak and wash them, then re-test them. Other items were obvious; he had been living on semi-food (crackers and sandwiches, fat-free munchies), instead of meats and vegetables to avoid getting high cholesterol! It accumulated in his skin fat and brain, there releasing benzene and phenol to lower the local immunity. He was Positive for these mutagens: 1,10-phenanthroline, betapropiolactone, benzanthracene, hy droxyurea, cycloheximide, vanadyl complexes, 20-methylcholanthrene, and phorbol. The tapeworm test showed five out of five types tested were Positive in his brain. Positive for Mycobacterium avium/cellulare, 3 streptomyces species and their products: erythromycin, protease, streptomycin, mitomycin C, and actinomycin D. The urethane must be coming from his plastic shunt since there was not a single defective or repaired tooth in his mouth. Three out of three Clostridium tests were Positive, as well as three out of three Streptococcus tests. If only there was clini cal support available at every minute, day or night, in case the tumorous cyst ruptured and flooded the brain, producing such huge seizures as to stop breathing! The safest approach was to kill everything, detoxify, and clear every thing at top speed, but without bursting the cyst-tumor. He was eat ing for dear life and was surprised to learn that I considered his low choles terol-cracker diet to be non-food, hardly to be offered to roaches. He would live in the environmentally safe motel with only borax water for personal and laundry chores. Black Walnut tincture daily and 2 capsules methylene blue powder daily (65 mg each). It would surely still have its dyes locked inside while the neighboring brain tissues were already cleared. Using a dye together with the cerebrum slide to specify the location where the dye was, we immediately found the tumor. We next prepared his brain and liver to receive aflatoxin by giving him 30 capsules glutathione for 5 days and progressed him through Day 2 and Day 3 of the cancer program (he had been repeating Day 1 all this time). At the cerebrum on his eighth day were all the same toxins and para sites we had originally cleared. For two days in a row he took the complete pro gram together with 30 capsules B2 each day. The cerebrum cleared up, but the cerebellum did not; would he suddenly buckle, never to walk again Cysteine and ozonated oil were added; all items were taken at maximum dose and George made not a single complaint. He began to have diarrhea (from the large dose of glutathione), and strange green pea shaped objects floated in his toilet bowl. On his eleventh day he was switched to 2 freeze dried green black wal nut hull capsules 4 times a day instead of 10 tsp. The 2-week program he had scheduled at our clinic was done, and the next week father and son did their own cooking. He was encouraged to enroll in the Syncrometer class so he could eventually do his own food testing. I estimated it could take six or more months before some reduction in size could be expected. At the next visit the entire toxic team that had once been in his brain was in his liver. He drank 2 cups of parsley tea and 3 cups of the remaining kidney herb tea daily to pro duce 1gallons of urine daily. Yet, there were no rabbit flukes in his gall bladder; they must be emerging from the cyst. This lowered immunity also allowed Streptococcus to grow in his skull, causing pain. Inor ganic germanium was Positive, but good germanium was also Positive so no p53 mutations were spotted. At the next visit things were only worse; the thiourea to pyruvic alde hyde ratios were already quite disturbed. In fact, vanadium was now added to the list of toxins accumulating in his skull inte rior. I believed toxins were seeping out of the cyst to gain a foothold and create a new tumor site in his skull. Their doctor believed he had stepped off a shelf into the abyss (of quackery) when he stated he was headed for Mex ico. Suddenly he tested Positive for rabbit fluke (which brings with it Clostridium and Strepto coccus). The plan was not to try to open the cyst for fear of cataclysm, but to simply keep the supplement pro tection in place to kill and detoxify everything as it slowly emerged. Fiber glass and freon emerged in large amounts; silicone and more asbestos emerged. George used to spray silicone on his glasses without taking them off first, he said, just to clean them. There was rabbit fluke again in hrs cerebrum and ferritin still coated his white blood cells there. He was offered the newest tapeworm treat ment and warned he could become a vegetable, but it would be done in the hospital under critical care observation. Then we checked the optic nerve location; both Taenia solium and Taenia sagi nata stages were present. And in another day all the tapeworm stages were gone, as well as Clos tridium and Streptococcus from the skull location. But the pineal gland white blood cells were still ferritin-coated and the gland was full of asbestos, silicone, and azo dyes. We searched for the toxic team that had so recently left his cerebrum and pineal gland. But the spleen white blood cells were loaded up with them, obviously eating and expelling them. George was now testing himself regularly and could predict what I would find at his office visit. Right after the toxic team arrived at the bladder, they seemed to return to the spleen. We tried 40 capsules vitamin B2 (12 gm) in a single dose plus glucuronate (3 x 250 mg) for 4 days running to capture the dyes. Glad that the 4 doses of 40 capsules B2 had not burst open his tumor cyst and wreaked havoc and disaster. Meanwhile, I had obtained a made-to-order slide of the brain containing the globus pal lidus. Perhaps now we could analyze its contents and monitor it correctly, instead of simply using the cerebrum slide. He could find his own acrylic acid, zearalenone, and benzene, soon deducing they were all coming from the flaxseeds he was eating daily! He noticed that tapeworm stages regularly moved from the tumor cyst to his optic nerve. But his high doses of special supplements soon killed them here, only to be followed by another entry. It was the right time to catch Coxsackie virus on the loose, indeed, both varieties A and B were Positive at the globus and cere brum. In mid-December, there was another burst of activity; his cerebrum was again full of all toxins liberated from the cyst. Christmas was around the corner and thoughts of home and mother stirred impatience. Shockingly, gadolinium was Positive and still very high at cerebrum, liver, and bone marrow, places that had been cleared of other toxins long ago. He still had the gadolinium in him from his first scan with contrast, nearly two years ago. He was also Positive for ytterbium, scandium, yttrium, terbium, thulium, and lanthanum (others not tested). Was the con trast material so impure that all the other lanthanides came along for the ride It would start late and end even later so the total time of its production would be about 27 seconds, instead of the normal 20 seconds, as seen with the Syncrometer. At cerebrum and globus, the lanthanides came associated with both ferrous and ferric iron deposits, as is usual. The cerebral and globus white blood cells were empty, were not eating the intruders. Wherever there were calcium and iron deposits the normal digestive enzyme pancreatin was missing. All normal tissues were supplied with pancreatin which lasted for many hours after a meal. Normal tissues also had phosphatydyl serine, a molecule in the cell membrane that could declare the cell was ready for digestion. A search of the lanthanide research lit erature showed that they have long been known to cause calcium precipita tion inside cells. But why were they present in the lysosomes along with iron Jan 15 no change deposits There was a strange possibility; the lanthanides and iron could be attracting each other due to their magnetic properties. We gave George such a patch, facing the North (by biological convention) side against his skin. He was taken off many other supplements since they were obviously not able to remove iron, lanthanides, and calcium deposits. A week later, there was still some thulium; even two weeks later there was thulium. The cell-flag for digestion, phosphatidylserine, was now Positive, and with it pancreatin. In fact, nucleosides were still present, the digestion flag was not up, and pancreatin was not there either. Coxsackie viruses were coursing about, but were found in the white blood cells, too, protecting him. Days later at the globus, hydroxyurea (from some distant Ascaris eggs) was still Positive. Only gallstones could easily explain this; he must have the eggs in his gallstones, forever seeding his brain and cyst with them. But two days after his cleanse he still had Ascaris eggs in liver, gall bladder, and bile ducts. A spot could still be found in his globus pallidus that harbored acrolein, a fat derivative similar to burnt grease and very carcino genic by scientific stan Feb 19 reduced by half dards. Of all the pancre atic enzymes seen there by Syncrometer, only lipase was still missing, and also missing in our supplement of pancreatin.

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