Biostim, also known as RU-41740 or C1740, is a unique immunomodulator. It is a compound extracted from the cell wall of a bacteria-Klebsiella pneumoniae - consisting mainly of two large glycoproteins (7,14). Biostim has been widely used in France to treat a variety of infectious conditions since 1982. Biostim has been extensively researched through human clinical (1-14), animal experimental (15-25), and in vitro cell studies (26-39) since 1980. Biostim has shown a broad range of immune modulating activity. It has enhanced the germ-killing power of neutrophils, macrophages and natural killer cells, the chief white blood cells responsible for non-specific or innate immunity (1,3,5,8,14,17,19-21,26,31-33,36,37,39). Biostim has diverse positive effects upon T lymphocytes (2,6,9,10,12,14-16). It enhances the conversion of B cells to antibody-forming plasma cells, increases antibody production, and improves vaccine response (4,9,10,14,22,27,38). Biostim causes some immune cells to secrete anti-cancer factors, and to become more active against tumor cells (19,31,39). It has restored some measures of immunity in cancer patients with weakened immunity (2,6,10,12). Biostim has repeatedly been shown to reduce infection in chronic bronchitis patients, in elderly infection-prone individuals, and in children prone to recurrent respiratory infections (1,5,7,11,13,14). And these are just some of the many immune benefits of this unique immune enhancer.
Biostim vs. lung infections
Chronic bronchitis is a condition of chronic lung inflammation, with excessive mucous production and proneness to recurrent lung infections. There are more than 2 million chronic bronchitis sufferers in France, where Biostim was developed. Bronchitis leads to 20,000 deaths per year there. (40)
Viallat and colleagues reported a 9 month double-blind trial of Biostim in 1983 (13). 38 people (average age: 62) got Biostim, 35 (average age: 56) got placebo. They had typically suffered chronic bronchitis for 15-20 years. The treatment was 2 mg Biostim or placebo for 6 days; then 1 mg Biostim or placebo for 8 days, 2 and 4 months later. After 3 months 78% of Biostim subjects were without infection, vs. 53% of placebo subjects. By the end of 9 months, the Biostim group averaged 13 days of lung infection, vs. 33 days for the placebo group. By month 9, antibiotic usage in the Biostim group averaged 11.5 days, vs. 41 days in the placebo group. The authors also noted: "No signs of intolerance and particularly no signs of immunotoxicity were observed...." (13).
Hugonot and co-workers conducted a large trial lasting 12 months with 155 Biostim subjects and 159 placebo subjects (11). These were elderly patients (average age: 82), admitted to chronic care medical facilities, suffering from various infection risk factors such as diabetes, obesity, cardiac and respiratory insufficiency, skin ulcers, chronic bronchitis, etc. Treatment was 2 mg Biostim or placebo for 8 days the first month, and 1 mg Biostim/day or placebo for 8 days at the beginning of months 2 and 3. After 6 months, the Biostim group had 90 patients without lung infection vs. 76 for placebo; after 9 months 82 Biostim subjects without infection vs. 64 for placebo; and 65 Biostim patients without infection vs. 51 for placebo at 12 months. There was a significant decrease in antibiotic use in the Biostim group compared to placebo throughout the entire 12 months of the trial: 7.4 days vs 11 days for the placebo group. By month 12 the average number of infections in the Biostim group was 0.77 vs. 1.1 in the placebo group - a 30% reduction in the Biostim group. The authors conclude: "The drug was well tolerated. This study showed that RU41740 is effective in protecting elderly and therefore fragile subjects against respiratory infections." (11).
Fietta and colleagues compared 3 and 6 month Biostim regimens in 40 chronic bronchitis patients in an 8 month study (1). One group got the standard Biostim regimen of 2 mg/day for 8 days in month 1, with 1 mg/day for 8 days in months 2 and 3. The other group got 2 mg/day for 8 days 6 months in a row. The results of the two groups were similar. The standard dose group had only 0.82 bronchitis exacerbations during the 8 month trial, compared to 2.7 during the same 8 month period the previous year. The high dose Biostim group averaged 0.88 exacerbations, vs. 2.9 the same period the previous year. The authors also reported that "Both treatments significantly improved phagocytosis index [a measure of germ-killing power] of both neutrophils and monocytes [precursors of macrophages], phagocytosis frequency and candidacidal activity of neutrophils.... The clinical and hematological tolerability of a long-term treatment with RU41740 proved very good and comparable to that of the short-term standard treatment." (1).
Fietta and colleagues also reported the benefits of Biostim in a 9 month study where standard dose Biostim was compared to placebo (5). They observed that "The drug enhanced the phagocytosis indexes of both polymorphonuclear [neutrophil] and mononuclear [monocyte/macrophage] phagocytes. Increased candidacidal activity of monocytes was also observed." (5) There were more patients with no bronchitis exacerbations in the Biostim group, and the mean number of exacerbations over 9 months was 1.66 for Biostim and 3.5 for placebo. The duration of bronchitis exacerbations averaged 15 days for Biostim and 36 days for placebo. "No side effects and no changes in routine hematological or biochemical blood tests were observed during the trial."
Biostim and cancer
While there is no evidence that Biostim is a cure for cancer, Biostim has been shown to be helpful to the health and well-being of cancer patients. It has also shown some signs of anti-cancer activity in cell and animal tests.
Lang and co-workers first reported a Biostim benefit to cancer patients in 1980 (12). Cancer patients, due either to their disease and/or its treatment by x-rays and chemotherapy, are prone to serious immune weakness. 8 mg/Biostim/day was given to 6 cancer patients for 15 days. All of the patients initially showed a complete lack of delayed cutaneous hypersensitivity (DCH) (also called "delayed typer hypersensitivity)." "Assessment of DCH... is a simple procedure for testing cell-mediated immunity in man and DCH deficiency has predictive value in many clinical settings." (6). "Restoration of delayed cutaneous hypersensitivity was observed in five of the six patients." (12)
Lang and colleagues gave various doses of Biostim or placebo to 51 lymphoma patients for 14 days. (6). The 8 mg/day dose of Biostim significantly enhanced the low DCH response compared to placebo or the 2 mg or 32 mg/day Biostim doses. The study authors note the importance of this finding: "That persistent cell-mediated immunity deficiency can be overcome by [Biostim] might have clinical implications since these patients [and cancer patients generally] show an increased incidence of infectious episodes." (6). They also observed that "no side effects were noted whatever the dose administered." (6)
Griscelli and co-workers gave 21 cancer patients suffering seriously impaired DCH 8 mg Biostim/day for 7 or 14 days (10). "16 patients showed a significant ... increase in DCH after treatment, regardless of its duration." (10)
Blomgren and colleagues gave 8 mg Biostim/day for 7 days once monthly for 3 months to 12 patients with advanced colorectal cancer (2). Over the course of the 3 month trial, they found a 300% increase in the ability of T lymphocytes from the cancer patients to proliferate in response to the mitogen PHA. Since T cells are the basis of cell-mediated immunity, and cell-mediated immunity is the essential, youthful form of acquired human immunity, this immunostimulating power of Biostim in cancer patients, further suggests its usefulness as adjunctive therapy in cancer patients. It was also noted that "None of the patients complained of any side-effects and there were no changes in results of routine laboratory tests ...." (2)
Sozzani and co-workers gave Biostim to mice by injection and orally (19). They found that Biostim increased the ability of natural killer (NK) cells to clear injected YAC-1 tumor cells from the mices' lungs and spleens. They also found through in -vitro testing that Biostim increased the cytotoxicity of human NK cells against K562 tumor cells up to 40%.
Blomgren exposed human monocytes to Biostim in vitro (31). He concluded that "The present study has shown that Biostim ... can induce human mononuclear cells to release soluble factors which inhibit growth of tumor cells as well as 3 different human glioma (brain) tumor cells lines were inhibited.
Vacheron and colleagues extracted mactophages from mice (39). These were then incubated with Biostim. "We found that macrophages activated by RU-41740 exhibited cytotoxic activity against tumor cells. Moreover RU-41740 was able to induce secretion by macrophage of a soluble cytotoxic factor [that inhibits tumor cell growth]." (39)
The available evidence thus suggests that Biostim may be useful to cancer patients for two reasons:
1. to enhance their weakened general immune activity, to protect from infections;
2. to increase the ability of the cancer patient's own immune cells to fight cancer cells.
8 mg/day seems to be the effective dose in cancer, as opposed to the 2 mg/1 mg dose used in other contexts.
One of the scourges of the modern world is chronic candidiasis - infection with the yeast Candida albi cans and its relatives (41,42). Over consumption of sugar and antibiotics promotes Candida overgrowth in the intestines, leading to a myriad of symptoms affecting both brain and body (41,42). With extreme immune weakness (as occurs frequently e.g. in AIDS patients) Candida may even penetrate into the body, especially the lungs and kidneys.
Biostim has shown activity against Candida in a variety of studies. The two studies by Fietta and colleagues discusses above in the "Biostim vs. Lung Infection" section both found increased Candida-killing power of neutrophils and macrophages in Biostim-treated patients (1,5).
Nielsen and Bonde compared the effect of 2 different doses of Biostim to placebo in 20 chronic bronchitis patients (3). 7 subjects got 8 mg Biostim/day every other week for 3 months, while 5 got 2 mg/day every other week, 8 subjects received placebo. All subjects suffered from a deficiency of monocyte Candida-killing power. Normal Candida phagocytic activity of monocytes is 3.0/monocyte, while the test subjects' monocytes averaged only 1.4. After Biostim treatment, the 2 mg group's: monocytes averaged 3.4 Candida cells killed/monocyte; the 8 mg group averaged 3.0; while the placebo group only increased from 1.6 to 2.0. Since monocytes/macrophages are the main phagocytic cells normally present in the lungs, Nielsen and Bonde concluded that the ability of Biostim to enhance abnormally low monocyte phagocytic activity may be a key factor in Biostim's ability to prevent lung infections.
Smets and co-workers injected 100,000 to 1.4 million Candida cells into mice (24). Some of the mice had been fed Biostim for 4 days before infection with Candida. The Biostim mice had double the survival time after infection compared with placebo mice. In addition, the number of virulent yeast cells recovered from the kidneys of the Candida-infected mice was reduced 60-70% in the Biostim group. Smets et al also found that Biostim increased mouse phagocytic cell (neutrophil) activation 200-300%, while human neutrophils incubated with Biostim showed a 200-1,000% increase in metabolic activity and superoxide production. They note that "PMN [neutrophils] are predominant [white] cells both in human blood... and in ...peritoneal cells ...; they are about 3 times more effective in the release of [germ-killing] activated oxygen species than macrophages and represent the major cell type involved in [fighting] c.albicans infection." (24)
Nielsen extracted monocytes from healthy human volunteers (30). The monocytes were briefly incubated with Biostim, then Candida cells were added to the Biostim-activated monocytes. Biostim increased the percentage of Candida cells killed from 47% (no Biostim) to 68% (0.1 mg/ml Biostim), while simultaneously increasing release of germ-killing superoxide by 45% Nielsen concluded that "The present study has shown a marked increase in human blood candidacidal activity in parallel with priming of the monocytes for enhanced superoxide anion release...." (30)
Biostim: Antibody booster
One of the two main forms of acquired immunity is humoral immunity - the production of antibodies that are active against specific germs, and which make it easier for neutrophils and macrophages to attack the antibody-coated germs (43). Biostim has been shown to enhance antibody production in both humans: and animal experiments.
Profeta and colleagues vaccinated 42 elderly volunteers with several different type A influenza strains (4). The subjects were given either 4 mg Biostim or placebo for 14 days, starting the day of vaccination. The antibody titres produced were typically 20-30% higher in the Biostim group, and a larger number of Biostim subjects achieved successful vaccination responses earlier, and in total numbers, compared to the placebo group.
Notto vaccinated young healthy volunteers against type A influenza virus (14). The volunteers were given 2, 4,or 8 mg Biostim or placebo for 14 days beginning on the day of vaccination. By 3 weeks post-vaccination, only 40% of the placebo group showed antibody titres indicating successful vaccination, while 75% of the 8 mg Biostim group and 90% of the 4 mg group demonstrated successful vaccination antibody titres. As Smets and colleagues observe, "As Biostim enhances the immune response to vaccination, it can be considered to have a B lymphocyte stimulating activity." (14)
Griscelli and co-workers performed an experiment with 10 healthy people previously vaccinated with tetanus vaccine at least 3 years earlier. They were given 8 mg Biostim for 14 days, but no tetanus booster, 10 more people previously vaccinated were treated with placebo and given a low-dose tetanus booster shot, while 24 people were given placebo and no booster shot (10). After 30 days, the antibody response in the Biostim group was almost 20 times higher than the group given placebo and no tetanus booster, and was roughly the same as the antibody response of the 10 people given placebo and tetanus booster. This experiment thus demonstrates the powerful effect of Biostim to increase existing antibody levels, without vaccination. The authors also reported that "No adverse effects were observed ...." (10).
Takada and co-workers tested guinea pigs with Biostim (22). Crystalline ovalbumin (protein) was dissolved in a water/oil emulsion and injected into the guinea pigs, with or without Biostim.
The antibody response to the injected ovalbumin was 300% higher in the Biostim guinea pigs. Wood and Möller performed experiments with mice to determine Biostim's effect on B cells (antibody forming cells) (35). They found that "RU-41740 polyclonally activates spleen cells to antibody synthesis in vivo and in vitro .... RU-41740 induced both IgM and IgG [antibody] synthesis in spleen cells ...." (35). They also observed that Biostim induced proliferation (i.e. increased the number) of B cells. Thus Wood and Moller concluded that "RU-41740 is a strong polyclonal B cell activator." (35)
Martinez-Mazza and colleagues studied the effect of Biostim on human B cells isolated from blood and spleen (27). They found that Biostim caused a major increase in IgG and IgM in B cells, compared to untreated B cells. IgM levels were increased 800-3700% in Biostim-treated B cells compared to untreated B cells, while IgG levels were increased 230-1200% compared to untreated cells. Guenounou and coworkers tested Biostim in mouse cell cultures (38). They report: that "RU-41740 is a selective B-lymphocyte activator ... RU-41740 also activates immunoglobulin [antibody] secretion by murine [mouse] B lymphocytes. Incubating spleen cells from... mice with RU-41740 results in cell proliferation and activation of antibody-forming cells." (38)
The evidence from human, animal, and cell studies is clear: Biostim enhances vaccination effect, B cell proliferation, and the ability of B cells to produce germ-fighting antibodies.
Biostim vs. germs
A host of animal studies has shown Biostim's power to enhance natural germ-fighting abilities. Takada and colleagues gave Biostim to test mice for 4 days before injecting them with L.monocytogenes bacteria. By day 14, 82% of the control animals had died, vs. 50% of the Biostim mice (22). Griscelli and colleagues reported that feeding Biostim to mice for 2-8 days before injecting them with various germs protected them from Listeria, Streptococcus, Klebsiella, E. coli, Proteus, Pseudomonas and Staph Aureus bacteria, as well as influenza and encephalomyocarditis viruses (10).
Smets and colleagues report on the effects of 4 days oral Biostim given before injection with virulent germs (14). They note that with Staph. pneumoniae, 5/10 Biostim animals survived after 20 days, vs. 1/10 controls. 9/10 Biostim animals injected with Klebsiella pneumoniae survived after 20 days, vs. 1/10 controls. 6/10 Biostim animals injected with Listeria monocytogens survived after 20 days, vs. 1/10 controls. Laval and co-workers studied the effects of Biostim on pigs (15). They gave: 3 groups of pigs placebo or high or low dose of oral Biostim for 8 days. On day 21, they injected Erysipelothrix bacteria into the skin of the pigs. Pigs are extremely sensitive to this particular bacteria. The diameter of the skin lesions produced in the two Biostim groups was only about 10-15% as great as in the placebo group. Biostim's immune activation is thus shown to be effective again a broad array of virulent microbes.
Biostim: Miscellaneous effects
Fiszer-Szarfarz and colleagues reported an unusual ability of Biostim in 1988. They discovered that Biostim markedly increased the activity of 4 enzymes of lung macrophages (18). These enzymes serve to break down the complex glycosaminoglycans that make up mucous. This is important because excessive lung production of mucous is a major problem in asthma, bronchitis, exphysema, and lung infections, impairing breathing ability (18). They also note that the high molecular weight hyaluronic acid typical of mucous, inhibits phagocytosis (germ-ingesting) by macrophages, but the low molecular weight hyaluronic acid, produced when mucous is digested by the 4 macrophage enzymes does not inhibit phagocytosis.
Thus, one more reason for anyone suffering from asthma, chronic bronchitis, recurrent lung infections or emphysema to take Biostim.
Another important benefit of Biostim is its ability to enhance antibiotic action. In one experiment, mice were injected with lethal doses of Staph germs on day 0. Some mice were given the antibiotic ampicillia from day 0; others were given Biostim from day 0 to day 4; and the third group was given Biostim plus ampicillin. By day 3, only 10% of the ampicillin-only group were alive; by day 18 40% of the Biostim-only group were still alive; while by day 18 90% of the Biostim plus ampicillin group were still alive (14).
In another experiment, mice injected with a lethal dose of Staph. were given Biostim for 4 days before injection; ampicillin from day 0; or both Biostim and ampicillin. By day 5 all the ampicillin-only mice were dead; only 4% of the Biostim-only group survived until day 11; 20% of the Biostim plus ampicillin group survived until the end of the experiment (14). It is thus probably a good idea to keep Biostim on hand, and any time it is necessary to take an antibiotic - especially if it's for a serious or life-threatening infection - begin an 8 day, 2 mg/day course of Biostim at the same time.
Capsoni and co-workers showed that Biostim has the ability to reverse the immunosuppressive effect of cortico-steroids (36). They extracted human neutrophils and tested them in vitro. The neutrophils were exposed to different levels of hydrocortisone (HC) or methyl-prednisolone (MP), and then tested for their ability to phagocytize (ingest) antibody-coated sheep red blood cells. Compared to control neutrophils, the HC-treated neutrophils had a 77% reduction in their ability to ingest the sheep red blood cells, while the MP-treated neutrophils were treated with Biostim and HC or MP, the phagocytic defect was completely reversed, with the neutrophils achieving the same level of phagocytosis as the controls. Given the well-known profound immunosuppressive power of corticosteroids, this is further proof of Biostim's broad-ranging immune enhancing power.
Scheffer and co-workers studied the effects of Biostim on the inflammatory response of various types of human white blood cells (34). They observed that Biostim significantly reduced neutrophil production of the spasmogenic leukotriene LTC4 when they were stimulated in a manner that tends to elicit LTC4 release. LTC4 plays a major role in asthma and cystic fibrosis (34). Scheffer et al conclude that:: "RU-41740 increases the expression of inflammatory reactions induced by weak stimuli and thus may be important for bacterial killing and elimination. It also inhibits an over-expression by potent stimuli and thus may act as an anti-inflammatory and in this regard it inhibits cell and tissue damage induced by inflammatory mediators." (34) Given that excessive inflammation is frequently a problem in asthma and various infectious conditions, this demonstrates yet another benefit of Biostim.
Biostim: The program
The standard protocol for Biostim usage is as follows: Biostim is swallowed whole, on an empty stomach, for 8 days at 2 mg (2 tablets) per day. Then one month after beginning Biostim, 1 mg/day is taken for 8 days. Finally after 2 months after the first Biostim dose, 1 mg is again taken for 8 days. This process is then repeated once yearly (11). However, it should be noted that in various human studies involving cancer patients, the daily dose was 8 mg/day (2, 6, 10, 12). Virtually all human Biostim studies report no, or no serious side effects, even at doses up to 32 mg/day. A few studies have reported stomach upset in a few patients. As for contraindications, the Biostim manufacturer's package insert states that "Biostim is not to be taken in the case of autoimmune illness. - It should not be given to children of less than a year old. - Although embryotoxic or teratogenic effects have not been seen in animal experimentation, its use is not recommended during pregnancy."
Given Biostim's extreme safety, those suffering extreme immune weakness may wish to do the 3 month Biostim program every 6 or 9 months, rather than only once yearly. Given the multifaceted immune-enhancing effects of Biostim, its safety, its low cost, and the low number of doses that need to be taken, Biostim may be the best immunopotentiating bargain available today.
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