Introduction on application of herbal medicine

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Introduction on application of herbal medicine Ali Sobhanizadeh1. Hoshang yadegari 1. Bahman Fazeli-nasab2*. Baratali Fakheri3. Sadegh Shahpesandi4 1- M.Sc student of Plant medicinal, University of Zabol 2- Scientific Member, center of Agricultural Biotechnology and Center of Agricultural Research, University of zabol 3- Assosiate professor, Dep of Agricultural biotechnology and Plant feeding, University of Zaol 4 M.Sc student of agronomy, University of Zabol Corresponding Author: [email protected]

Abstract In this review we describe and discuss several approaches to select higher plants as candidates for drug development with the greatest possibility of success. We emphasize the role of information derived from various systems of traditional medicine (ethno medicine) and its utility for drug discovery purposes. But unfortunately, there is limited scientific evidence to establish the safety and efficacy of most herbal, but concerns over safety and a consideration of other medical therapies may temper the decision to use these products. Conclusions Herbal products are not likely to become an important alternative to standard medical therapies unless there are changes to the regulation, standardization, and funding for research of these products. Keywords: Herbal medicine, Depression, Cancer, Diabetes mellitus, efficacy, regulation, side effects Introduction Natural Products, especially plants, have been used for the treatment of various diseases for Thousands of years. Terrestrial plants have been used as medicines in Egypt, China, India and Greece from ancient time and an impressive number of modern drugs have been developed from them. The first written records on the medicinal uses of plants appeared in about 2600 BC from the Sumerians and Acadians (Samuelson, 1999). According to World Health Organization, 80 % of the people living in rural areas depend on medicinal herbs as primary healthcare system (Larkin, 1983). Nearly 1 in 5 adults in the United States report taking an herbal product (Barnes et al., 2002). In fact, for most of history, herbal medicine was the only medicine. Even as recently as 1890, 59% of the listings in the US Pharmacopeia were from herbal products (swerdlow, 2000). Although many herbs are primarily of historical interest,

thousands of herbal products are available over the counter and commonly used by patients in the United States. Therefore, an understanding of the composition, regulation, safety, and efficacy of herbs may assist clinicians in advising patients about the use of these products. An herb can be any form of a plant or plant product, including leaves, stems, flowers, roots, and seeds. These plants can either be sold raw or as extracts, where the plant is macerated with water, alcohol, or other solvents to extract some of the chemicals. The resulting products contain dozens of chemicals, including fatty acids, sterols, alkaloids, flavonoids, glycosides, saponins , and others (Rotblatt and Ziment, 2000). An Australian survey reported that 12% of 3000 subjects used herbal medicines. Several surveys reported that 32 37% of Americans used herbal medicines in a given year (Brevoort, 1998). In Germany, herbal medicine is very much part of medical and social culture, and tens of millions of prescriptions are written for herbal medicines each year (Barrett et al., 1999). An herbal medicine is defined as a plant-derived product used for medicinal and health purposes (Bauer., 2000; Bateman et al., 1998). Humans have been using plant products for medicinal purposes since the Neanderthal period, i.e. 60 000 years ago. Herbal medicines include a wide spectrum of substances ranging from home-made teas prepared from collected herbs to medicinal products that are approved by national regulatory bodies (De-smet, 1995). At least 122 distinct chemical substances derived from plants are important pharmaceutical agents in developed countries. In the pharmacopoeias of developed countries, 25% of drugs are substances first isolated from plants and a further 25% are modifications of chemicals first found in plants. (Table 1)(Barrett et al., 1999).

Table 1. Medicines derived from plants (Barrett et al., 1999). Drug Plant Use Atropine Atropa belladonna Anticholinergic Cocaine Erythoxylon coca Local anaesthetic Colchicine Colchicine autumnale Anti-gout Curare Chondrodendon tomentosum Neuromuscular blocker Digoxin Digitalis purpurea Anti-arrhythmic Ephedrine nervous system stimulant Ephedra sinica Vasoconstrictor; central 

Etoposide (mayapple root) Levodopa Morphine(poppy) Pilocarpine Salicylates (aspirin)(willow bark) Scopolamine(henbane) Taxol

Podophyllum peltatum Mucuna deeringiana Papaver somniferum Pilocarpus jaborandi Salix alba Datura metel Yew tree Mongol

Depression Depression is one of the top five most prevalent diseases worldwide. By 2020 it is expected to be the second-leading cause of disability globally (Smith et al., 2008). Depression typically presents as lowered mood, difficulty in thinking, loss of interest, and physical complaints such as headache, disturbed sleep, loss of energy, and change in sex drive(Tierney et al., 2006; Mann, 2005). It incurs substantial personal, economic, and social costs for both the individuals afflicted and those close to them. (Hansson, 2002). In Australia, 40 percent of women and 30 percent of men are estimated to experience one or more episodes of major depression during their lifetime. The prevalence of major depression is reported as 7.5 percent in Australia, 8 percent in Canada, and 5.4-8.9 percent in the United States (Smith et al., 2008; Andrews and Titov, 2007). While there are many potential precipitating factors, it is currently believed that depression is primarily the result of biochemical alterations in the brain (Tierney et al., 2006; Mann, 2005). Yet, a number of adverse reactions occur with pharmaceutical antidepressant administration, including anticholinergic effects, gastrointestinal effects including nausea and constipation, orthostatic hypotension, arrhythmias, weight gain, and sexual dysfunction (Mann, 2005). In an attempt to avoid such unwanted adverse reactions, as well as being prompted by a desire to use something natural, individuals are seeking alternatives to pharmaceutical medications. Population-based studies in Australia, Europe, and the United States have shown that the use of complementary and alternative medicine (CAM) is widespread (Thomas et al., 2004; Zhou and Lai, 2008). The e need for effective and well-tolerated agents for the treatment of depression has prompted researchers to more rigorously examine herbal medicines that have traditionally been used to treat this condition (Lecrubier et al., 2002). The following herbs have assigned to treat depression.

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(Bensky et al., 2005). Saffron stigma was found to be significantly more effective than placebo in reducing HAM-D scores in individuals suffering from mild-tomoderate depression. The saffron group showed a considerable improvement in symptoms by week 2 of the trial, in comparison to placebo, illustrating the short amount of time taken to influence clinical outcomes (Akhondzadeh et al., 2005). When saffron stigma was compared to pharmaceutical antidepressant agents it was found to be equally effective as fluoxetine (Prozac ) and imipramine in improving depression scores, and significantly better tolerated than imipramine (Akhondzadeh et al., 2004; Noorbala et al., 2005). While not appearing to be traditionally used as an herbal medicine, saffron petals are significantly less expensive than the stigmas, which prompted researchers to examine their potential in the treatment of depression. When compared to placebo, administration of saffron petal resulted in significant reductions in HAM-D scores, with a decrease in depression symptoms reported by week 2 of the trial (Moshiri et al., 2006). Lavender Lavender has had a long tradition of use in the treatment of conditions afflicting the digestive and nervous systems. Its traditional uses are similar to current usage as a carminative, to promote appetite, and to relieve spasm, flatulent colic, and nausea (Moore, 2009). e stomach (Grieve, 1994). Suggests its long use as a treatment against lowered mood and depression. Akhondzadah et al (2004) investigated lavender alone, imipramine alone, and a combination of lavender and imipramine in the treatment of mildto-moderate depression in a three-arm, comparative study. Both the lavender-only and the imipramine-only treatment groups showed significant improvements in depression scores from baseline, although the improvements observed in the imipramine group were significantly greater than in the lavender-only group (Akhonzadeh et al., 2003).

Saffron Saffron has long been revered as both spice and medicine by a number of cultures. Frescos uncovered in Akrotiri, Greece clearly depict the use of saffron stigma as a medicine over 3,600 years ago (Ferrence and Bendersky, 2004). Several historical texts suggest an antidepressant effect. A traditional Chinese medicine (TCM) text from the

Echium

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Cytotoxic agent Anti-parkinsonian Analgesic Parasympathomimetic Analgesic; antipyretic Anti-emetic Cytotoxic agent

Taxus baccata was reported to use in the Indian Ayurvedic medicine for the treatment of cancer. Paclitaxel is significantly active against ovarian cancer, advanced breast cancer, small and nonsmall cell lung cancer. Camptothecin, isolated from the Chinese ornamental tree Camptotheca acuminate (Nyssaceae), was advanced to clinical trials by NCI in the 1970s but was dropped because of severe bladder toxicity. Topotecan and irinotecan are semi-synthetic derivatives of camptothecin and are used for the treatment of ovarian and small cell lung cancers, and colorectal cancers, respectively (Creemer et al., 1996; Bertino, 1997). Epipodophyllotoxin is an isomer of podophyllotoxin which was isolated as the active antitumor agent from the roots of Podophyllum species, Podophyllum peltatum and Podophyllum emodi (Berberidaceae). Etoposide and teniposide are two semi-synthetic derivatives of epipodophyllotoxin and are used in the treatment of lymphomas and bronchial and testicular cancers (Harvey, 1999). Homoharringtonine isolated from the Chinese tree Cephalotaxus harringtonia (Cephalotaxaceae), is another plantderived agent in clinical use (Itokaw and Wang, 2005). Combretastatins were isolated from the bark of the South African tree Combretum caffrum (Combretaceae). Combretastatin is active against colon, lung and leukemia cancers and it is expected that this molecule is the most cytotoxic phytomolecule isolated so far (Ohsurni et al., 1998; Petit, 1987).

Echium is an herb native to Iran, where it is the tea of Echium flowers is a beverage frequently drunk by Iranian locals, where it is believed to possess mood enhancing and anxiolytic effects(Sayyah, 2006). In line with Iranian usage, Culpeper also remarked on this is thought to be most effectual to comfort the heart and expel sadness, or causeless melan 1995). The study by Sayyah et al (2006) aimed to further investigate this aspect of Echium in a randomized, double-blind, clinical trial. Echium was evaluated in comparison to placebo in the treatment of mild-to-moderate depression. Although at week 4 of the six-week trial, there was a significant lowering of depression symptoms in the Echium group compared to placebo, at week 6 no significant difference between the two groups was observed; the difference, however, was close to having statistical significance (Sayyah, 2006). Cancer Million deaths, and 24.6 million per-sons living with cancer around the world in 2002. Cancer, after cardiovascular disease, is the second leading cause of death (Kutluk and Kars, 1998; Turgay et al., 2005). In the United States, where one in four deaths is due to cancer. The National Cancer Institute collected about 35,000 plant samples from 20 countries and has screened around 114,000 extracts for anticancer activity. Of the 92 anticancer drugs commercially available prior to 1983 in the US and among worldwide approved anticancer drugs between 1983 and 1994, 60% are of natural origin. Documentation of the Ayurvedic system recorded in Sushruta and Charaka dates from about 1000 BC (Kappor, 1990). The first agents to advance into clinical use were the isolation of the vinca alkaloids, vinblastine and vincristine from the Madagascar periwinkle, Catharanthus roseus (Apo-cynaceae) introduced a new era of the use of plant material as anticancer agents. They were the first agents to advance into clinical use for the treatment of cancer. Vinblastine and vincristine are primarily used in combination with other cancer chemotherapeutic drugs for the treatment of a variety of cancers, including leukemias, lymphomas, advanced testicular cancer,

Herbs with Anticancer Activity Allium sativum contains more than 100 biologically useful secondary metabolites, which include alliin, alliinase, allicin, Sallyl- cysteine (SAC), diallyldisulphide (DADS), diallyltrisulphide (DATS) and methylallyltrisuphide (Charfenberg et al, 1990). Aloe vera contains aloe-emodin, which activates the macrophages to fight cancer. Aloe vera also contains acemannan, which enhances activity of the immune cells against cancer. Aloe vera is found to inhibit metastases (Pecere et al, 2000). Plant-derived anticancer agents for future development Numerous types of bioactive compounds have been isolated from plant sources. Several of them are currently in clinical trials or preclinical trials or undergoing further investigation. Flavopirido is a synthetic flavone, derived from the plant alkaloid rohitukine, which was isolated from Dysoxylum binectariferum Hook. f. (Meliaceae). It is currently in phase I and phase II clinical trials against a broad range of tumors, including leukemia, lymphomas and solid tumors. Synthetic agent roscovitine (which is derived from natural product olomucine,

discovery of paclitaxel from the bark of the Pacific Yew, Taxus brevifolia Nutt. (Taxaceae), is another evidence of the success in natural product drug discovery.Various parts of Taxus brevifolia and other Taxus species (e.g., Taxus Canadensis, Taxus baccata ) have been used by several Native American Tribes for the treatment of some noncancerous cases (Crag and Newmann, 2005).

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originally isolated from Raphanus sativus L. (Brassicaceae), is in Phase II clinical trials in Europe (Manju et al., 2012). Combre-tastatins were isolated from the bark of the South African tree Combretum caffrum (Eckl. & Zeyh). Kuntze (Combretaceae) (Pettit et al., 1987).

medicine (Wadkar et al., 2008). The plants provide a potential source of hypoglycemic drugs because many plants and plant derived compounds have been used in the treatment of diabetes. Many Indian plants have been investigated for their beneficial use in different types of diabetes and reports occur in numerous scientific journals. Ayurveda and other traditional medicinal system for the treatment of diabetes describe a number of plants used as herbal drugs. Hence, they play an important role as alternative medicine due to less side effects and low cost. The active principles present in medicinal plants have been reported to possess pancreatic beta cells re-generating, insulin releasing and fighting the problem of insulin resistance (Welihinda et al., 1982). Hyperglycemia is involved in the etiology of development of diabetic complications. Hypoglycemic herbs increase insulin secretion, enhance glucose uptake by adipose or muscle tissues and inhibit glucose absorption from intestine and glucose production from liver. (Table 2)(Hongxiang-hui et al., 2009).

Diabetic Diabetes mellitus is a common and very prevalent disease affecting the citizens of both developed and developing countries. It is estimated that 25% of the world population is affected by this disease. Diabetes mellitus is caused by the abnormality of carbohydrate metabolism which is linked to low blood insulin level or insensitivity of target organs to insulin (Maiti et al., 2004). Despite considerable progress in the treatment of diabetes by oral hypoglycemic agents, search for newer drugs continues because the existing synthetic drugs have several limitations. The herbal drugs with anti-diabetic activity are yet to be commercially formulated as modern medicines, even though they have been acclaimed for their therapeutic properties in the traditional systems of Table 2. Medicinal plants with anti-diabetic and their reported effect on experimental models (Kavishanker et al., 2001). Botanical Name Family Antidiabetic and other beneficial effects Achiliea santolina L. Asteraceae Hypoglycemic, antioxidant Areca catechu L. Arecaceae Hypoglycemic Bombax ceiba L. Malvaceae Hypoglycemic Butea manosperma (Lam) Caesalpinaceae Anti-hyperglycemic Croton cajucara Benth Euphorbiaceae Anti-hyperglycemic Cynodon dactylon Pers Poaceae Anti-hyperglycemic Eriobotrya japonica Lindl. Rosaceae Hypoglycemic Eriobotrya japonica Lindl. Gentianaceae Hypoglycemic, anti-hyperlipidemic Globularia alypum L. Globulariaceae Hypoglycemic, increases plasma insulin levels Gymnema sylvestre R. Br. Asclepiadaceae Hypoglycemic. Hypolipidemic Hintonia standleyana Rubiaceae Anti-hyperglycemic Ibervillea sonorae S. Cucurbitaceae Acute and chronic hypoglycemic

without first demonstrating safety and efficacy, as is required for pharmaceutical drugs. Also, the FDA bears the regulatory burden of proving that a dietary supplement is unsafe before it can be removed from the market which is in direct contrast to drugs, where a manufacturer must provide the FDA with evidence of safety and efficacy before a product can be sold (Heneman, 2005).

Regulation The Dietary Supplement Health and Education Act (DSHEA) of 1994 classifies herbs as dietary supplements. This law defines supplements quite Supplements therefore include vitamins, minerals, herbs, amino acids, enzymes, organ tissues, metabolites, extracts, or concentrates. A major difference between a drug and a dietary supplement is that dietary supplements may not claim to

Safety, Toxicity, and Side Effects Because herbs are plants, they are often

It is interesting to note that dietary supplement manufacturers are allowed to make certain

many different side effects to herbs have been reported and recently reviewed (Ernst, 1998; DeSmet, 2002). Including effects from biologically active constituents from herbs, side effects caused by contaminants, and herb drug interactions. Case reports of nephropathy caused by the use of certain

vaguely worded claims of health benefits. For example, an Echinacea product (often used to treat or prevent the common cold) might claim to supplements can be produced, sold, and marketed

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Chinese herbs are common. A particularly morbid case series describes 105 patients in Belgium who had been taking a Chinese herbal product for weight loss and developed nephropathy caused by the herb Aristolochiafangchi. Forty-three patients developed end-stage renal failure, and 39 had prophylactic kidney removal. Eighteen of these patients were found to have urothelial carcinoma, which was shown to be related to the formation of DNA adducts from the aristolochic acid in this herb (Nortier et al., 2000). Another common toxicity to herbal medicines involves pyrrolizidine alkaloids, which are complex molecules found in certain plants that may be used or inadvertently added to herbal medicines (including comfrey, which is still available in the United States). These alkaloids produce hepatotoxicity through a characteristic veno-occlusive disease that may be rapidly progressive and fatal (Stickel et al., 2005). Contaminants in herbal products may be particularly problematic in medicines imported from Asia. A study examining the contents of 260 Asian patent medicines found that 25% of products contained high levels of heavy metals and another 7% contained undeclared drugs, purposefully and illegally added to produce a desired effect (Ko, 1998). A systematic review found that ephedra led to a 2- to 3-fold increased risk of nausea, vomiting, psychiatric symptoms, and palpitations compared with placebo (Shekelle et al., 2003). Because of this and other evidence, ephedra was banned by the FDA on April 12, 2004(DHHS and FDA., 2004). Shortly after the ephedra ban, the 7 largest manufacturers of ephedra-containing products star which contained the herb citrus aurantium. This herb, also known as bitter orange, contains synephrine, which has many of the same pharmacological properties as ephedrine (Hoffman and Taylor., 2001). And therefore the potential to cause many of the same side effects. Use of a combination of an herbal product containing citrus aurantium and caffeine has been shown to cause statistically significant increases in systolic and diastolic blood pressure (approximately 9mmHg) and pulse (16.7 beats per minute) in healthy adults (Haller et al., 2005). Patients taking such products may have an elevated pulse and blood pressure or all of which may be caused by the caffeine and citrus auranitum-containing supplement. Unfortunately, the true frequency of side effects for most herbs is not known because most have not been tested in large clinical trials and because surveillance systems are much less extensive than those in place for pharmaceutical products. A review conducted by the Office of the Inspector General concluded that surveillance systems designed to detect adverse reactions to herbs are inadequate and probably

detect less than 1% of all events. In the study of internet marketing, more than half of herbal products illegally claimed to treat, prevent, diagnose, or cure specific diseases (Morris and Avorn, 2003). Conclusion Medicinal plants have contributed a rich health to human beings. Plant extracts and their bioactive compounds present in them which are responsible for anticancer activity have to be screened for their valuable information. This review had given some of the plants possessing anticancer activity for various types of cancer. Diabetes is a serious metabolic disorder. Differences in social structure, psychic stress, obesity, hormonal imbalance and heredity are optimizing the growth of pandemic. Hence, plants have been suggested as a rich, as yet unexplored source of potentially useful antidiabetic drugs. However, only a few have been subjected to detailed scientific investigation due to a lack of mechanism-based available in vitro assays (Oubre et al., 1997). While studies on saffron (both stigma and petal) were consistently positive, since none of the trials on lavender, Echium, or Rhodiola have been replicated, it is impossible to make definitive statements regarding the efficacy of these three herbal medicines for depression (Ferrence and Bendersky, 2004). Approximately 1 in 5 U.S. adults reports using an herbal product within the past year. Unfortunately, for most of the roughly 20,000 herbal products available in this country, there is little evidence regarding safety or efficacy. However, as one third to one half of all pharmaceutical drugs were originally derived from plants, there is clearly a potential to find effective therapies from the natural environment. The current regulation of herbs does not ensure that available products are safe, and false and illegal marketing claims are common. Several simple changes to the regulation of these products could dramatically improve the appropriate use of herbs. Future research will be best served by the creation of national standards for the constituents of specific herbs, greater incentives for research, and the development of study designs that reduce costs and study duration (Bent, 2008). References [1]Akhondzadeh S, Fallah-Pour H, Afkham K. 2004. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial. BCM Comp Altern Med 4: 12-19. [2]Akhondzadeh S, Kashani L, Fotouhi A. 2003. Comparison of Lavandula angustifolia Mill.

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