8.1. A “proof-of-concept”, double blind, parallel group study comparing the immune modulating and lipid lowering effects of beta-1,3/1,6-glucan (Immutol) with that of placebo (cellulose) in subjects with mild to moderate hypercholesterolemia (Biotec Pharmacon ASA, N-9008 Tromsø, Norway, 2003).
This study was carried out with 140 healthy individuals who according to standards in Norway could be defined as having mild to moderate hypercholesterolemia, but in some other countries were regarded as healthy and not subject to any cholesterol lowering treatment. The primary objective was to record eventual effects on blood CRP levels, since there is a likely link between elevated blood cholesterol and inflammations that may result in increased CRP. In accordance with this hypothesis, the average CRP-level in the study group went down compared to placebo after intake of 0.7 gram micro-particulate beta-1,3/1,6-glucan per day for 8 weeks. But since the majority in the study groups were healthy, most of the analytical figures for CRP were within the healthy range, whereas high values of CRP dropped off in the study group compared to placebo. Studies with individuals having inflammations and hence elevated CRP-levels are therefore logical follow-up of this combined safety/”proof-of-concept” study.
8.2. Randomized phase I/II trial of a macrophage-specific immunomodulator (PGG-Glucan) in high-risk surgical patients (Babineau et al. 1994b)
A double-blind, placebo-controlled, randomized, single center phase I/II trial of PGG-glucan was conducted in high-risk surgical patients. Thirty-four patients at high risk of postoperative infection undergoing major abdominal or thoraric surgery were randomized in a 2:1 ratio to receive PGG-glucan or placebo. 0.5 mg/kg of PGG-glucan and saline placebo were administered in multiple, sequential doses by intravenous infusion (continuous infusion for 1 hour) 12-24 hours before surgery, 1 to 4 hours before surgery, 48 hours after surgery, and 96 hours after surgery. The patients were evaluated before surgery and until their discharge from the hospital. In addition, long-term follow- up was performed 4 and 8 weeks postoperatively. Statistical analyses were done using the chi square test and analysis of variance.
No adverse drug experiences associated with PGG-glucan infusion were observed.
Patients who received PGG-glucan had significantly fewer infectious complications (3.4 infections per infected patient vs. 1.4 infections per infected patient, p=0.05), decreased intravenous antibiotic requirement (10.3 days vs. 0.4 days, p=0.04), and shorter intensive care unit length of stay (3.3 days vs. 0.1 days, p=0.03). The hospital length of stay was shorter for patients in the active group, but this did not reach statistical significance. Even if the number of infections was reduced in the PGGglucan group, the number of patients infected did not differ between the two groups. None of the in vitro tests of microbicidal activity of neutrophils and macrophages against S. aureus, E. Coli and C. albicans were statistically significant, but the monocytes from patients treated with PGG-glucan showed a trend toward increased microbicidial killing activity against S. aureus and C. albicans.
8.3. A phase II multicenter, double-blind, randomized, placebo-controlled study of three dosages of an immunomodulator (PGG-Glucan) in high-risk surgical patients (Babineau et al. 1994a)
A double-blind, placebo-controlled, randomized, multicenter phase II trial of three dosages of PGG-glucan was conducted in high-risk surgical patients. 67 patients scheduled for major noncardiac thoraric or abdominal surgery were randomized in a 1:1:1:1 ratio to receive saline placebo or PGG-glucan at a dose of 0.1 mg/kg, 0.5 mg/kg, 2.0 mg/kg. After six patients were assigned to receive a dose of 2.0 mg/kg, this dose was reduced to 1.0 mg/kg based on minor adverse experiences in healthy volunteers who received a dose of 2.25 mg/kg. The patients received multiple, sequential doses by intravenous infusion (continuous infusion for 1 hour), one dose was administered 1 to 6 hours before surgery and three doses were administered after surgery (within 4 hours, at 48 and 96 hours after surgery). The patients were evaluated before surgery and until their discharge from the hospital. In addition, long-term follow-up was performed 4 and 8 weeks postoperatively. Statistical analyses were performed using the chi square test with Yates’ correction.
Of the 67 patients enrolled, 64 were evaluable. Two patient withdrew before study completion owing to adverse experiences: An episode of hypertension, diaphoresis and nausea following the third dose of 0.1 mg/kg and an episode of maculopapular rash on the abdomen and trunk following the second dose of 2.0 mg/kg. The incidence and severity of adverse events was comparable in all groups. No serious adverse evnts were considered to be related to PGG-glucan administration. A dose-response trend with regard to infection incidence among patients who receive PGG-glucan was observed, although this did not reach statistical significance. Serious infections occurred in four patients who received placebo and in three patients who received PGG-glucan at a dose of 0.1 mg/kg. However, only one patient who received PGGglucan at a high dose had a serious infection.
8.4. Effect of PGG-glucan on the rate of serious postoperative infection or death observed after high-risk gastrointestinal operations (Phase III study) (Dellinger et al. 1999)
A double-blind, placebo-controlled, randomized, multicenter trial with PGGglucan after high risk gastrointestinal operations was conducted at 39 medical centers in the USA. 1249 patients scheduled for a gastrointestinal procedure lasting 2-8 hours were randomized to receive saline placebo or PGGglucan 0.5 mg/kg or 1.0 mg/kg, stratified into colorectal (planned procedure involving incision in the colon or rectum) and non-colorectal (no incision planned) strata. The patients received 4 doses of study drug by intravenous infusion, one dose was administered within 12 hours prior to surgery, and three doses were administered after surgery (within 4 hours after the first dose, at 48 and 96 hours after start of surgery). All patients received antibiotic prophylaxis according to protocol.
1177 patients constituted the intent-to-treat population. Treatment effects were tested using a Cochran-Mantel-Haenszel c2 test for differences in mean scores adjusting for investigator and stratum. There was no significant difference in the primary end point events, serious infection and/or death, between any of the groups. When analysing the treatment effects separately for the colon and non-colon strata, there was a reduction in the incidence of infection and death in the PGG-glucan groups (36% incidence) compared to the placebo group (22% incidence) in the non-colon stratum, although this was not statistically significant. Examination of the colon stratum failed to demonstrate any treatment effect.
44 patients died within 30 days, with no significant differences among the treatment groups for patients who died with or without infection. PGG-glucan was well tolerated. There was a slight increase in fever, hypertension, nausea, and vomiting seen primarily in the 1.0 mg/kg dose group. Serious adverse events were common in all groups, reflecting the serious operations and high-risk nature of the patients, and were not different between groups.
8.5. Infection prevention in patients with severe multiple trauma with the immunomodulator beta 1-3 polyglucose (glucan) (Felippe et al. 1993).
To study the possible prevention of pneumonia and sepsis in patients with multiple trauma with head injury, beta 1,3-glucan was used prophylactically in patients who were not infected within 48 hours of admission to the hospital. Forty-one patients were stratified using the Trauma Score, included in the double-blind controlled trial and randomized into a control group (n=20) or a glucan group (n=21). The first nine patients received 30 mg glucan i.v. every 24 hrs, with a mean of 312±250 mg per patient during 8.8±5.0 days. The next 12 patients received 30 mg glucan i.v. every 12 hrs, with a mean of 685±376 mg per patient during 11±6 days. Significant decreases (55.0 to 9.5%) in the pneumonia incidence, the sepsis incidence (35.0 to 9.5%), and the mortality rate to infection (30.0 to 4.8%) were observed in patients treated with glucan. The overall mortality rate, cerebral deaths excluded, was 42.1% in the control group and 23.5% in the glucan group.
Weakness and tiredness was observed in 17 of the patients, and headache, body pain, stomatitis and pharyngitis in one of the patients each. The side effects were rare, light and did not require interruption of treatment, but a slight reduction of doses.
8.6. Beneficial effect of enhanced macrophage function in the trauma patient (Browder et al. 1990).
A prospective, randomized, double-blind study was conducted to evaluate the efficacy of soluble glucan in 38 trauma patients undergoing surgery (exploratory laparotomy or thoracotomy for trauma). Glucan 50 mg/m2 (n=21) or saline placebo (n=17) was given i.v. daily for 7 days after operation. All patients received prophylactic antibiotics. The total morbidity rate, but not the mortality rate from sepsis, was statistically significant reduced in the glucan group (0% vs 29%, p<0.05). The glucan patients had a transient significant increase in IL-1 (143.4%±19.3% vs 78.6%±11.7%, p<0.05), but there was no difference in the serum TNF levels of placebo or glucan treated patients.
8.7. Effectiveness of beta-glucan collagen for treatment of partial-thickness burns in children (Delatte et al. 2001).
The efficacy of a beta-glucan/collagen matrix (BGC), which combines the carbohydrate beta-glucan with collagen in a meshed reinforced wound dressing, has been evaluated in a retrospective chart review of 225 consecutive pediatric burn patients. Of the 225 charts reviewed, 43 patients (19%) were treated with BGC as a primary wound dressing, and 130 patients (58%) received standard treatment (daily dressing changes with silver sulfadiazene or bacitracin ointment) without the use of BGC or split-thickness skin grafting. Statistical comparisons of the treatment groups did not reveal any difference in terms of days to healing. Thirtyfour patients (79%) had the BGC remain intact while the wound healed underneath, with good cosmetic results, minimal analgesic requirements, and no need for repetitive dressing changes, while nine of the patients (21%) had the BGC removed before wound healing due to progression of the burn or nonadherence. BGC is maintained to markedly simplify wound care and to decrease post-injury pain. BGC is also believed to act as an effective barrier against bacterial contamination.