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). Glycyrrhizin (GL) is a conjugate of glycyrrhetinic acid (GA) and glucuronic acid. Oral GL is metabolized in the intestine to GA and intravenous (IV) GL is metabolized into GA when excreted through the bile into the intestines. GL and GA exhibit similar properties and have been shown to be effective for Hepatitis A, B, C; HIV; herpes (I, II, zoster, perhaps 6); lichen planus, influenza, CMV 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, CMV), condyloma and other "viral" presentations.1-5
GL 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. GL is a powerful free radical scavenger and it increases gamma interferon, T cells and natural killer cells.
It selectively inhibits cytolytic reactivity of the complement system by inhibiting the cytolytic reaction leading to inflammatory host cell injury. It may enhance immune adherence responsible for immune phagocytosis and regulation of antibody production in protective immunity against invaders and it inhibits the arachidonic acid cascade.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. INF decreases risk to progression to hepatocellular carcinoma only in sustained virulogical responders. When ribavirin is used with INF, 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 INF is still 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
SNMC is composed of monoammonium glycyrrhizinate (as glycyrrhizin) 4 mg; aminoacetic acid 40 mg; L-cysteine HCL 2 mg; sodium sulfite 1.6 mg per 2 ml ampoule. A 20 ml ampoule provides 40 mg GL, 400 mg glycine and 20 mg L-cysteine. The therapeutic IV dose range is 40-60 ml 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 pseudo-aldosteronism 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: (A) received 100 ml SNMC per day for 3 wks and group B received 40 ml/day for 3 wks. The patient population consisted of: HBV, HCV and cirrhosis with 49 percent of patients previously treated with IFN therapy showing no improvement of ALT. 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: Group A: 23 of 44 cases (52.3 percent) improved and Group B: 12 of 26 cases (26.1 percent) improved. Group A showed significant improvement compared to B.1
Reductions in ALT is best prognostic predictor rather than viral load with respect to later development of liver cancer. A retrospective 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 SNMC group, 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 or those unlikely to respond (genotype 1/cirrhosis) 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 or compared to another group receiving a placebo. SNMC was administered either as an IV drip diluted with 100 ml glucose 5 percent for 15-20 minutes (80, 160, 240 mg GL) or SNMC was given undiluted injected directly into a vein via butterfly in 3-5 minutes (200 mg GL). 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 wk (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 GL 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 GL or GA 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). They were administered 40 ml (80 mg GL) 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 GL) 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 linear 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. The incidence of liver cancer increases in parallel with the mean ALT score. Oral treatment with GL and IV treatment with SNMC has been shown to significantly improve hepatitis B with marked improvement on indices of liver function and negative conversion of HbsAg (Hep B surface antigen).4-5
Glycyrrhizin and HIV
AIDS patients with high CD4/CD8 ratios improved significantly with SNMC (5 mg GL/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. GL inhibited viral replication and had interferon inducing NK 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 GL. GL inhibits HIV replication in cultures of peripheral blood mononuclear cells from HIV infected patients. In 31 percent of samples, GL inhibited more than 90 percent of HIV replication. Virucidal effects include interference with cell binding, and induction of endogenous interferon gamma. GL affects protein kinase II, casein kinase II and transcription factors such as activator protein 1 and nuclear factor kappa B.4-5
SARS and Corona Virus
No treatment for SARS (severe acute respiratory syndrome) has been established. GL inhibits SARS-associated corona virus replication and inhibits absorption and penetration during the early steps of the replication cycle. GL found to be most effective when given both during and after the absorption period.4-5
Herpes
In vitro studies show GL is effective against varicellea zoster inactivating more than 99 percent when incubated with GL for 30 minutes. GL demonstrates an additive effect when given with acyclovir and beta-interferon. HSV-1 & 2, and EBV are inactivated in vitro by GL.
Cytomegalovirus (CMV)
GL is effective against CMV in vitro and in vivo. Liver dysfunction improved in 4 cases and CMV disappeared after GL given IV by the age of 12 month. In 6 infants treated with IV GL (10-20 mg/kg/day), liver dysfunction normalized and CMV disappeared significantly sooner than controls. Six infants received oral GL 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 GL 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. GL therapy resulted in shorter hospital stay, lower-grade fever and lower cost of therapy.7
Summary of GL Effects
Human studies showing efficacy of GL include: hepatitis B, hepatitis C, HIV, URTIs, CMV and SARS. In vivo animal studies of GL efficacy include: influenza, herpes encephalitis and Candida albicans. In vitro studies of GL 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 shown that Phyllanthus had a positive effect on clearance of HbsAg (Hepatitis B surface antigen). No significant difference of clearing of HBsAg, HBeAg and HBV DNA was demonstrated between Phyllanthus and INF. Phyllanthus plus INF showed a better effect of clearance of HBeAg, HBV DNA than INF alone. Phyllanthus has a significant effect on antiviral activity. Phyllanthus was better than INF 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, & 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. It prevents the attachment to susceptible host cells. Research has suggested that monolaurin is virucidal and bactericidal by solubilizing the lipids and phospholipids in the envelope of the pathogen causing the disintegration. Recent evidence has also indicated that the antimicrobial effect is related to its interference with signal transduction in cell replication. It prevents the uncoating of viruses necessary for replication and infection 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 Herbalcidin™) 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
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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.
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4. Fiore C, Eisnhut M, Krausse R et al. Antiviral effect of Glycyrrhiza species. Phytother Res. 2008;22:141-148.
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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.