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A New Herbal Drug for Early Stage Alzheimer’s
Indian Club Moss – (Lycopodium selago var. appressum) Photo: © Jim Stasz @ USDA-NRCS PLANTS Database Whilst the battle rages for the use and distribution of Alzheimer’s disease (AD) drugs, including donepezil, risatigmine and galantamine, between public demand with the two drug companies ‘Eisai Limited’ and ‘Pfizer’ against NICE (National Institute for Health and Clinical Excellence), it is perhaps a good time to look backwards to go forwards for alternatives. Back in the 1990s, Chinese Club Moss [Huperzia serrata (Thunb.) Trev. syn. Lycopodium serratum (Thunb.)], the Chinese herbal medicine ‘Qian ceng ta’, was investigated by French researchers (1999)1 who isolated the alkaloid ‘Huperzine A’. They said it is a molecule, which is potent and a selective inhibitor of acetylcholinesterase, and that this was a potential medicine for AD. Acetylcholinesterase2 is an enzyme that degrades the neurotransmitter acetylcholine in the brain, and acetylcholine3 is a neurotransmitter that appears to be involved in learning and memory, which is severely diminished in the brains of persons with AD. This herbal derivative of Chinese Club Moss (huperzine-a) was indeed an important discovery. Furthermore, the French researchers stated that several pharmacological and clinical studies showed that huperzine-a improves the mnesic capacity i.e. memory capacity, and cognitive functions. It was also found to be a neuroprotective agent. They said: “This molecule which possesses a high pharmacological potential is under clinical evaluation for the palliative treatment of Alzheimer’s disease. In addition, its use in the pre-treatment of poisoning by organophosphorous nerve agents could be another indication. Although a quantity of research has been done on huperzine-a, there is no research back-up for it’s traditional uses, which have a wide range, and it seems not to have gone a great deal further regarding getting into the mainstream of AD drugs treatment. One may well ask why? Chinese Club Moss – Traditional Uses: Taking a conglomeration of sources, it appears that Chinese Club Moss (Huperzia serrata syn. Lycopodium serratum Thunb.) has been used for centuries in China to treat colds, fever, inflammation, pain and menstrual cycles.5 It has been used for muscle strains, and rheumatological conditions such as arthritis.6 The plants are also known to contain chemicals that may promote loss of water from the body and help to reduce swelling due to water retention.7 A decoction of the plant is antispasmodic. The spores of the plant are dusted on wounds or inhaled to stop bleeding noses. They can also be used to absorb fluids from injured tissues, and used as a dusting powder to prevent pills sticking together.8 Huperzine A for Early Stage Alzheimer’s In August 2000, a lack of natural resources meant that this herbal medicine was not available in the West. But scientists at the Mayo Clinic in the US, Virginia Tech and the Hong Kong University of Science and Technology were working on plans to develop a synthetic form of the compound which could be made available to patients in the West. At that stage the compound’s effects had only been studied in animals.9 Lead researcher, Paul Carlier, associate professor of chemistry at Virginia Tech, presenting his findings to a meeting of the American Chemical Society in Washington, said: “No work has been done in humans and even if the compounds prove effective in humans, it will be as a treatment of the memory loss in the early stages of the disease. This approach could never cure Alzheimer’s and after the disease progresses to a certain point, these drugs could not restore mental function.” But isn’t that precisely what the ‘battle’ for AD drugs for the early stage of the disease is about and something is required now!10 There are precautionary considerations about using the herb, from its somatic effects to side-effects, such as an increased risk of having seizures for individuals who have or who have had epilepsy and potential danger in its ability to effect changes in heart rhythm; plus there’s no indication for its effect upon the developing foetus, an infant or small child. The herb’s use is therefore not recommended during pregnancy, while breast-feeding, or during early childhood.11 Other less severe side-effects include blurry vision, diarrhoea, dizziness, drooling, nausea, slowed heartbeat, stomach cramps and sweating.12 These effects sound perilous, but compared with the official analysis for side-effects, interactions and contraindications of many other drugs in use ‘out there’ it’s use may not prove to be impractical or beyond the pale. According to ‘EDrugs Digest’ some prescription drugs inhibit acetylcholine. Some ‘anticholinergic’ drugs are used to prevent bed-wetting, relieve stomach cramps, and treat nausea. Huperzine-A, if taken together with anticholinergic drugs, the effects of both it and the drug may be lessened to unpredictable extents, which drugs include: atropine, dicyclomine (Bentyl), Levsin, propantheline, glycoyrrolate (Robinul), Transderm Scop and any others additional to these prescription drugs. However, it is also stipulated that both the effects and risk of side-effects may be increased if Huperzine-A is taken at the same time as a prescription drug that also reduces acetylcholinesterase activity. In addition to Aricept and Cognex et al, ‘choliergic’ drugs include Mestinon (pyridostigmine) and Neostmine, which may be used to treat myasthenia gravis;13 and bethanechol (Urecholine), which may be used for the treatment or urine retention. Taking a jump in time, in March 2005 the first preclusion regarding the source for Huperzine-A emerged. Chinese researchers got their expertise together and analyzed different species of Huperziaceae plants. The highest content of HupA (Huperzine-A) was found in Phelgmarius carinatus. Members of the genus Phlegmariurus possessed higher levels of the compound than the Huperzia species.14 There were also variations in HupA content according to habitat, e.g. H. serrata plants growing in humid forests contained significantly more HupA than plants growing in less humid environments. The Huperzine-A content also varied by season, with the highest levels being found in mid-autumn and the lowest levels in early spring, which suggested that HupA is turned over in the plant.15 By this time clinical trials in China had demonstrated the HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer’s disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs i.e. Acetylcholinesterase Inhibitors in use!16 This was fantastic news! Although more study needs to be done on the possible effects of compounds huperzine A, huperzine B, huperine, and other chemicals derived from Chinese Club Moss, synthetic forms of huperzine A have been made in chemical laboratories and they appear to be as effective as natural huperzine-A in studies. Huperzine A had also been combined or “hybridized” with the prescription drug tacrine (Cognex), an AChEI approved by the US Food and Drug Administration (FDA) for treating Alzheimer’s disease.17 In January of this year, Hong Kong researchers found that the effects of a memory enhancing NLPR tetra-peptide (MEP), which was highly efficient in the rescue of cognitive abilities of brain-lesioned mice and in particular, the effective doses of MEP were about two orders of magnitude lower than that of ‘Cognex’, which is currently being used as a therapeutic treatment for AD.18 Moreover, MEP and HupA were effective at reduced doses when the two were co-administered, providing a rationale for their combined usage in the treatment of cognitive deficits.19 There is another problem attached to the use of the plants’ compounds, namely ‘supply and demand’. In spring this year, Chinese researchers undertook a survey of the two plant families that supply huperzine compounds for treatments for AD. Because of the content of Lycopodium alkaloids like huperzine-A, which are used to treat a number of human ailments, the Huperziaceae have been experiencing a rapid decline in China, mostly due to over-harvesting. The main objectives of the study were to catalogue the plants’ resources including the occurrence, general distribution, and abundance of the various Huperziaceae species in China; and to determine traditional use and pharmaceutical values of each species.20 Ethnobotancial studies of these plants revealed that 33 of these species are used by the local communities for medicinal purposes. The most popular species being H. serrata, which has the greatest decline. The good news is. that there will be a mandatory change in collection practice and general attitude towards these plants. The introduction of conservation plans and training of the local communities regarding appropriate collection practices, because their marketing in China is required to reverse the trend of decline among this and similar species. In addition, development of cultivation or other propagation practices, such as ‘in vitro’ propagation, would have the added benefits of socio-economic uplift of the local communities and sustainability of this important source of Huperzine-A.21 This is massively important to not only China, but for the 20 million people affected with AD worldwide, for as Iranian researchers stated in the same period, clinical drug trials in patients with AD have focused on drugs that augment levels of acetylcholine in the brain to compensate for the loss of cholinergic function.22 The most highly developed and successful approaches to date have employed AChEIs (Acetylcholinesterase Inhibitors).23 Although some FDA approved drugs are available for the treatment of AD, the outcomes are often unsatisfactory, and there is a place for alternative medicine, in particular, herbal medicine.24 Huperzine-A keeps being announced in glowing terms, but where is it? An American doctor recently wrote, for many years this compound has been used in China to treat patients with memory decline and AD. Huperzine A appears to be the natural equivalent of prescription AD drugs Aricept, Exelon and Razadyne. It is similar in that it boosts the presence of acetylcholine in the brain. Amazingly, it may be more effective and better tolerated, and since it is a natural compound may also be thousands-fold cheaper.25 Astonishingly, Huperzine A may also have additional unique effects that could slow down the progression of AD (at least according to Dr. Paul Aisen, the neurologist who is leading the new study at Georgetown University Medical Centre).26 Dr. Kaplan goes on to say, although it is at present being studied in the US in a phase II trail, it’s currently available in your local Natural Food Market (in the United States).27 It was reported from North Carolina, USA, last month that a national clinical trial is taking place at the University of North Carolina Hospitals using Lycopodium serratum, which is already being sold in stores with nutritional supplements. The study is sponsored by the ‘National Institute on Ageing’ and is one of the growing number of federally funded research studies focused on natural and alternative therapies.28 The centres of the ‘National Institute of Health’ expect to spend $300.5 million in complementary and alternative medicine research in the 2007 budget year.29 Apparently, even with that recent financial commitment, research in this area is limited, making it difficult for doctors to get information that is essential to understanding the risks and benefits of certain treatments. Patients in the trial receive either a placebo or dose of Huperzine-A larger than what is currently available in stores (US). After the placebo-controlled phase, all patients take doses of Huperzine A for 8 weeks and have the option to continue taking it if they believe it is helping.30 The consolation is that mostly what’s ‘over there’, comes over here. However, if the pharmaceutical industry can’t or won’t produce an adequate synthetic Huperzine-A drug, it would be some way towards helping AD sufferers to prevent deterioration in the early stages of the disease if this alternative cheaper herbal option was to be made available, especially for those patients who are currently not having a very NICE time! References: 1. [Huperzine a: an actylcholinesterase inbibitor with high pharmacological potential] Pilotaz F, Masson P. Centre de Recherhes du Service de Sante des Armees Emile Parde, Dept. de Toxicologie, La Tronche. [Article in French] Ann harm Fr. 1999 Sep; 57(5):363-73. 2. Acetylcholinesterase: An enzyme that degrades the neurotransmitter acetylcholine in the brain and other tissues of the body. 3. Acetylcholine: a chemical substance that sends signals between nerve cells (called neurotransmission) and is therefore called a neurotransmitter. Neurotransmitters are secreted by neurons (nerve cells) into space between neurons called the synapse. Acetylcholine is a primary neurotransmitter in the brain, and is associated with memory and cognition. It is a neurotransmitter which plays an important role in memory. It is used for control of sensory input signals and muscular control. ACh is a stimulatory transmitter. When released by muscle nerves, it makes those muscles contract. It is made form the precursor nutrient ‘choline’ and there is some evidence that increased dietary choline can increase production and use of acetylcholine. Also, many drugs affect the production and release of this neurotransmitter. 4. Choline: A natural substance required by the body that is obtained form various foods, such as eggs: also available in food supplements. Choline is an essential component of acetylcholine. It protects against damage to cells by oxidation and is found in all living cells. Choline is a vitamin B-factor and plays a role in nerve function. It also helps to maintain normal kidney and bladder function. 5. ’Herb can improve memory’ BBC News Online 23rd August, 2000 – http://news.bbc.co.uk/1/hi/health/891368.stm & http://memory.uscf.edu/Education/Treatment/alternative_treatments.html 6. Huperzine A –What is it? - http://www.luhs.orf/health/kbase/htm/mdx-/ame0/2887/mdx-ame0287.htm 7. Huperzine A (Chinese Club Moss, Hp A; Huperizia serrata, Lycopodium serrata, Qian Ceng Ta, Shuangyping) – “EDrug Digest” - http://www.drugdigest.org/DD/PrintablePages/herbMonograph/0,11475,552633,00.html 8. Lycopodium serratum – Thumb. – http://www.pfaf.org/database/plants.php?Lycopodium+serratum 9. ’Herb can improve memory’ BBC News Online 23rd August, 2000 – http://news.bbc.co.uk/1/hi/health/891368.stm 10. Ibid. 11. Huperzine A (Chinese Club Moss, Hp A; Huperizia serrata, Lycopodium serrata, Qian Ceng Ta, Shuangyping) – “EDrug Digest” - http://www.drugdigest.org/DD/PrintablePages/herbMonograph/0,11475,552633,00.html 12. Ibid. 13. Myasthenia gravis: A chronic autoimmune disease/disorder, and disease of the neuromuscular junction, characterized by chronic fatigue and muscular weakness (especially in the face and neck), caused by a deficiency of acetylcholine at the neuromuscular junctions. 14. ‘Is there a better source of huperzine A than Huperzia serrata? Huperzine A content of Huperziaceae species in China.’ Ma X, Tan C, Zhu D, Gang DR. State Key Laboratory of Drug Research, Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China. J Agric Food Chem. 2005 Mar 9; 53(5):1393-8. 15. Ibid. 16. ‘Neuroprotective effects of huperzineA. A natural cholinesterase inhibitor for the treatment of Alzheimer’s disease.’ Wang R, Tang XC. State Key Laboratory of Drug Research, Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China. 17. Huperzine A (Chinese Club Moss, Hp A; Huperizia serrata, Lycopodium serrata, Qian Ceng Ta, Shuangyping) – “EDrug Digest” - http://www.drugdigest.org/DD/PrintablePages/herbMonograph/0,11475,552633,00.html 18. ‘Effects of a memory enhancing peptide on cognitive abilities of brain-lesioned mice: additivity with huperzineA and relative potency to tacrine.’ Xu Z, Zheng H, et al. Dept. of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, China. J Pept Sci. 2006 Jan;’ 12(1):72-8. 19. Ibid. 20. ’A survey of potential huperzine A natural resources in China: the Huperziaceae.’ Ma X, Tan C, et al. State Key Laboratory of Drug Research, Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China. J Ethnopharmacol. 2006 Mar 8; 104(1-2):54-67 Epub 2005 Oct. 21. Ibid. 22. ‘Herbal medicine in the treatment of Alzheimer’s disease.’ Akhondzadeh S, Abbasi SH. Psychiatric Research Centre, Roozbeh Hospital, Tehran Uv. of Medical Sciences, Tehran, Iran. Am J Alzheimers Dis Other Demen. 2006 Mar-Apr; 21(2):113-8. 23. Ibid. 24. Ibid. 25. ‘Chinese Club Moss can Improve Memory’ by Dr. R. L. Kaplan, 2nd October 2006. – http://www.smart-kit.com/169/ 26. Ibid. 27. Ibid. 28. ‘Plant the focus of Alzheimer’s study’ Associated Press, 20th October 2006. 29. Ibid. 30. Ibid.
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