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The Virucidal, Bactericidal and Fungicidal Effects of Glycyrrhizin, Phyllanthus Species and Monolaurin

By Shari Lieberman, PhD, CNS, FACN

Antibiotic, antiviral and antifungal resistance has become a worldwide problem for numerous organisms. The need for safe, effective virucidals, bactericidals and fungicidals not subject to resistance are desperately needed. As microorganisms become resistant to existing drugs, stronger, more toxic drugs are often required to overcome resistance. However, over the course of time these drugs become resistant as well. This review will focus on the promising research that has been conducted on glycyrrhizin, Phyllanthus and monolaurin demonstrating their broad-spectrum activity against a host of microorganisms.

Glycyrrhizin

Glycyrrhizin has been used in Japan for more than 20 years orally and as the intravenous drug Stronger Neo-Minophagen C (SNMC). Oral glycyrrhizin is metabolized in the intestine to glycyrrhetinic acid (GA) and intravenous (IV) glycyrrhizin is metabolized into glycyrrhetinic acid when excreted through the bile into the intestines. Glycyrrhizin and glycyrrhetinic acid exhibit similar properties and have been shown to be effective for Hepatitis A, B, C; HIV; herpes (I, II, zoster (shingles virus), perhaps 6); lichen planus, influenza, CMV (cytomegalovirus) and cancer. Personal experience and reports of effectiveness show it is effective against chronic fatigue immune deficiency syndrome (CFIDS) and the viruses associated with this condition (EBV (Epstein-Barr) virus, CMV), condyloma (genital wart virus) and other "viral" presentations.1-5

Glycyrrhizin has antiviral activity by inhibiting some RNA transcriptases (e.g. HIV) and an indirect activity by decreasing cell membrane permeability (e.g. hepatocyte injury). It inactivates viruses and inhibits viral proliferation. Glycyrrhizin is a powerful free radical scavenger and it increases gamma interferon, T cells and natural killer cells.

It selectively inhibits an immune system process that leads to inflammatory host cell injury. It may enhance immune adherence responsible for immune phagocytosis (the process by which pathogens "digest" foreign invaders) and regulation of antibody production in protective immunity against invaders. It also inhibits a process in the body known as the arachidonic acid cascade, which is linked to inflammation.4-5

Glycyrrhizin and Hepatitis

Hepatitis C is occurring at epidemic proportions with an estimated 3.9 million infected in the USA, which is 4 times those infected with HIV, and 170 million worldwide with a reported 8,000-10,000 deaths per year. Mortality is expected to triple by 2010. It increases the risk of death from liver disease 17-fold and increases the risk of death from liver cancer by 6-fold.6

Current treatment prognosis with interferon (INF) and antivirals provide less than a 30 percent response rate after 1 year. Of those who exhibit viral clearance, 30-70 percent relapse within the first few months. A sustained response of at least 6 months occurs in 10-15 percent of patients and serious side effects occur such as myalgia, fatigue, fever, headache, nausea, leukopenia, thrombocytopenia, alopecia, irritability, depression, thyroid abnormalities, pulmonary complications and retinal damage. The treatment is often worse than the disease as many patients cannot function or work during treatment. Interferon decreases the risk of progression to hepatocellular carcinoma only in sustained virulogical responders. When ribavirin is used with interferon, reports show a 28-66 percent sustained response in patients although personal communications with infectious disease specialists reveal much poorer response rates. The side effects of combined treatment with ribavirin are significant and serious with an increased risk of hemolytic anemia. Pegylated interferon, in which polyethylene glycol is added to make the interferon last longer in the body, is given with ribavirin and adverse effects and outcome is similar to standard therapy. The treatment is extremely expensive and unaffordable without prescription insurance coverage.1-7

The intravenous drug form of glycyrrhizin, SNMC, is composed of monoammonium glycyrrhizinate (as glycyrrhizin) 4 mg; aminoacetic acid 40 mg; L-cysteine HCL 2 mg; and sodium sulfite 1.6 mg per 2 ml vial. A 20 ml vial provides 40 mg glycyrrhizin, 400 mg glycine and 20 mg L-cysteine. The therapeutic IV dose range is 40-60 ml and as high as 100 ml. The oral therapeutic dose may be as high as 200 mg/day. SNMC has aminoacetic acid and L-cysteine added to prevent pseudoaldosteronism, a condition resulting in sodium retention, potassium depletion and hypertension. However, pseudoaldosteronism is rarely reported at therapeutic doses and can be treated with spironolactone or higher intakes of potassium.4-5

A comparative study was conducted by dividing at random 100 cases into two groups. Group A received 100 ml SNMC per day for 3 weeks and group B received 40 ml/day for 3 weeks. The patient population consisted of: HBV (hepatitis B virus), HCV (hepatitis C virus) and cirrhosis with 49 percent of patients previously treated with interferon therapy showing no improvement of ALT liver enzyme. ALT reductions (rather than viral load) are the best prognostic predictor with respect to later development of liver cancer. Cases were rated "markedly improved" if ALT levels dropped to less than 1.2 times normal upper limit and "improved" if ALT levels dropped to less than 1.2-1.5 upper limit. After intervention the results revealed that in group A, 23 of 44 cases (52.3 percent) improved and in group B, 12 of 26 cases (26.1 percent) improved. Group A (the higher dose group) showed significant improvement compared to B (the lower dose group).1

Another study examined collected data on hepatitis C cases treated with SNMC followed for 15 years. Eighty-four patients received 100 ml/day of SNMC for 8 weeks, and thereafter received a maintenance dose of 2-7 times/week for 2-16 years. They were compared to 109 control patients receiving only oral botanical/nutritional supplements. The ALT fell to normal in 35.7 percent of the SNMC group, and 6.4 percent of the control group. After being followed for 15 years the incidence of cirrhosis was 21 percent in the SNMC group compared to 37 percent in the control group. Liver cancer incidence after 15 years was 12 percent in the SNMC group and 25 percent in the control group.2

Fifty-nine patients with chronic hepatitis C, non-responders to interferon or those unlikely to respond to interferon were included in a study where they either received SNMC 3 times per week or 6 times per week for a total of 4 weeks and the results of the two groups were compared to another group receiving a placebo. SNMC was administered either as an IV drip for 15-20 minutes (80, 160, 240 mg glycyrrhizin) or SNMC was given undiluted injected directly into a vein in 3-5 minutes (200 mg glycyrrhizin). The proportion of patients with ALT normalization at the end of treatment was higher in actively treated patients than in placebo; and higher in those receiving SNMC 6 times per week (47 percent) versus 3 times per week (26 percent). Many of the patients asked for prolongation of SNMC therapy rather than interferon because they felt better during glycyrrhizin therapy. Since persistently high ALT greater than 80 IU/L with chronic hepatitis C is associated with more rapid development of liver cancer than persistently low ALT levels less than 80 IU/L, the authors suggest oral glycyrrhizin or glycyrrhetinic acid should be for maintenance therapy.3-5

A 13-year follow up study with SNMC was conducted with chronic hepatitis C patients. The therapeutic schedule of SNMC was aimed at suppressing ALT levels (below 75 U/L). The patients were administered 40 ml (80 mg glycyrrhizin) of SNMC 5-6 times per week and if ALT was lowered the maintenance therapy was 3 times per week. If this failed to lower ALT levels then SNMC was increased to 100 ml (200 mg glycyrrhizin) 5-6 times per week until patients responded. The maintenance dose was tailored to keep ALT levels low. Liver cirrhosis occurred significantly less frequently in 178 patients on long-term SNMC than in 100 controls (28 percent vs. 48 percent at year 13). Liver cancer developed significantly less frequently in 84 patients on long-term SNMC than in the 109 controls (13 percent vs. 25 percent at year 15). The author notes a relationship between the cumulative ALT score and the increase in the stage of fibrosis, irrespective of the stage of fibrosis found in the first biopsy. To prevent progression of fibrosis the cumulative ALT score needs to be kept increasingly lower as the stage of fibrosis increases. Furthermore, the incidence of liver cancer increases in parallel with the mean ALT score. Oral treatment with glycyrrhizin and IV treatment with SNMC has been shown to significantly improve hepatitis B with marked improvement on indices of liver function and lowering of HbsAg (Hep B surface antigen), the levels of which are often linked to active disease.4-5

Glycyrrhizin and HIV

AIDS patients with high CD4/CD8 ratios (also known as helper cell/suppressor cell ratios) improved significantly with SNMC (5 mg glycyrrhizin /kg). Almost half the patients improved during treatment. In another study SNMC was given to patients with haemophilia A with HIV infection who were asymptomatic. Glycyrrhizin inhibited viral replication and had interferon-inducing, natural-killer-cell enhancing effects. It was extremely effective in preventing progression to AIDS and improved CD4/CD8. In vitro studies have shown that cell-to-cell infection by HIV1, HIV-2, and T-cell lymphotropic virus type 1 is inhibited by glycyrrhizin. Glycyrrhizin inhibits HIV replication in cultures of cells from HIV-infected patients. In 31 percent of samples, glycyrrhizin inhibited more than 90 percent of HIV replication. Virucidal effects include interference with cell binding, and induction of endogenous interferon gamma. Glycyrrhizin also affects protein kinase II and casein kinase II. Kinases regulate many aspects that control cell growth, movement and cell death.

It also affects transcription factors, groups of proteins that read and interpret the genetic "blueprint" in the DNA, such as activator protein 1, which regulates gene expression in response to bacterial and viral infections, and nuclear factor kappa B, which plays a key role in regulating the immune response to infection.4-5

SARS and Corona Virus

No treatment for SARS (severe acute respiratory syndrome) has been established. Glycyrrhizin inhibits SARS-associated corona virus replication and inhibits absorption and penetration during the early steps of the replication cycle. Glycyrrhizin is found to be most effective when given both during and after the absorption period.4-5

Herpes

In vitro studies show glycyrrhizin is effective against varicellea zoster (herpes) inactivating more than 99 percent when incubated with glycyrrhizin for 30 minutes. Glycyrrhizin demonstrates an additive effect when given with acyclovir and beta-interferon. Herpes simplex virus 1 and 2 (HSV-1 and 2), and Epstein Barr virus (EBV) are inactivated in vitro by glycyrrhizin.4-5

Cytomegalovirus (CMV)

Glycyrrhizin is effective against CMV in vitro and in vivo. Liver dysfunction improved in 4 cases and CMV disappeared after glycyrrhizin was given through IV by the age of 12 months. In 6 infants treated with IV glycyrrhizin (10-20 mg/kg/day), liver dysfunction normalized and CMV disappeared significantly sooner than controls. Six infants received oral glycyrrhizin at a dose of 25 mg/day (2-4 mg/kg) for 12 weeks with similar results demonstrating oral efficacy.4-5

Upper Respiratory Tract Infections

Patients with upper respiratory tract infections (URTIs) received either glycyrrhizin or placebo in a double-blind, placebo-controlled randomized study. Forty-one patients received 40 mL GL (SNMC) per day and 269 patients received IV placebo. Glycyrrhizin therapy resulted in shorter hospital stay, lower-grade fever and lower cost of therapy.7

Summary of GL Effects

Human studies showing efficacy of glycyrrhizin include: hepatitis B, hepatitis C, HIV, upper respiratory tract infections, cytomegalovirus and SARS. In vivo animal studies of glycyrrhizin efficacy include: influenza, herpes, encephalitis and Candida albicans. In vitro studies of glycyrrhizin demonstrate efficacy against hepatitis A, herpes I, II, EBV, zoster, Vaccina virus, Newcastle disease, Vesicular stomatitis, Flaviviruses, respiratory syncytial virus, Kaposi sarcoma-associated herpes virus and H. pylori.

Phyllanthus And Hepatitis

Researchers conducted a systematic review of 22 randomized trials for Phyllanthus on chronic hepatitis B (HBV) infections. Combined results showed that Phyllanthus had a positive effect on clearance of HbsAg (Hepatitis B surface antigen). No significant difference of clearing of HBsAg, and HBV DNA was demonstrated between Phyllanthus and interferon. There was also no significant difference between Phyllanthus and interferon in clearing of HBeAg, an antigen of hepatitis B virus sometimes present in the blood during acute infection, usually disappearing afterward but sometimes persisting in chronic disease. Phyllanthus plus interferon showed a better effect of clearance of HBeAg and HBV DNA than interferon alone. Phyllanthus has a significant effect on antiviral activity and was better than interferon for ALT normalization. Phyllanthus amarus and urinaria show positive effects on HBsAg/HBeAg while only urinaria shows a positive effect on HBV DNA.8

Twenty-five compounds from Phyllanthus were studied for in vitro effects on hepatitis B. Niranthin, nirtetralin, hinokinin and geraniin suppressed effectively both HBsAG and HBeAG. Niranthin showed the best anti-HBsAG activity; hinokinin, showed the most potent anti-HBeAG activity.9

Monolaurin

Lauric acid was discovered as the most active antiviral and antibacterial substance in human breast milk. Monolaurin is the glycerol ester of lauric acid and is more biologically active than lauric acid. Monolaurin has been shown to be active against (in vitro): Influenza virus, Pneumovirus, Paramyxovirus (Newcastle), Morbillivirus (Rubella), Coronavirus (Avian Infectious, Bronchitis virus), herpes simplex I & II, CMV, EBV, HIV, measles, leukemia virus, Simliki forest virus, HPV, Visna virus, Vesicular stomatitits virus, respiratory syncytial virus, Dengue virus (type 1-4), and lymphocytic choriomeningitis. It is effective against Gram Positive Bacteria including: Anthrax, Listeria monocytogenes, Staphylococcus aureus, Groups A, B, F, and G streptococci, Streptococcus agalactiae, Mycobacteria Clostridium perfringens and Gram Negative Bacteria including: Chlamydia pneumonia, Neisseria gonorrhoeae, H. pylori, Mycoplasma pneumonia, and Vibrio parahaemolyticus. It has also been shown to be effective against yeast, fungi and molds including Aspergillus niger, Saccharomyces cerevisiae, Ringworm/Tinea, Malassezia species, Penicillium citrinum, and Candida utilis. A number of protozoa like Giardia lamblia are also inactivated or killed by Monolaurin. Monolaurin acts by disrupting the lipid bylayer of the virus and prevents the attachment to susceptible host cells. Recent evidence has also indicated that it prevents replication and removes all measurable infectivity by directly disintegrating the viral envelope making the virus more susceptible to host defense.10

Conclusion

There are no known side effects of Phyllanthus or monolaurin and resistance has not been seen with any of these natural compounds including glycyrrhizin. Blood pressure should be monitored and a high potassium diet implemented with patients on glycyrrhizin. There may be a synergy combining these 3 natural compounds (as in the new formula Nutracidin) enhancing the virucidal, bactericidal and fungicidal effects. The effective doses may also be lower. Many patients presenting with viral symptoms may be co-infected with bacteria and fungi (and vice versa); therefore the broad spectrum effects of these compounds may optimize patient outcomes.

References

1. Iino S, Tango T, Matsushima T et al. Therapeutic effects of stronger neo-minopahgen C at different doses on chronic hepatitis and liver cirrhosis. Hepatol Res. 2001;19:31-40.

2. Kumada H. Long-term treatment of chronic hepatitis C with glycyrrhizin [Stronger Neo-Minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncol 2002;62(suppl):94-100.

3. Okuno T, Arai K, Shindo M. Efficacy of interferon combined glycyrrhizin therapy in patients with chronic hepatitis C resistant to interferon therapy. Nippon Rinsho. 2004;52(7): 1823-7.

4. Fiore C, Eisnhut M, Krausse R et al. Antiviral effect of Glycyrrhiza species. Phytother Res 2008;22:141-148.

5. Numazaki K. Glycyrrhizin therapy for viral infections. African J Biotech. 2003;2(10):392-393.

6. Patrick L. Hepatitis C: Epidemiology and review of complementary/alternative medicine treatments. Alt Med Rev. 1999;4(4):220-221.

7. Yanagawa Y, Masatsune O, Fujimoto E et al. Effects and cost of glycyrrhizin in the treatment of upper respiratory tract infections in members of the Japanese maritime self-defense force: preliminary report of a prospective, randomized, double-blind, controlled, parallel-group, alternate day treatment assignment clinical trial. Curr Ther Res. 2004;65(1):26-3.

8. Liu J, Lin H, McIntosh H. Genus Phyllanthus for chronic hepatitis B virus infection: a systematic review. J Viral Hepat. 2001;8:358-366.

9. Huang RL, Huang YL, Chen CC et al. Screening of 25 compounds isolated from Phyllanthus species for anti-human hepatitis B virus in vitro. Phytother Res. 2003;17(5):449-53.

10. Lieberman S, Enig MG, Preuss HG. A review of monolaurin and lauric acid: natural virucidal and bactericidal agents. Alternative & Complementary Therapies 2006;12(6):310-314.

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