The FDA has just notified small pharmacies that they will no longer be allowed to manufacture or distribute injectable vitamin C – despite its remarkable power to heal conditions that conventional medicine can’t touch. Please help reverse this outrageous decision!
Let’s get this straight. The government acknowledges the risk of a worldwide flu pandemic. It acknowledges that conventional drugs cannot cure big viruses-like the mononucleosis and hepatitis viruses, many influenza viruses, and many others. It acknowledges that many bacteria have become resistant to antibiotics and are killing increasing thousands. It acknowledges the risk of a worldwide drug-resistant TB pandemic.
Despite acknowledging all this, it now insists on wiping out one of the best potential treatments for these conditions and for certain cancers as well. And why is this being done? What possible rationale is offered? Because it’s dangerous? No. Because it can’t be patented and therefore won’t be taken through the standard FDA approval process. No matter that vitamin C is one of the least toxic components of our food supply and liquid forms of it have been used safely for decades.
By the way, here is what is not safe. Don’t substitute home-made vitamin C solution for pharmaceutical grade liquid. That is not safe for injection. If the FDA action leads someone to do that, the FDA should be held responsible for the results.
The government, instead of banning intravenous vitamin C, should instead be supporting research into it. Even though IV C is being used in burn units around the world, including in the US, and has been adopted by the military for this purpose, the National Institutes of Health (NIH) refuses to fund any studies using intravenous C in patients. There are privately funded studies currently underway, but of course these cannot continue if the FDA bans the substance.
With at least one of the pharmacies, the FDA seems to be banning injectable magnesium chloride and injectable vitamin B-complex 100 as well. These two substances are routinely added to intravenous C to make the “Myers Cocktail,” used especially for conditions such as chronic fatigue syndrome, and infectious diseases such as hepatitis, AIDS, mononucleosis, and flu. The FDA is not going after the Myers Cocktail directly, but is rather attacking each individual substance used to make the cocktail, and may conceivably be going after injectable vitamins and minerals in general, despite such injections being given under the care of a qualified physician.
Each of us reading this should think, “Intravenous C could someday save my life.” Dr. Jonathan Collin, editor of the Townsend Letter, discusses the case of a man in New Zealand who nearly died from swine flu. After developing a severe fever and upper respiratory infection, his condition deteriorated and he became comatose. Eventually even a ventilator was insufficient to keep him breathing because his lungs were so compromised by pulmonary edema. After weeks of heroic intervention, doctors decided there was no chance of survival and nothing further should be done for him.
The family asked the hospital to administer intravenous vitamin C. After much disagreement, the hospital gave him 25 grams of vitamin C every 6 hours. There was so much improvement over the next two days that the hospital decided to reinstate his intensive care – but they discontinued the vitamin C, saying that he had improved only because they had rolled him onto his side or his stomach instead of keeping him on his back! Not surprisingly, his condition once again deteriorated.
The family moved him to another facility that reluctantly allowed the IV vitamin C (albeit at a lower dose), and his lung function gradually improved. He came out of coma after four weeks, and after taking vitamin C orally, he gradually improved enough to be discharged. One year later, he was back to flying his plane and surveying his farm in New Zealand. None of the doctors who fought so hard to prevent his treatment with vitamin C have ever acknowledged their error.
Even people in perfectly good health may not be getting enough vitamin C. We recently noted the research that up to 87% of Americans are vitamin D deficient. But studies also show that many people may be deficient in vitamin C as well. A recent study on 1,000 Canadian adults found 33% had suboptimal levels of vitamin C – one in seven was “very deficient” – which could place them at increased risk for chronic health problems. Those who were vitamin C deficient were also more likely to have larger waists, greater body mass, and higher blood pressure.
The study’s author, Dr. Ahmed El-Sohemy, suggested eating fruits and vegetables high in vitamin C, such as citrus fruits and peppers, or taking supplements. The recommended dietary allowance (RDA) in adults is 90 mg per day for men and 75 mg for women, though some experts say a minimum daily dose of 120 to 200 mg is more appropriate, and some routinely take much higher doses themselves. Research also shows that people suffering from various diseases may benefit from larger amounts. In the case of the common cold, a review of published trials found that amounts of 2 grams per day appear to be more effective than 1 gram.
But there is a big difference between oral vitamin C and intravenous C. One maintains your health. The other seems to directly attack pathogens and cancer cells. Vitamin C taken orally will not do this, because the concentration does not seem sufficient to accomplish the task.
Please take action immediately! Please contact the FDA here, and tell them to take their job of protecting our health seriously – by allowing injectable vitamin C, magnesium chloride, and vitamin B-complex 100 to continue being manufactured and sold! And don’t accept the answer that these substances need to be taken through the full FDA approval process. These are not patentable substances and no one will pay billions to do that. To require a standard approval process for them is identical to banning them, as the FDA know full well.
Alliance for Natural Health, Tue, 04 Jan 2011 22:49 CST
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1 in 6 Americans infected with herpes
Highest rates found among blacks, women
WASHINGTON, March 9 (Reuters) – About 16 percent of Americans between the ages of 14 and 49 are infected with genital herpes, making it one of the most common sexually transmitted diseases, U.S. health officials said on Tuesday.
Black women had the highest rate of infection at 48 percent and women were nearly twice likely as men to be infected, according to an analysis by the U.S. Centers for Disease Control and Prevention.
About 21 percent of women were infected with genital herpes, compared to only 11.5 percent of men, while 39 percent of blacks were infected compared to about 12 percent for whites, the CDC said.
There is no cure for genital herpes, or herpes simplex virus type 2 (HSV-2), which can cause recurrent and painful genital sores and also increases the likelihood of acquiring and transmitting the AIDS virus. It is related to herpes simplex virus 1, or oral herpes, which causes cold sores.
Several drugs are available to treat herpes symptoms and outbreaks, including acyclovir, which is available generically or under the Zovirax brand name, and valacyclovir, known generically as Valtrex — both made by GlaxoSmithKline PLC (GSK.L). Ganciclovir, sold as Zirgan, is made by privately-held Sirion Therapeutics, Inc.
The CDC estimates that more than 80 percent of people with genital herpes do not know they are infected.
“The message is herpes is quite common. The symptoms can be often very innocuous,” Dr. John Douglas of the CDC said in a teleconference.
“Because herpes is so prevalent it becomes … a really important reason to use condoms on a consistent and correct basis with all of your partners,” Douglas said.
Douglas said the increased rate of infection in blacks is not do to increased risk behavior but likely due to biological factors that make women more susceptible as well as the higher rate of infection within black communities.
The CDC estimates that there are 19 million new sexually transmitted disease infections every year in the United States, costing the health care system about $16 billion annually.
Source: Reuters By JoAnne Allen
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Comment: A little over 25 years ago a paper was published in the journal Science showing that BHT (Butylated hydroxytoluene), a common food preservative, could inactivate herpes simplex and other lipid-coated viruses in lab dishes. Two years later another paper in the same journal reported similar results, but this time in live animalsâ€”dietary BHT could prevent chickens from dying of Newcastle disease. Like herpes simplex, NDV (the virus that causes Newcastle disease) is lipid-enveloped, i.e., its nucleic acid core is sheathed in a fatty membrane. Viruses of this type require an intact membrane to be infective. BHT seems to work against such viruses by disrupting (“fluidizing”) their viral membranes. BHT is so effective against lipid-enveloped viruses, why donâ€™t doctors prescribe it for their patients? The answer is that almost none of the controlled studies on the antiviral properties of BHT have been performed on humans; most of the experiments thus far have been conducted in lab dishes (in vitro) or in animals. A human clinical trial of BHT cannot be performed because the Food and Drug Administration (FDA) has approved BHT for use only as a food preservative, not as a medicine. But that hasnâ€™t stopped some people from using BHT on their own to treat herpes or other viral conditions.
Since it is not considered a natural product, the U.S. Food and Drug Administration has prohibited its sale as a supplement (although approving its use in food as a preservative).Â BHT is therefore sold as a food preservativeâ€¦ To use this product in a government-approved manner, “add BHT to cooking oils or salad dressings to retain their freshness.”
ScienceDaily (Feb. 2, 2010)
The development of antibiotics gave physicians seemingly miraculous weapons against infectious disease. Effective cures for terrible afflictions like pneumonia, syphilis and tuberculosis were suddenly at hand. Moreover, many of the drugs that made them possible were versatile enough to knock out a wide range of deadly bacterial threats.
Unfortunately, antibiotics have a fundamental limitation: They’re useless against viruses, which cause most infectious diseases. Antiviral drugs have proven far more difficult to create, and almost all are specifically directed at a few particular pathogens — namely HIV, herpes viruses and influenza viruses. The two “broad-spectrum” antivirals in use, ribavirin and interferon-alpha, both cause debilitating side effects.
Now, researchers from the University of Texas Medical Branch at Galveston, UCLA, Harvard University, the U.S. Army Medical Research Institute of Infectious Diseases and Cornell University have teamed up to develop and test a broad-spectrum antiviral compound capable of stopping a wide range of highly dangerous viruses, including Ebola, HIV, hepatitis C virus, West Nile virus, Rift Valley fever virus and yellow fever virus, among others.
UCLA researchers led by Dr. Benhur Lee — corresponding author on a paper on the work appearing in the Proceedings of the National Academy of Science — identified the compound (which they call LJ001), after screening a “library” of about 30,000 molecules to find a one that blocked the host cell entry of deadly Nipah virus. Subsequent experiments revealed that LJ001 blocked other viruses that, like Nipah, were surrounded by fatty capsules known as lipid envelopes. It had no effect on nonenveloped viruses.
“Once we started testing more and more, we realized that it was only targeting enveloped viruses,” said Alexander Freiberg, director of UTMB’s Robert E. Shope, M.D. Laboratory, the Biosafety Level 4 lab where much of the cell-culture work was done, as well as mouse studies with Ebola and Rift Valley fever viruses. “We followed up and determined that it was somehow changing the lipid envelope to prevent the fusion of the virus particle with the host cell.”
Additional experiments indicated that while LJ001 also interacted with cell membranes, whose composition is nearly identical with that of virus envelopes, it caused them no ill effects. The reason, according to the researchers: Cells can rapidly repair their membranes, but viruses can’t fix their envelopes.
“At antiviral concentrations, any damage it does to the cell’s membrane can be repaired, while damage done to static viral envelopes, which have no inherent regenerative capacity, is permanent and irreversible,” said Lee.
UTMB authors of the PNAS paper include graduate student Sara Woodson and adjunct associate professor Michael Holbrook, former director of the Shope BSL4 lab and principal investigator on the UTMB portion of the project. UCLA contributors are Mike Wolf, Tinghu Zhang, Zeynep Akyol-Ataman, Andrew Grock, Patrick Hong, Natalya Watson, Angela Fang, Hector Aguilar, Robert Damaoiseaux, John Miller, Steven Chantasirivisal, Vanessa Fontanes, Oscar Negrete, Paul Krogstad, Asim Dasgupta, Kym Faull and Michael Jung. Other authors are Jianrong Li and Sean Whelan of Harvard; Matteo Porotto and Anne Moscona of Cornell; and Anna Honko and Lisa Hensley of USAMRIID.
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Comment: The article below originally appeared in the April 1995 issue of ForeFront–Health Investigations. I’m posting this because of the previous post titled “New Target Discovered for Treatment of Cancer” dated January 11th, 2010 which deals with the same mechanism that caused birth defects in the 1960′s and was known by some to be the best treatment for Kaposi’s sarcoma as well as macular degeneration, prostate cancer and Crohn’s disease to name a few. The orphan drug is of course Thalidomide.
Thalidomide was developed in Germany in the 1950s by Chemie Grunenthal for use as a sedative. One of its attractive features was that it was not lethal when people took large overdoses. For several years, thalidomide was widely marketed in Europe. In 1961, thalidomide was found to cause serious birth defects (when used during early pregnancy) and was withdrawn from the European market. It never gained approval in the U.S. because of the snail’s pace at which the FDA works. Since then, the American public has been peddled the idea that thalidomide is a demon drug that was kept off the US market by FDA vigilance.
The truth, then and now, is that thalidomide is an invaluable drug that is safe when used properly. In 1965, it was found to be an effective inhibitor of ENL, a complication of leprosy. In Brazil, where leprosy is a significant problem, thalidomide has been readily available. During the 70s and 80s, a variety of autoimmune diseases began to be successfully treated with thalidomide: rheumatoid arthritis, lupus, and many others. In 1989, non-microbial aphthous ulcerations of the mouth and throat that sometimes occur in people with AIDS were reported to be successfully treated with thalidomide. Now, six years later, thalidomide is receiving attention as a therapy for other aspects of HIV disease and cancer because of its ability to suppress tumor necrosis factor and angiogenesis (the growth of new blood vessels). This therapeutic approach will be tested clinically in the early part of 1995.
Tumor Necrosis Factor
Tumor necrosis factor (TNF) is a cytokine, a class of chemical messenger that facilitates communication between cells. Cytokines can also serve as vital growth factors. A number of cytokines, including TNF and IL-6 (interlukin-6), are over-produced during HIV infection. Not only do HIV-infected cells (T-cells and macrophages) produce particularly high amounts of TNF, but TNF (and other cytokines) increase viral replication in HIV-infected cells. By inhibiting TNF production, thalidomide produces an antiviral effect. Both TNF and IL-6 are believed to be involved in angiogenesis and Kaposi’s sarcoma (KS), which is the most common tumor occurring in HIV-infected individuals.
Angiogenesis and KS
Angiogenesis is the process by which small blood vessels (capillaries) are formed in new tissue. This process may be essential to expanding tumors that need new blood vessel growth to obtain needed nourishment. Angiogenesis also appears to become uncontrolled in KS lesions (the extensive new vascularization giving them their characteristic purplish or dark coloration). The ability of thalidomide to inhibit angiogenesis provides a scientific rationale for its use in KS and cancer.
Growth Factors for Kaposi’s Sarcoma
Capillaries are composed of a microscopic tubule made from a continuous layer of endothelial cells surrounded by a layer of connective tissue for support. In arteries, the contractile outer layer is formed by vascular smooth muscle cells. These smooth muscle cells contribute to regulating blood pressure in the capillaries. Capillaries also contain a ring-like sphincter of smooth muscle at their opening which regulates blood flow into the capillaries.
Capillary beds are optimized for blood/tissue exchange of nutrients, gases (such as oxygen) and migrating immune cells. The smaller diameter of capillaries and the slower blood flow through them means that nearly all of the blood comes into contact with the walls of the tubule. Capillary endothelial cells thus have greater access to circulating cytokines than the endothelial cells of the larger arteries and veins. During inflammation, elevated levels of IL-6, like TNF, induce vascular relaxation, leakiness of plasma fluids, and increased migration of immune cells into the extravascular spaces.
KS cells are not HIV-infected. They go through several developmental stages, each dependent on a possibly different group of secreted cytokines. In early stages, KS cells transplanted into tissue culture need additional cytokines and growth factors to proliferate. Cells derived from more advanced KS lesions produce their own growth factors and proliferate independently, thus taking on a cancer-like growth quality.
The administration of TNF alone to HIV-infected persons with KS causes a consistent and significant worsening of their KS lesions. TNF causes AIDS-KS cells to proliferate. (AIDS-KS cells are from a specific cell-line standardized for research purposes which were originally derived from an AIDS patient with KS.)
Since 1991, several studies have shown that thalidomide therapy reduces blood levels of TNF in people with leprosy or HIV. Cell-culture experiments have shed light on the mechanism for this effect: thalidomide accelerates the breakdown of messenger RNA molecules that contain information needed by cells to produce TNF.
TNF is angiogenic, in part, by promoting the expression of enzymes secreted from endothelial cells and macrophages which degrade the underlying extracellular matrix that surrounds blood vessels. Such enzymes are required for new vessels to elongate, branch and invade the surrounding tissues.
When degraded, the extracellular matrix releases growth factors such as basic fibroblast growth factor (FGF). FGF is released by wounding and promotes healing by inducing the proliferation of blood vessel cells and nearby fibroblasts (cells specialized to produce connective (structural) tissue).
FGF is one of the prominent cytokines expressed by AIDS-KS cells. When it is injected into mice, FGF causes KS-like lesions by excessive capillary proliferation. Genetic engineering techniques which block FGF expression inhibit both KS cell growth in culture and lesion formation in mice. The ability of FGF to induce these lesions is augmented (in a synergistic fashion) by the HIV protein tat, which is secreted by HIV-infected cells.
Tat stimulates the proliferation of both normal endothelial cells and KS- lesion-derived cells. When combined with a small amount of TNF, tat causes normal endothelial cells to take on KS-like qualities.
Tat increases TNF production and works synergistically with low amounts of TNF to induce IL-6 secretion byendothelial cells. IL-6 is an important growth factor for KS cells and is secreted by AIDS-KS cell cultures.
Thalidomide and KS
Given the central role of TNF and other cytokines in angiogenesis and KS, it is especially fortuitous that thalidomide not only decreases TNF production (in people), but also inhibits FGF-induced angiogenesis (in rabbits).
Oxidative Stress and KS
Increased oxidative stress (from free radicals) and reduced antioxidant defenses are characteristic of both HIV infection and Kaposi’s sarcoma (KS). One of the body’s key antioxidant molecules is glutathione, a scavenger of highly reactive molecules (free radicals) which would otherwise alter or damage important cellular constituents. Low glutathione levels occur in AIDS and ARC, and this deficiency causes a buildup of free radicals, an increase in TNF activity, and inhibition of T-cell proliferation.
In normal endothelial cells, low glutathione levels are associated with diminished proliferation. However, in endothelial-like cells derived from advanced KS lesions, decreased levels of glutathione are associated with increased KS-cell proliferation. Thus, free radicals (such as superoxide and related molecules) may function as growth factors for AIDS-KS cells.
The development of KS depends on natural repair processes evolved for coping with injury. As an example, when blood vessels are damaged in a tissue injury (thereby reducing oxygen levels), the damaged tissue responds by forming new blood vessels to bring in more oxygen. After heart attacks (occlusion of coronary arteries), collateral vessels are formed to help bring blood to oxygen-starved tissues. In cell culture experiments, even a partial oxygen deficiency (hypoxia) promotes the replication of endothelial cells and tubule formation by stimulating the production of free radicals and cytokines, including TNF. Severe blood loss in mammals, which diminishes oxygen supply, also results in a rise in TNF levels.
During inflammation and infection, TNF induces the generation of superoxide, an oxidizing free radical used by certain immune cells to destroy engulfed microorganisms. Massive systemic bacterial infections result in extremely high levels of TNF that can influence capillary tone and cause low blood pressure, septic shock, and even death. Chronic infection (as in AIDS or ARC) leads to long-term exposure of blood vessels to a variety free radicals and cytokines produced by activated immune cells.
Significantly, TNF and FGF induce superoxide production in endothelial cells (and fibroblasts). Contributing to the buildup of superoxide is the HIV protein tat, which has been reported to decrease synthesis of the antioxidant enzyme superoxide dismutase (SOD). Low glutathione levels (and corresponding high free radical levels) are immunosuppressive because they decrease T-cell response to T-cell growth factor (IL-2). Low glutathione levels also promote inflammation by enhancing T-cell response to TNF. Similarly, low glutathione levels in KS cells augment cytokine-induced angiogenesis. In cell culture, the production of macrophage-derived angiogenic factors is decreased by anti-oxidant nutrients, which scavenge free radicals. This may define a preventive role for antioxidants in KS.
Thalidomide and Birth Defects
The cytokines and growth factors expressed during hypoxia-induced angiogenesis are complex and involve additional cell types. For example, hypoxia induces the production of vascular endothelial growth factor (VEGF) by vascular smooth muscle cells. Although normal endothelial cells do not produce it, AIDS-KS cells secrete VEGF and thereby stimulate their own growth and proliferation.
In another example of cytokine synergy, small doses of VEGF and FGF (which separately do not promote endothelial cell growth) together induce marked angiogenesis. The production of VEGF and FGF by vascular smooth muscle cells is also regulated indirectly by other cytokines that are associated with HIV infection, AIDS, KS and hypoxia.
The value of thalidomide in the treatment of KS may be closely related to the birth defects caused by prenatal exposure. As limbs grow out of embryonic limb buds, increased oxygen demands must be met by increased angiogenesis. By inhibiting both the production of and response to certain cytokines, thalidomide prevents the formation of blood vessels required to bring blood and oxygen to the growing limbs. Deprived of blood and oxygen, the limbs cease growing and fail to differentiate into fingers and toes. There is no genetic damage (mutation) involved in this effect.
Cancer and Angiogenesis
In a similar manner, hypoxic conditions in the center of expanding tumors induce the production of new capillary sprouts and tubules. Abnormal cytokine levels are required for this process as well. Without angiogenesis, tumor foci would not grow beyond 2-3 mm in diameter. In support of this principle, Judah Folkman et al. have proposed that thalidomide might be valuable as an anti-angiogenic adjunct to standard anti-cancer drug protocols. Damage-induced angiogenic diseases of the eye, such as diabetic retinopathy and age-related macular degeneration, are also candidates for treatment with thalidomide.
Is There a KS Cofactor?
The presence of KS in 25% or more of homosexuals with AIDS but in only 1% of hemophiliacs with AIDS implies the presence of a KS-inducing cofactor in homosexuals with KS that is absent in HIV-infected hemophiliacs. Such a factor could be sexually transmitted. Several previously unidentified genes isolated from KS lesions have recently been identified as DNA sequences from herpes virus. These genes have not been found in blood vessels or other tissues from persons not infected with HIV.
In addition to other viruses previously suggested to be involved in the development of KS, researchers have also proposed that certain AIDS-associated bacterial products may function as KS-inducing agents. If a non-HIV infectious agent were found to contribute towards KS in persons with AIDS, such a factor would favor the use of a multiple-drug protocol for KS.
Thalidomide and Cancer
National Cancer Institute-directed clinical trials of thalidomide are intended for KS, and cancers of the breast, brain, prostate and skin (melanoma). Many cytokines that are highly expressed in KS are also excessively produced by cancer cells. Not only do these cytokines promote angiogenesis, but they sometimes act as growth factors for the tumor itself. Under these circumstances, cytokines overstimulate cellular machinery which is normally activated only periodically, and then only just preceding cell division. Cells that usually cease dividing when they come into contact with another cell then grow uncontrollably.
Among other cytokines, FGF is produced by melanomas and by breast and brain cancer cells (that also secrete VEGF). Increased FGF levels in an individual’s blood and urine are correlated with poor survival in a variety of cancers. FGF functions as a growth factor for melanoma cells by increasing their replication rate; when FGF’s production is blocked, cell culture growth is suppressed. Within solid tumors, FGF also acts on non-cancer cells (such as fibroblasts) to stimulate the production of connective (fibrous) tissue needed for their structural support.
In various cancers cells, as in KS cells, excessive levels of certain free radicals may activate pathways that encourage high rates of replication and that increase the ability of certain cytokines to effect cell growth. Free radicals directly damage (mutate) DNA and may produce a series of lasting alterations in the cellular machinery involved in growth and division.
Higher-than-normal rates of replication of precancerous cells might decrease the ability of these cells to repair their DNA damage prior to the initiation of replication. An accumulation of DNA damage might cause tumors to progress to more advanced stages with increased aggressiveness.
A variety of cytokines promote metastasis (the spreading of cancer cells throughout the body) by inducing the production of extracellular matrix-degrading enzymes and by increasing the permeability of blood vessels. For the same reasons, these cytokines encourage tumor invasion into the surrounding tissues.
TNF, which is often elevated during human cancers, increases the ability of melanoma cells to colonize to distant sites in a recipient animal. By producing both TNF and its receptor, melanoma cells (but not their normal progenitors) might stimulate their own growth.
The proportion of cells expressing TNF in breast cancer increases with the aggressiveness of the tumor. TNF production was localized in tumor-associated macrophages immediately adjacent to breast cancer (tumor) cells but not in the tumor cells themselves. The lack of TNF receptors in breast cancer tissue implies the involvement of endothelial activation and tissue-degrading enzymes in invasiveness and metastasis.
By inhibiting both the response to FGF and the production of TNF, thalidomide, might suppress the replication and metastasis of melanoma and perhaps other cancers. Furthermore, thalidomide might undercut the physical requirements of expanding tumors by not only preventing new blood vessel formation but possibly by inhibiting the activity of connective tissue cells like fibroblasts.
We should not let the adverse effects of thalidomide on the human fetus blind us to its potentially valuable role in the treatment of diseases in adults. The FDA’s politicization of the thalidomide incident as popular justification for their institution has resulted in a long-standing reluctance to see thalidomide investigated for autoimmune diseases and HIV-associated aphthous ulcers. This prejudice has resulted in shortages of thalidomide and delays of cancer trials.
Beyond birth defects, the next most serious side effect of thalidomide is peripheral neuropathy (pain or numbness in the hands, lower legs, and especially in the feet). Neuropathy typically occurs only after long-term use, but it can also make preexisting neuropathy worse. Permanent nerve damage can be prevented if detected early, and nerve electrical abnormalities may precede clinical symptoms. In some individuals, neuropathy begins after several months of moderate to high use. If peripheral neuropathy does occur, the condition will return to normal more quickly if its use is discontinued as soon as symptoms develop.
Thalidomide’s most immediate side effect is drowsiness (for which it was originally developed). Except for the side effects from fetal exposure, thalidomide is less dangerous than a number of drugs presently in common use for a variety of conditions.
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by A.Y. Oubre
Hypericin, a photochemical extracted from St. Johns Wort (Hypericum perforatum) and related species, has been shown to have potent, broad spectrum antimicrobial activity. This compound is an aromatic polycyclic anthrone, a class of colored or pigmented chemical substances which have photosensitizing activity. In both in vitro (laboratory) and in vivo (animal) studies, low, non-toxic doses of hypericin significantly inhibited the replication of several viruses, including HIV, influenza A, cytomegalovirus (CMV), Herpes simplex 1 and 2 (HSV-1 and HSV-2), and Epstein-Barr virus (EBV). Hypericin and its chemical relative, pseudohypericin, produce antiviral activity through a different mechanism of action than do AZT and other nucleoside antiviral agents. Hypericin does not appear to directly alter the activity of reverse transcriptase although it does block the formation of HIV synctium. Recent findings have shown that the antiretroviral action of this compound disrupts uncoating of the lipid envelope of both DNA and RNA viruses, thus preventing infected cells from releasing HIV copies. Theoretically, hypericin and AZT, in combination, may have synergistic antiviral effects against HIV. On the other hand, hypericin actually may increase the toxicity of antiretroviral nucleosides such as AZT, ddI, or ddC.
Traditionally, extracts of St. Johns Wort (which contain hypericin) have been used as an antidepressant, possibly by acting as a MAO inhibitor. The psychotropic effects attributed to hypericin in St. Johns Wort extract suggest that the pigment compound can cross the blood brain barrier (possibly treating neuropsychological symptoms such as dementia). Laboratory investigations indicate that hypericin may be beneficial as an HIV therapy. However, its administration should be carefully monitored by a physician. The levels of hypericin found in most commercially available extracts of St. Johns Wort generally are not sufficient to be therapeutically effective against viral infections.
Liver function should be tested periodically in persons taking hypericin. Also, extreme photosensitivity has been observed in a few cases of people taking this high doses (in excess of 10 mg per day) of this compound. Finally, there is a very small possibility that adverse reactions could occur on occasion between hypericin and other foods or drugs which interfere with MAO inhibitors.
Active principles in St. Johns Wort
The quantity and quality of active principles in Hypericin species vary according to geographical locale, climate, time of day, and time of year. St. Johns Wort contains dianthrone derivatives, mainly in the form of hypericin and pseudo-hypericin as well as flavonoids. Small amounts of coumarins, phenolic carboxylic compounds, phloroglucinol derivatives, monoterpenes, sesquiterpenes, n-alkanes, n-alkanols, carotenoids, and beta-sitosterol are present. The roots contain zanthones. Practitioners and consumers should note that St. Johns Wort extracts, whether standardized or not, consist of other active ingredients in addition to hypericin and pseudohypericin.
Both in-vitro (test tube) and in-vivo (animal) pre-clinical studies suggest that hypericin (and, to a lesser extent, pseudo-hypericin) may have therapeutic benefits for HIV infection and other retroviral diseases. Certain compounds other than hypericin extracted from Hypericum species have antibiotic activity. marked antiretroviral effects, however, have been reported primarily for hypericin which is isolated mainly from Hypericum perforatum. However, synthetic hypericin has been used in recent studies.
In in-vitro and in-vivo studies, both hypericin and pseudohypericin (extracted from Hypericum triquetifolium) had antiviral activity against several retroviruses. In one experiment, mice were simultaneously injected with low doses of the compounds and with Friend leukemia virus (FV). This aggressive retrovirus normally causes rapid splenomegaly (swelling of the spleen) and acute erythroleukemia in mice. However, these symptoms were effectively suppressed by the addition of hypericin. Splenomegaly had not occurred ten days after infection at the close of the study. No infectious virus could be recovered from the spleen. Also, viremia normally associated with FV was absent. Mice treated with hypericin and pseudohypericin survived a much longer time than mice treated with a toxic antiviral (N3dthd). Unlike most antiretroviral drugs, hypericin (given in a single dose of low concentration) was effective without being cytotoxic. Even when it was administered after viral infection had already started, it still inhibited the onset of disease.
In in-vitro studies, mouse cell lines were infected with radiation leukemia virus (Rad LV) and then incubated with hypericin. The activity of reverse transcriptase in these cells was suppressed through indirect mechanisms. In contrast to nucleoside analogues, polycyclic diones such as hypericin interfere directly with the viral replication cycle during stages in which virions are assembled or intact virions are shedded from immature cores. Alternatively, these aromatic compounds may directly inactivate mature retrovirus that contains normal, assembled cores. Other findings indicate that hypericin is able to inactivate virions and block viral release from infected cells by interacting with the cell membrane.
Unpublished data show that hypericin disrupts the formation of synctia in HIV disease as well as in de novo infection of cells. In in-vitro studies, hypericin showed selective activity against HIV and modest inhibition of reverse transcriptase. In vitro research also revealed that hypericin lowered viral activity in whole human blood taken from HIV infected persons. “Wild” strains of HIV taken directly from infected patients are sometimes more resistant to antiviral agents than are viral strains bred in the laboratory.
Other investigations indicate that the antiviral effects of hypericin on murine cytomegalovirus (MCMV), Sindbus virus (SV), and HIV are enhanced by exposure to fluorescent light. Hypericin and to some degree, pseudohypericin, were effective against FV and HSV-1 when the viruses were first incubated with the compounds for one hour at 37 degrees C before mice were infected. Pre-incubation for one hour at 4 degrees C, however, produced no antiviral effects. The authors of this study (who are scientists at Lilly Research Laboratories) reported that hypericin and pseudohypericin were effective in vitro against enveloped viruses such as HSV and influenza when the cultures were pre-incubated with these agents at 37 degrees C. They also correctly showed that hypericin and its analogue inhibit DNA and RNA viruses, but not viruses which lack a lipid envelope. The Lilly researchers, who call AZT a preferred therapy for HIV, however, claim that single dose administration of hypericin is not efficacious. Human clinical trials are needed to evaluate the appropriate dose ranges at which hypericin is therapeutic but nontoxic, and to assess the differences, if any, between natural and synthetic hypericins. In animal studies, natural sources of hypericin (in combination with its analogue, pseudohypericin), showed greater antiviral activity that did synthetic hypericin. Preliminary findings thus far strongly indicate that the wide spectrum antiviral properties of hypericin, its experimental effectiveness at low concentrations, and its unconventional mechanisms of antiviral action make it a promising candidate for a new class of HIV therapies.
Mechanisms of action
Hypericin and pseudohypericin had no effect on purified reverse transcriptase alone. They did not alter levels of intracellular viral mRNA. Instead, hypericin lowers the number of mature viral particles without suppressing intracellular levels of viral mRNA. The concentrations of viral antigens on the cell surface were also unaffected by hypericin. These findings, as a whole, imply that the compounds interfere with viral assembly, budding, shedding or stability at the level of the cell membrane When hypericin was added to viral-infected cell cultures, red fluorescence appeared at localized areas on the lipid surface membrane.
Unlike nucleoside analogues, polycyclic diones such as hypericin have no effects on transcription, translation, or transport of viral proteins to the cell membrane. They are not directly active against reverse transcriptase even though reverse transcriptase activity was reduced in infected cells that had first been incubated with hypericin. Cells treated with hypericin form immature or abnormally assembled cores. This indicates that hypericin may block the processing of gag-encoded precursor polypeptides. Hypericin, whether in the intracellular medium or bounded to the membrane, is thought to lower the activity of reverse transcriptase by interfering with protein synthesis. (It is noteworthy that the antiviral effects of harmine, a photoactive alkaloid, involve disrupted kinase activity in enveloped RNA viruses.)
Viral particles are not formed when gag-related polyproteins fail to be cleaved or synthesized. Gag-related polyproteins, therefore, may play a decisive role in the virucidal actions of hypericin. Reverse transcriptase within the core of the assembled virus probably takes the form of an inactive enzyme or proenzyme. Mechanisms involving viral-encoded proteases or kinases might be required to activate reverse transcriptase. These mechanisms could transform the enzyme from a nonfunctional to a functional state. Both hypericin and pseudohypericin are thought to influence protease activity. In turn, altered protease activity could disrupt the cleavage or synthesis of gag-related polyproteins. As a result, immature viral cores would be formed. Alternatively, by selectively binding to viral polyproteins, hypericin could interfere with the gag and gag-pol polyproteins needed for viral assembly. Thus, hypericin could block the process whereby RNA packages encapsulated viral particles.
Some investigators, however, propose that hypericin lyses infectious virion by interacting directly with the viral envelope instead of disrupting gag-encoded precursor polyproteins or modifying other proteins. In any case, the antiviral properties of hypericin appear to involve its interactions with the cell membrane or cell surface recognition sites. Molecular modifications at or near the surface provide a model for rationally designing a new class of anti-HIV agents. Such therapies may be able to block HIV-encoded protease located in the gag-pol region. Importantly, drugs of this type would not be toxic like AZT and other agents whose pharmacological actions are based on direct inhibition of reverse transcriptase.
The aromatic, ringed structure encircled by six phenolic hydroxy groups seems critical to the antiviral activity of the hypericin molecule. Quinone groups, which often have antiviral properties, also exert photodynamic effects. Hypericin is thought to generate singlet oxygen. However, free radical quenchers can interfere with singlet oxygen reactions involving hypericin thereby reducing its antiviral properties.
Hypericin has a unique molecular structure in which one-half of the molecule is hydrophilic (water loving) while the other half is hydrophobic (water repelling). The top, bottom and side (non-polar) of the hypericin molecule which contains the methyl groups are hydrophobic. It is thought that the molecule might bond to the outer surface of the cell membrane. Presumably, the hydrophobic side would be immersed in fat Singlet oxygen, though less reactive than triplet oxygen, binds with two-electron targets, including, for example, the double bonds found in polyunsaturated fatty acids. The hydrophilic sides, in contrast, could hydrogen-bond to the aqueous media.
Discrepancies between in vivo findings from different studies on the antiretroviral effects of hypericin and pseudo-hypericin may be due partly to variations in light. However, differences in hypericin isolation methods and in the strains of mice used also could account for variable findings in several investigations. The antiviral effects of hypericin are largely but not completely, attributed to its photodynamic properties. In the presence of light, hypericin completely inhibited infection of cell cultures of equine infectious anemia virus (EIAV). On exposure to fluorescent light, hypericin inactivated MCMV, Sindbis virus (SV), and HIV-1. Both membrane virions and virus-infected cells were more strongly inactivated by visible light. (Polyacetylene phenylheptatriyine (PHY), a substance purified from the plant, Bidens pilosa, also shows antiviral activity against membrane-bound viruses such as MCMV. The antiviral effects, which involved interactions between PHY and membrane, occurred in the presence of long wave ultraviolet light). Significant advances in photobiological research have been made in recent years. New findings demonstrate clearly that photodynamic action accounts for the antiviral properties of several natural product derivatives, including hypericin.
Light is required for the photosensitization of hypericin. The compound absorbs light quanta and generates it in the form of singlet oxygen. In so doing, hypericin triggers the photo-oxidation of cellular components, including, for example, the photohemolysis of red blood cells. The underlying mechanism of photodynamic reactions is not fully understood. It is thought to involve interactions between oxygen and light as well as sensitizing pigment which binds to the cell membrane.
In photodynamic reactions mediated by hypericin, singlet oxygen serves as the main oxidant. Singlet oxygen has a strong affinity for pi electron-systems found in compounds such as polycyclic diones. The pi electrons, responsible for the photoactive properties of hypericin, absorb visible and ultraviolet light and then reemit it within the range of green and red light. The two hydroxy groups and the two methyl groups flanking each side of hypericin’s eight ringed structure do not lie within the same plane. Instead, they repel each other, placing strain on the benzenoid structure. This causes the hypericin molecule to twist and become unstable. Hypothetically, the steric strain could increase the energy state of the pi electrons. This would allow them to form temporary bonds with singlet oxygen which, at a later point, could be released to disrupt mechanisms of viral replication. Pi electrons therefore, seem to play a major role in the antiviral activity of hypericin.
The “impressive light-mediated antiviral activities” of hypericin have been shown in several studies. Sindbus virus (SV), for example, was 99% inhibited in the presence of light. In the dark, however, the antiviral effects of hypericin were reduced by more than two orders of magnitude. On exposure to light (650-700nm.), hypericin undergoes type II photosensitization in which singlet oxygen and other reactive molecular species are produced. Though not as destructive as free radicals (which are generated in Type I photosensitization, singlet oxygen could damage viral membranes, thereby interfering with proteins and nucleic acids. Nonetheless, hypericin also has some degree of virucidal activity in the dark, though much less so than in light. It is thought that the antiviral effects produced in the absence of light take place through a different mode of action than light-mediated virucidal activity. Protein kinase C, for example, may represent an alternative target for hypericin’s antiviral action in the absence of light.
One of the therapeutic advantages of hypericin is that it works by multiple steps. Hypericin is probably able to interrupt various phases in the replication of enveloped retroviruses. These stages include polyprotein cleavage and protein alterations as well as assembly, budding and shedding of viral components. The compound’s disadvantages as an anti-HIV agent involve its potential toxicity when patients are exposed to sunlight. Also, it has been reported that in humans, hypericin is more effective in suppressing HSV-1 and HSV-2 than HIV. Future research is required to elucidate the mechanisms through which hypericin generates and reacts with singlet oxygen in triggering antiviral effects.
Clinical trials were conducted the early 1990′s by Dr. Bihari in New York City recommending the following regimen. For the first two weeks, patients take 10 mg once a day for two weeks. During the second two weeks, the dosage alternates between 10 mg per day on the first day, 20 mg on the second day, 10 mg on the third day, and so forth. The ultimate dosage is given during the fifth and sixth weeks when patients are given 20 mg per day.
It has been proposed that beta-carotene, a known free radical quencher, be administered in combination with hypericin. Theoretically, this might reduce any toxic side-effects associated with hypericin’s generation of free radicals. Some investigators, however, have warned that quenchers also may lessen the anti-viral properties of hypericin. The role of beta-carotene and other free-radical scavengers in hypericin therapy deserves further clarification.
Hypericin, a pigment molecule with photodynamic activity, has dramatic antiviral activity, especially in the presence of light. Like several other plant derived substances, hypericin only inhibits viruses with membranes. It has antiviral effects against a wide range of retroviruses, including HSV-1, HSV-2, (murine) CMV, and HIV-1. In contrast to nucleoside agents such as AZT, hypericin and its chemical relative, pseudohypericin, do not directly affect the activity of reverse transcriptase. Rather, these agents seem to disrupt various stages of viral replication, including assembly, budding, shedding and possibly protein synthesis, all of which depend on the integrity of the viral membrane.
Hypericin and related compounds, with their alternative targets for virucidal activity, comprise a new class of potential anti-HIV drugs. It is not yet known how effective hypericin will be in human AIDS. Preliminary findings, however, strongly suggest that this compound is one of the most promising, new anti-HIV prototype molecules currently under investigation.