OBJECTIVE: The fermented wheat germ extract (FWGE) nutraceutical (Avemar), manufactured under "good manufacturing practice" conditions and, fulfilling the self-affirmed "generally recognized as safe" status in the United States, has been approved as a "dietary food for special medical purposes for cancer patients" in Europe. In this paper, we report the adjuvant use of this nutraceutical in the treatment of high-risk skin melanoma patients. METHODS: In a randomized, pilot, phase II clinical trial, the efficacy of dacarbazine (DTIC)-based adjuvant chemotherapy on survival parameters of melanoma patients was compared to that of the same treatment supplemented with a 1-year long administration of FWGE. RESULTS: At the end of an additional 7-year-long follow-up period, log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p = 0.0137. Mean OS: 66.2 months (FWGE group) versus 44.7 months (control group), p = 0.0298. CONCLUSIONS: The inclusion of Avemar into the adjuvant protocols of high-risk skin melanoma patients is highly recommended.
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fermented wheat germ extract
Adjuvant fermented wheat germ extract (Avemar) nutraceutical improves survival of high-risk skin melanoma patients: a randomized, pilot, phase II clinical study with a 7-year follow-up
| Avemar, dacarbazine (DTIC), fermented wheat germ extract, Growth signaling pathways, melanoma, nutraceutical, Ribose synthesis |
Effect of Avemar and Avemar + vitamin C on tumor growth and metastasis in experimental animals
Because of the observed immunostimulatory actions of a new fermented wheat germ extract--with standardized benzoquinone composition--we have investigated the eventual tumor growth- and metastasis-inhibiting effects of this preparation (Avemar) applied alone or in combination with vitamin C. Tumor models of different origin [a highly metastatic variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice were applied. The metastasis-inhibiting effects of the treatments have been studied both in the presence and in the absence (following surgical removal) of the transplanted primary tumors. Combined treatments with Avemar and vitamin C—administered synchronously--profoundly inhibited the metastasis formation in all the applied tumor models while, treatments with vitamin C alone did not exert such an inhibiting effect on the metastasizing process. The degree of the observed metastasis inhibition in certain models was significant, while in others--although it was meaningful--did not prove to be significant. It is noteworthy that treatment with Avemar alone in certain models exerted a more pronounced inhibiting effect on metastasis formation than the synchronous combined treatment with Avemar and vitamin C. Furthermore, if the time schedule of the combined treatment was changed (vitamin C--instead of being administered synchronously--was given one hour after the treatments with Avemar), the vitamin C rather decreased the metastasis inhibiting effect of Avemar. It should be mentioned however, that in the case of rat nephroblastoma, a different response was observed: while, in the case of synchronous combination significant inhibition of metastasis formation was observed, treatment with Avemar alone did not produce metastasis-inhibition. It is noteworthy that in this model the metastasis-inhibiting effect of the synchronous combination treatment proved to be even more pronounced if Avemar was administered in a 100 times smaller dose than its regularly applied dosage. Treatment with Avemar and vitamin C--administered in combination or separately--in the majority of experimental models (with the exception of rat nephroblastoma) did not inhibit the growth of the primary tumors. It is reasonable, therefore, to suppose that in the observed metastasis-inhibiting effect the eventual proliferation inhibiting effect of these remedies does not play an important role. According to the results of other experiments--carried out in our laboratory in parallel with those described here--Avemar proved to have a meaningful immunostimulatory effect. It might therefore be suggested that the observed metastasis-inhibiting effect of this preparation may be mainly due to its immunostimulatory properties. The possible therapeutic benefits of Avemar and Avemar plus vitamin C are also discussed.
Effect of Avemar--a fermented wheat germ extract--on rheumatoid arthritis. Preliminary data
| Agarwal RP, Apáthy A, Bálint G, Blazsó G, Ehrenfeld M, Falkay G, Gaál M, Heimbach JT, Herbacek I, Hidvégi M, Kharkevitch GY, Paksy A, Resetár A, Shoenfeld Y, Szende B, Telekes A |
OBJECTIVE: To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA). METHODS: Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used.RESULTS: At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed. CONCLUSION:Supplementation of standard therapies with a continuous administration of Avemar is beneficial for RA patients.
Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients
| Babosa M, Borgulya G, Fekete G, Garami M, Hauser P, Hidvégi M, Kharkevitch GY, Müller J, Paksy A, Schuler D, Szabó E |
PURPOSE: An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (Avemar) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC. METHODS: Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups. RESULTS: During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05). CONCLUSIONS: The continuous supplementation of anticancer therapies with the medical nutriment MSC helps to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers.
| Avemar (MSC), cyclooxygenase, Dacarbazine, febrile neutropenia, fermented wheat germ extract, pediatric cancer |
Fermented wheat germ extract induces apoptosis and downregulation of major histocompatibility complex class I proteins in tumor T and B cell lines
| Demydenko D, Fajka-Boja R, Farkas E, Graser G, Hidvégi M, Ion G, Kennepohl E, Monostori E, Resetár A, Shoenfeld Y, Telekes A, Tömösközi-Farkas R, Vizler C |
The fermented wheat germ extract (code name: MSC, trade name: Avemar), with standardized benzoquinone content has been shown to inhibit tumor propagation and metastases formation in vivo. The aim of this study was to understand the molecular and cellular mechanisms of the anti-tumor effect of MSC. Therefore, we have designed in vitro model experiments using T and B tumor lymphocytic cell lines. Tyrosine phosphorylation of intracellular proteins and elevation of the intracellular Ca2+ concentration were examined using immunoblotting with anti-phosphotyrosine antibody and cytofluorimetry by means of Ca2+ sensitive fluorescence dyes, Fluo-3AM and FuraRed-AM, respectively. Apoptosis was measured with cytofluorimetry by staining the DNA with propidium iodide and detecting the cell population. The level of the cell surface MHC class I molecules was analysed with indirect immunofluorescence on cytofluorimeter using a monoclonal antibody to the non-polymorphic region of the human MHC class I. MSC stimulated tyrosine phosphorylation of intracellular proteins and the influx of extracellular Ca2+ resulted in elevation of intracellular Ca2+ concentration. Prominent apoptosis of 20-40% was detected upon 24 h of MSC treatment of the cell lines. As a result of the MSC treatment, the amount of the cell surface MHC class I proteins was downregulated by 70-85% compared to the non-stimulated control. MSC did not induce a similar degree of apoptosis in healthy peripheral blood mononuclear cells. Inhibition of the cellular tyrosine phosphatase activity or Ca2+ influx resulted in the opposite effect increasing or diminishing the Avemar induced apoptosis as well as the MHC class I downregulation, respectively. A benzoquinone component (2,6-dimethoxi-p-benzoquinone) in MSC induced similar apoptosis and downregulation of the MHC class I molecules in the tumor T and B cell lines to that of MSC. These results suggest that MSC acts on lymphoid tumor cells by reducing MHC class I expression and selectively promoting apoptosis of tumor cells on a tyrosine phosphorylation and Ca2+ influx dependent way. One of the components in MSC, 2,6-dimethoxi-p-benzoquinone was shown to be an important factor in MSC mediated cell response.
A multicentric prospective open trial on the quality of life and oxidative stress in patients affected by advanced head and neck cancer treated with a new benzoquinone-rich product derived from fermented wheat germ (Avemar)
| Cella F, Chiavenna G, Ferrari C, Giannoni A, Iyer A, Kharkevitch GY, Nichelatti M, Ragni G, Ronzani G, Rovera GM, Sukkar SG |
Abstract Background and aim: Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name Avemar) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of Avemar in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods: A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with Avemar in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the Avemar group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results: The levels of OS significantly decreased after 2 months in the group receiving Avemar (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in Avemar has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer.
| D-ROMs test, diabetes, DOCA-salt, fermented wheat germ extract, Head and neck cancer, hypertension, metabolic syndrome, Oxidative stress, Quality of life, remodeling |
First clinical data of a natural immunomodulator in colorectal cancer
BACKGROUND/AIMS: MSC (trade-name AVEMAR) is a per os applicable complex of multiple, biologically active molecules obtained from fermented wheat-germ extract. Preclinical studies suggest potent anti-metastatic activity and it has a favorable toxicity profile. It has been aimed in a pilot-scale, phase II clinical study to document whether or not MSC as a support to surgery or plus chemotherapy adds any therapeutic benefit compared to the same combination without MSC in colorectal cancer. METHODOLOGY: From 1998 to June 1999, 18 control patients and 12 consecutive colorectal cancer patients respectively, were enrolled into this study. All patients underwent curative surgery. The control group (18 patients) received no other therapy or adjuvant chemotherapy alone. The MSC group (12 patients) received MSC alone or plus adjuvant chemotherapy. Until now, the median follow-up has been 9 months. RESULTS: Interim data of the study document that in the MSC group no new metastases, neither hepatic nor other, have occurred, so far. On the contrary, several new metastases have developed in the control group. CONCLUSIONS: Orally administered MSC is a potent candidate to be regarded as a supportive therapy to surgery or plus chemotherapy for colorectal cancer patients.
| Avemar, colorectal cancer, combination therapy, fermented wheat germ extract, growth inhibition, metastasis, phase II clinical trial, supportive therapy |
Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells
| Balogh A, Boren J, Boros LG, Cascante M, Hidvégi M, Lapis K, Marin S, Semjen G, Szende B, Tömösközi-Farkas R |
The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption. uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation-related and cell differentiation-related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation-related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture.
| Avemar, Avemar pubmed, Cell proliferation, fermented wheat germ extract, Nonoxidative glucose metabolism, Pentose cycle, Ribose synthhesis |
Effect of Avemar--a fermented wheat germ extract--on rheumatoid arthritis. Preliminary data
| Agarwal RP, Apáthy A, Bálint G, Blazsó G, Ehrenfeld M, Falkay G, Gaál M, Heimbach JT, Herbacek I, Hidvégi M, Kharkevitch GY, Paksy A, Resetár A, Shoenfeld Y, Szende B, Telekes A |
OBJECTIVE: To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA). METHODS: Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used.RESULTS: At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed. CONCLUSION:Supplementation of standard therapies with a continuous administration of Avemar is beneficial for RA patients.
Effect of Avemar and Avemar + vitamin C on tumor growth and metastasis in experimental animals
Because of the observed immunostimulatory actions of a new fermented wheat germ extract--with standardized benzoquinone composition--we have investigated the eventual tumor growth- and metastasis-inhibiting effects of this preparation (Avemar) applied alone or in combination with vitamin C. Tumor models of different origin [a highly metastatic variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice were applied. The metastasis-inhibiting effects of the treatments have been studied both in the presence and in the absence (following surgical removal) of the transplanted primary tumors. Combined treatments with Avemar and vitamin C—administered synchronously--profoundly inhibited the metastasis formation in all the applied tumor models while, treatments with vitamin C alone did not exert such an inhibiting effect on the metastasizing process. The degree of the observed metastasis inhibition in certain models was significant, while in others--although it was meaningful--did not prove to be significant. It is noteworthy that treatment with Avemar alone in certain models exerted a more pronounced inhibiting effect on metastasis formation than the synchronous combined treatment with Avemar and vitamin C. Furthermore, if the time schedule of the combined treatment was changed (vitamin C--instead of being administered synchronously--was given one hour after the treatments with Avemar), the vitamin C rather decreased the metastasis inhibiting effect of Avemar. It should be mentioned however, that in the case of rat nephroblastoma, a different response was observed: while, in the case of synchronous combination significant inhibition of metastasis formation was observed, treatment with Avemar alone did not produce metastasis-inhibition. It is noteworthy that in this model the metastasis-inhibiting effect of the synchronous combination treatment proved to be even more pronounced if Avemar was administered in a 100 times smaller dose than its regularly applied dosage. Treatment with Avemar and vitamin C--administered in combination or separately--in the majority of experimental models (with the exception of rat nephroblastoma) did not inhibit the growth of the primary tumors. It is reasonable, therefore, to suppose that in the observed metastasis-inhibiting effect the eventual proliferation inhibiting effect of these remedies does not play an important role. According to the results of other experiments--carried out in our laboratory in parallel with those described here--Avemar proved to have a meaningful immunostimulatory effect. It might therefore be suggested that the observed metastasis-inhibiting effect of this preparation may be mainly due to its immunostimulatory properties. The possible therapeutic benefits of Avemar and Avemar plus vitamin C are also discussed.