The Acquired Immune Deficiency Syndrome (AIDS) is an epidemic, now verging on Pandemic proportions in the world. In the US, AIDS has occurred predominantly among homosexual and bisexual men, heterosexual young women, intravenous drug users, and recipients of blood or blood products; however, AIDS is not limited to these populations.

Since its first recognition in 1981, the number of AIDS cases reported to the Centers for Disease Control (CDC) has exceeded 1, 000,000 cases in the United States, with more than 750,000 patient deaths thus far. Since the discovery of the human immuno-deficiency virus in 1984 (10), the case definition of AIDS for national reporting in the United States has been revised(2) to include new opportunistic diseases. Pneumocystis carinii pneumonia (PCP) and Kaposi's sarcoma (KS) account for a large percent of these cases (61% and 26.5%, respectively), with other infections presenting in much smaller numbers: Esophageal Candidiasis (10.2%), Cryptococcosis (6.2%), Atypical Mycobacteriosis (3.9%), Toxoplasmosis (3.1%), Cytomegalovirus (4.9%), Herpes simplex (3.7%), and Cryptosporidiosis (3.3%).

Three other diseases - Strongyloidosis, Papovavirus and Primary Lymphoma account for less than 2% of the cases reported. Most of these patients are young (39% are between 20 and 49 years old) and can be categorized into five groups: homosexuals and bisexuals (73%), IV drug abusers (17%), hemophiliacs (1%), sexual contacts (4%), and transfusion recipients (2%)(43). The revised CDC definition includes persistent generalized lymphadenopathy, the acute retroviral syndrome, asymptomatic seropositivity, and neurologic consequences as part of the spectrum of HIV-related disease.

The incidence of persistent generalized lymphadenopathy syndrome (PGL) is unknown in homosexual men who have been exposed to the AIDS virus. It has been estimated that 15-23% of gay men have persistent lymphadenopathy in 2 or more extra- inguinal sites (1). Since individuals who are antibody positive for AIDS virus and who have persistent lymphadenopathy are at risk to progress to full-blown AIDS, it is imperative to pursue therapies that treat this infection or minimize its progression. Reports of up to 50% progression rate of PGL patients to AIDS at 5 years of follow-up are available (1,17). Patients with PGL have an impaired cellular immune function with a decrease in T-helper cells and frequently an increase in T-suppressor cells. B-lymphocytes tend to be hyperactive (14). In comparing patients with PGL, ARC, or AIDS, to homosexual controls, PGL and ARC patients are not as immunologically impaired as AIDS patients, but tend to be more impaired than normal controls (3). Immune functional studies have also been abnormal with a decrease in NK activity and a diminished proliferative response to mitogens and antigens (20).

Because PGL and ARC patients have a less severe form of immune cellular deficits than full-blown AIDS patients, a treatment to repair T-lymphocyte dysfunction has been suggested in an effort to restore the immune system. (24,45) Interferon has been used to treat KS (15). The use of interleukin-2 (IL-2) in AIDS patients has been tried after in vitro verification of improved NK cell function, enhanced lymphocyte proliferative response, increased immune interferon release and cytomegalovirus-specific cytotoxicity (22). Unfortunately, to date none of these agents have been found sufficiently effective for treating AIDS or PGL.

Patients with AIDS manifest a variety of life threatening opportunistic infections, kaposi's sarcoma, lymphoma, and other malignancies. These occur because of an underlying immunologic deficit characteristically associated with a loss of T-Lymphocytes of the Helper subset which carry the CD4 antigen on their cell membrane. In addition, other immunologic and hematologic abnormalities are associated with AIDS. These include elevations in serum immunoglobulins, beta-2 microglobulin, as well as the appearance in circulation of high levels of an acid labile interferon alpha, tumor necrosis factor (1,2,3) and immune complexes. Leukopenia, thrombocytopenia, and anemia are common. Human T Cell Lymphotrophic retroviruses belonging to the human immunodeficiency virus (HIV) family have been etiologically linked to AIDS. Although the pathogenesis of AIDS remains obscure, HIV is believed to play an essential role because of its' affinity for lymphocytes of the CD4 phenotype. HIV can be isolated from the majority of AIDS patients. It is found in cells other than helper T-lymphocytes, notably in macrophages.

Individuals who are at greatest risk for developing AIDS are those seropositive for HIV who manifest some of the immunologic and hematologic abnormalities noted above, particularly a loss of CD4 T-lymphocytes. Such individuals, who have not experienced an AIDS defining opportunistic infection, may develop some clinical manifestations such as generalized lymphadenopathy, weight loss, diarrhea, fever, and oral thrush. It is imperative to pursue therapies for these individuals that will prevent or minimize disease progression.

HIV in its weakness as a retrovirus has been associated with a fatal form of immune deficiency with a long incubation period.(43) During some stage of its infectivity it can be stopped.(40) An effective immunostimulator is needed to restore the weakened cellular immunity. A combination of therapies, possibly including IL 2, may be needed (22,23,29).

The most compelling demonstration of the efficacy of such therapies would be the prevention of disease progression in a treated group compared to a group receiving placebo in a well controlled proposed study . In addition, if we can recognize some quantifiable biological abnormalities that are strongly predictive of rapid disease progression, a careful scrutiny of the effects of a particular intervention may suggest some benefit should amelioration of these biological abnormalities be observed.

LENTINAN AS TREATMENT FOR HIV

Lentinan is a purified polysaccharide preparation (molecular weight 500,000 daltons) from AJINOMOTO, in Japan, composed of a Beta(1--3) glucan and some Beta(1--6) glucosidic side chains(4) in a triple helix configuration (11). Lentinan, extracted from the edible mushroom Lentinus edodes (Berk.) Sing, was discovered in 1969 to have antitumor activity against mouse sarcoma 180 (7). Originally thought to be an immunomodulator, Lentinan is now recognized to act as an immunopotentiator by stimulating the T-cell mediated cytotoxic immune response and also by affecting nonspecific macrophage mediated response (7,11). Recent in vitro studies indicate that Lentinan augments cytotoxic activity of NK cells (7,11,18,19) and enhances interleukin-1 (IL-1) production (9,13). Interferon levels have also been increased with the addition of Lentinan to tissue cultures (18).

Lentinan has also been shown in vitro to augment DNA synthesis in PMNC (polymorphonuclear cells) and to increase immuno- globulin production (IgM, IgG) by pokeweed mitogen-induced PMNCs (4,18,19).

In animal models, Lentinan administration leads to an increase in serum acute phase proteins, augmentation of histamine sensitivity, and enhancement of the inflammatory response which peaks 3-4 days post-administration and decreases after 7 days (16). Hydrocortisone, anti-inflammatory drugs and dexamethasone were found to inhibit activation of the inflammatory response (16), while thyroxine and hydrocortisone prevent antitumor activity (11). The LD50 for Lentinan was >1500 mg/kg in mice (11).

In the Rhesus monkey, an intravenous dose of 0.5 mg/kg given as an infusion for 26 weeks was found to have significant antitumor activity. Higher doses (up to 30 mg/kg per day x 26 weeks) were associated with skin rash, development of foam cells in the liver and presence of a palpable spleen and lymph nodes (4).

In 235 cancer patients, Lentinan used in combination with standard chemotherapy (mitomycin C and 5-FU or tegafur) to define its antitumor activity and to document its side effects. Results were most positive and beneficical. Life expectancy was increased significantly with clinical improvement in tumor response to the treatment regimen. An increase in peripheral blood lymphocytes was also observed (3).

In 145 patients, Lentinan was tested in inoperable gastric cancer (25). In combination with tegafur, one, two, and three year survival rates were observed as 19.5% (p<0.01), 10.4% (p=0.1) and 6.5% (p<0.06) respectively; by comparison, survival rates on (5FU) or tegafur alone were 2.9%, 2.9%, and 0%. Side effects were mild, occurring in 6.8% of the patients. Reported side effects included skin eruption and redness, chest pressure, nausea and vomiting, headache, hot flashes, sweating, fever and bone marrow suppression.

Four hemophiliacs with HIV infection were given one 10 mg dose of Lentinan (25). Leukocytes and neutrophils transiently increased, and T-cell colony formation also increased. Then, two additional hemophiliac patients received 3 doses of Lentinan 10mg. every one or two days and exhibited intensified reactions with each injection. In two patients with HIV antibodies, Lentinan administration surprisingly caused these antibodies to disappear (5). NK activity also increased from 36% and 29% up to 81% and 82%, respectively. Five hemophiliacs with immune suppression due to HIV infection received Lentinan 10 mg once weekly for up to 18 months (42). Three patients demonstrated immunologic improvement with increases in T4 lymphocytes, T4/T8 ratio and an increase in the phagocytic activity of PMN cells. One patient noted symptomatic improvement after eight weeks of therapy. No side effects from Lentinan administration were reported in these patients (42). These past studies have shown impressive results on immune system function.

Lentinan (MW 500,000 daltons) as a purified polysaccharide of a Beta glucan extracted from the edible mushroom Lentinus edodes has specific RNA type coding for the T helper cell. For many years, Lentinan has safely been used as an antitumor agent in Japan and has been demonstrated to have both immune potentiating activity by stimulating the T-cell mediated cytotoxic immune response and also positively effecting a non-specific macrophage mediated responses.

EARLY Results OF LENTINAN USE AT SFG

In one study (SFGH), ten patients each were administered 2, 5, or 10 mg of Lentinan or placebo IV once a week for eight weeks. In the second study (CRI), two groups of 20 patients each were administered 1 or 5 mg of Lentinan IV twice a week for 12 weeks, and 10 patients were administered placebo (vehicle containing mannitol plus dextran 40) IV twice a week. Entry criteria were one HIV positive test, CD4 levels of 200-500 cells, age 18-60, without current opportunistic infections. Side effects were mostly mild, especially when infusion was carried out over a 30 minute period. In the SFGH study, where administration was over a 10 minute period, there were 9 side effects severe enough to be reported to the FDA (one case each of anaphylactoid reaction, back pain, leg pain, depression, rigor, fever, chills, granulocytopenia and elevated liver enzymes) and there were four patients who discontinued therapy because of side effects. In the CRI study, where infusion was over a 30-minute period, there were no side effects reportable to the FDA and there were four dropouts due to side effects or personal preference. Most side effects resolved promptly on discontinuation of the medication Lentinan , and all of them were relieved within 24 hours.

Patients in this study have demonstrated a trend toward increases in CD4 cells and neutrophil activity without toxicity. Because of the small numbers, these values do not have statistical significance. Although most patients in these trials did not have measurable p24 levels, in the CRI trials of eleven patients with elevated p24 levels, six out of nine on Lentinan and two on placebo had decreases in p24 levels. These results are provocative and need confirmation. No other anti-HIV agent to date has such low toxicity.

An adequate dose of oral or IV Lentinan in an early infected individual may reverse the antibody status or decrease immune suppression from HIV infection. (39,40). Such a reaction indicates a very useful potential treatment and possible restorative. Prevailing FDA studies are based on the assumption that if the HIV viral genome can be weakened sufficiently using antiviral drugs (DDI or AZT) , then Lentinan in combination with IL 2, could hypothetically restore the T-cells to normal and arrest the infection process.(43,44)

As DNA synthesis of uninfected CD4 cells increases, due to the immunopotentiation of Lentinan , activated cytokines and macro-phages would boost cellular immunity. By returning natural killer cell activity to normal and stimulating Interleukin-2, (3) Lentinan can promote viral destruction intracellularly. (22,35,40). This aspect of Lentinan's activity , in combination with other therapies using reverse transcriptase inhibitors, such as AZT or DDI, would increase specific antibodies for targeting infected cells to decrease HIV viremia.(29)

Lentinan has been proven effective orally in mice forcibly administered 1 mg. of Lentinan in saline.(33) This low dose resulted in significantly higher T-cell levels, helper cell levels, and H/S ratio and significantly lower suppressor-cell levels than did the control group after only four weeks of twice weekly use. Lentinan has already been shown effective in treating gastric carcinomas in Japan. (32,30,31) A preclinical screen by NCI proved a reduction in lung metastases and prolonged survival time in mice given Lentinan IM with minimal toxicity . (22)

In a clinical 4 year study of 68 of my private patients, 11 volunteered to ingest as little as 0.2 mg of Lentinan daily, orally, in the form of Reishi-Shigen(TM) powder, produced by Gourmet Mushrooms ; no side effects were reported by those using the powder in their daily diets as a food supplement. The control group of 56 patients not using Shiitake extract had a lower percentage of "active T-cells" than the long term users of the powder. (4)

Twenty years later, the powdered Shiitake is available through our website.

In human studies currently underway in Spain, UK, Italy, California and Portugal , the efficacy of mycological products as immune system stimulants is being evaluated as an adjuvant in treating herpes, Chronic Fatigue Syndrome, hepatitis and other viral infections and in certain immune deficiency states including Acquired Immune Deficiency Syndrome. The determination of '"'active T-cell'"' levels, yielded on analysis, a statistically significant increase in T cells . Daily use of a Lentinan containing powder, orally, produced an increase in CD4 numbers in healthy humans without side effects.

Abrams et al (45) have reported on a phase I/II pilot study of Lentinan in AIDS. Side effect incidence appears to be strongly related to the rate of infusion of Lentinan. In the SFGH study, where infusion was done over a ten-minute period, there were 9 instances of side effects reported to the FDA of 237 doses of Lentinan (29). In contrast, Bihari et al have also conducted a phase I/II pilot study of Lentinan in AIDS at the CRI in New York City, where infusions were carried out over thirty-minutes, no side effects were reported to the FDA of about 944 doses of Lentinan (46). Side effect incidence at the SFGH appeared to be somewhat dose related. However, these effects were not statistically significant since the placebo group had almost as many side effects as the high dose. Ongoing research as to Lentinan's efficacy when combined with DDI has not been yet completed but the results indicate that Lentinan decreased the toxicity of DDI. (39)

Lentinan is safe and it presents a potential simple non-toxic, relatively inexpensive treatment for HIV infection.(33,35,36m 44, 45, 46) Interestingly, Lentinan also offers potential treatment for other viruses such as Herpes, Influenza , TB, Hepatitis and even some parasites. Theoretically, Lentinan would be most useful in HIV positive individuals who are less immunocompromised. (23,24,33, 35).

Lentinan can be found in the product Triton-MRL, available exclusively through our WellnessMD Store. The powdered Biomass containing a one third mixture of Shitake mushrooms is grown in California, free of heavy metals or pesticides and shipped in sealed containers to Britain. Here the premier combination of the three most immune activating mushrooms, Shiitake, Cordyceps and Coriolus are mixed and formed into tablets which have been shown to affect CD4 cells.

Author:

Abraham H. Kryger, MD, DMD

IND:# 41,674 PROTOCOL: 92.1009

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