CURRENT PHARMACOLOGIC Investigations and Clinical Applications
As mentioned above, pathogen burden and microbial infections are a newly-recognized risk factor for CHD. This is seen especially in the setting of the chronic inflammation induced by persistent, low-grade infections. NK cells, as a first line of defense against those infections, therefore may play a role in CHD development. The general NK cell activity enhancement of RBAC previously established, its potential for direct impact on bacterial infection was thus investigated .
RBAC* was found to enhance oxidative bursts in neutrophils and monocytes, and phagocytosis of E. coli in a dose-dependent manner. Incubation of RBAC alone with 31 types of bacteria showed no retardation of bacterial growth, and RBAC-treated phagocytic cells in the absence of bacteria showed no oxidative bursts. These findings indicate that RBAC does not have direct antibiotic activity, but rather acts as a modulator of phagocyte function [27 ].
Obesity/Metabolic Syndrome & Non–Insulin-Dependent Diabetes Mellitus (NIDDM) To investigate the potential of RBAC* for reducing cardiovascular risk markers (inflammation, lipids, and glucose) a single-blind, pilot trial was conducted in overweight subjects with elevated baseline inflammation levels. The primary objective was to assess the efficacy of this agent on the reduction in inflammation as indicated by high-sensitivity C-reactive protein (hs-CRP) levels, an inflammation biomarker which is produced in the liver corresponding generally to elevations in IL-6.
Endpoints were measured at baseline, 7 days, 30 days, and 60 days, and preliminary data analysis revealed no significant effect on hs-CRP in the study population. This again is indicative of a primary immunomodulatory effect without evidence of the immunosuppressive effect putatively requisite to impact hs-CRP levels.
Cancer Chronic inflammation can lead to pre-malignant conditions which, in the presence of depressed immunity, can progress unchecked into malignancies. Some examples of this are inflammation induced by h. pylori leading to gastric cancer, HPV infection and inflammation leading cervical cancer, sunburn leading to skin cancer, Barrett’s esophagitis leading to esophageal cancer, and hepatitis B or C leading to hepatocellular carcinoma.
Given the previously established apoptosis-sensitizing effect of RBAC on human leukemia cells, the chemotherapy-sensitizing activity of RBAC was evaluated with human breast cancer cells (MCF-7 and HCC70 cell lines) in vitro. MCF-7 and HCC70 cells were cultured with daunorubicin (DNR) in the presence of varying concentrations of RBAC* (100-1000 μg/ml) for 3 days. At a concentration of 500μg/ml, RBAC significantly enhanced the accumulation of DNR in MCF-7 cells and HCC70 cells over controls as determined by flow cytometry. Using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) to assay cancer cell survival, RBAC effectively decreased the DNR IC50 in MCF-7 cells compared to DNR alone by 3-, 5- and 5.5-fold, at concentrations of 100, 500 and 1000 μg/ml respectively. RBAC also enhanced the DNR sensitivity of HCC70 cells, decreasing the DNR IC50 of these cells by 2.5-fold [28 ].
To investigate the anti-tumor activity of RBAC in vivo, Solid Ehrlich Carcinoma (SEC) tumors were established in female Swiss albino mice via intramuscular inoculation with Ehrlich Ascites Carcinoma (EAC) cells. The mice were treated with RBAC* (40 mg/kg body weight) via intraperitoneal injection 3 times per week from day 8 until day 35. Injection with RBAC caused a significant diminution in tumor volume (63.27%) and tumor weight (45.2%) as compared to controls (p<0.01). More importantly, RBAC also induced a 1.8 fold increase in SEC cell apoptosis percentage. No adverse effects due to RBAC treatment were observed [29 ].
A phase I pilot study is also underway to evaluate the safety and toxicity of RBAC in combination with subcutaneous interleukin-2 therapy in patients with advanced malignancies. Patients must have advanced malignancy that has progressed and for which the primary treating physician believes standard and acceptable therapies have been exhausted. All patients will receive RBAC at 3 g/d orally for four weeks at which point the dose of RBAC will be dropped to 1 g/d continuous dosing. Interleukin- 2 (IL-2) will then be added and administered subcutaneous (SQ) daily Mondays through Fridays for four weeks followed by two weeks rest (six week cycle). Subjects will be monitored for toxicity, and restaging will occur every 2 cycles from starting of IL-2 dosing (12 weeks). Subjects will receive therapy until disease progression or undue toxicity. This study is currently entering the recruitment phase.
Discussion
The Immunosenescence model and corresponding scientific literature indicate that the pathophysiologic state of functional decline characteristic of what is termed Aging arises from an immune system-based etiology. Further, our ongoing clinical and laboratory investigations into the impact of Allotypic Immuno-Modulator (AIM) therapy on the amelioration of the diseases and disorders associated with Aging is in full concordance with this tenet.
The studies reported above show a wide range of efficacy of the oligo-arabinoxylan AIM RBAC in contexts consistent with an Immunosenescence- reversal effect. The data demonstrate RBAC as an: ² Allotypic Immuno-Modulator demonstrating a generalized balancing effect on proinflammatory cytokines and an enhancement of innate immune system function, with specific activity upon the NK cell compartment; ² CHD risk-lowering modality via its enhancement of microbial pathogen phagocytosis; ² Effective chemotherapy-sensitizer, and potential novel adjuvant to the conventional treatment of breast cancer; ² Apoptosis promoter in solid tumors free of adverse side effects.
Further considerations could be extended to include two additional problem areas which face adults of advancing age: impaired wound healing and vaccination response. It has been proposed that in the case of impaired wound healing a possible mechanism underlying in the elderly may be a diminished local production of proinflammatory cytokines by macrophages [30 ]. Appropriately activated, these immunochemical messengers serve to trigger the natural inflammatory processes which are essential to wound healing and recovery from illnesses.
Adults of advancing age also tend to mount a weaker response to vaccination [31 ]. Given the activity of RBAC in enhancing B-cell proliferation and mitogen response, and the prevalent use of and reliance upon vaccines in this population, AIM therapy could significantly impact quality of life in this population via restoration of generalized immunocompetence [ 32 ]. As well, vaccine response studies represent a potential clinical tool for assessment of AIM therapy in the reversal of immunosenescence.
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