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ORGANIC GERMANIUM / GERMANIUM SESQUIOXIDE — SCIENCE WEBSITE
The Authoritative Germanium Sesquioxide Resource
Welcome to the most comprehensive compilation of published abstracts for germanium sesquioxide studies. The goal of this website is to provide rapid access to public information in a format which is simple to navigate. While examining the content contained on this site, we urge you to keep in mind an important fact. Having something peer reviewed and published lends a certain level of credibility. However, we are all subject to the frailties and errors of being human. For this reason, you will find information which is apparently contradicting. If we look closely, there is always a logical explanation as to why such contradictions surface but this extends beyond the scope and purpose of the site and is best addressed in a different forum.
Bis(2-carboxyethylgermaniumsesquioxide)
Germanium Sesquioxide, Ge-132, Organic Germanium, Propagermanium, Repagermanium.
Essential Definitions:
Spirogermanium, Germanium Dioxide, Germanium Lactate Citrate, Organic Germanium, Inorganic Germanium.
•Analytical •Antimutagenic •Antioxidant •Antiviral •Arthritis •Atherosclerosis •Bioavailability •Cancer •Cataracts •Cervix •DNA Repair •Fibrosis •Free Radical Scavenging •Hazards •Heart •History •Immune System •Kidneys •Inflammation •Liver •Osteoporosis •Pain Management •Pharmacology •Reviews •Safety •Uterus
[Determination of GeO2 in germanium-132 by phenylfuorone] Guang Pu Xue Yu Guang Pu Fen Xi. 1999 Aug;19(4):585-6.
Dong Y, Shen H.
Changzhou Sanitation and Anti-epidemic Station, 213003 Changzhou.
Inorganic (GeO2) in carboxyethyl germanium sesquioxide (germanium-132) was determined by phenylfuorone spectrometry. The method is convenient and has good precision and accuracy. The recovery of GeO2 is 93%-107%.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=
15818963&query_hl=2&itool=pubmed_DocSum
[Respective determination of inorganic germanium and germanium-132 in foods]Guang Pu Xue
Yu Guang Pu Fen Xi. 1998 Feb;18(1):77-80.
Chen Q, Yang H.
Research Center for Eco-Environmental Sciences, Academia Sinica, 100085 Beijing.
Inorganic germanium and carboxyethyl germanium sesquioxide (germanium-132) in health drinks were respectively determined by hydride generation-atomic fluorescence spectrometry (HG-AFS). The conditions of respective determination of inorganic germanium and germanium-132 in natural foods
were preliminarily discussed.
Analytical product study of germanium-containing medicine by different ICP-MS applications.
J Trace Elem Med Biol. 2004;18(1):9-16.
Krystek P, Ritsema R.
Laboratory for Analytical Chemistry, National Institute for Public Health and the Environment (RIVM) P.O. Box 1, 3720 BA Bilthoven, The Netherlands. petra.krystek@rivm.nl
For several years organo-germanium containing medicine has been used for special treatments of e.g. cancer and AIDS. The active substances contain germanium as beta-carboxyethylgermanium sesquioxide ((GeCH2CH2COOH)203/"Ge-132"), spirogermanium, germanium-lactate-citrate or unspecified forms. For humans, germanium is not essential and in general the toxicity of the mentioned organo-germanium compounds is low. Acute and chronic toxic effects of inorganic germanium dioxide have been demonstrated. It is obvious that especially inorganic germanium has a higher potential of negative effects. Therefore, a widespread analytical product control is indispensable. Inductively coupled plasma mass spectrometry (ICP-MS) is the preferred technique and different applications were developed for controlling various parameters: (i) A speciation method using high performance liquid chromatography (HPLC) coupled with quadrupole (Q-) ICP-MS was developed for the identification of organo-germanium species in medicine. (ii) The nuclear magnetic resonance (NMR) technique was applied to confirm the molecular structure and to determine the molecule concentration. (iii) The total concentration of germanium in the medicine was determined in the diluted sample by high resolution (HR-) ICP-MS. (iv) For a general overview, a multi-element screening method of 56 elements with HR-ICP-MS was developed. The semi-quantitative mode was used for quantification and elements of higher abundance are reported. (v) Investigations about matrix-based interferences on masses of isotopes, which are generally determinable without remarkable problems. Isotopes like e.g. 85Rb, 88Sr, 89y, 90Zr, 93Nb and the isotopes of Ba are strongly interfered by different Ge-based molecules and need to be analysed in a higher resolution mode than used for other common matrices.
Prevention of trabecular bone loss in the mandible of ovariectomized rats. J Oral Sci. 2004 Jun; 46(2):75-85.
Jiang G, Matsumoto H, Yamane J, Kuboyama N, Akimoto Y, Fujii A.
Department of Pharmacology, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
The effect of therapeutic agents on trabecular bone loss in the mandible was investigated in ovariectomized rats. Eighty-seven Wistar SPF female rats were ovariectomized (OVX) or given a sham operation (Sham), and maintained on a diet containing 0.1% calcium. Four weeks later, groups of OVX rats were treated with estriol (E3), calcitonin (CT), etidronate, or 2-carboxyethylgermanium sesquioxide (Ge-132). The Basal group was maintained on a diet containing 1.0% calcium, and the OVX and sham groups on a diet containing 0.1% calcium. The trabecular bone mineral density (BMD) and trabecular bone mineral content (BMC) in 11 mandibular slices from 0.5 mm at the mesial margin of the first molar to 0.5 mm at the distal margin of the third molar, were measured using peripheral Quantitative Computed Tomography (pQCT). The BMD in the OVX group was lower than that in the Sham group, and decreased BMC was observed only in the molar region. BMD and BMC were increased in the etidronate-treated group, but only BMC was increased in the CT group. E3 treatment increased BMD and BMC; significant increases were also observed beneath the molar. Ge-132 treatment increased both BMD and BMC, especially the latter.
Germane facts about germanium sesquioxide: II. Scientific error and misrepresentation. J Altern Complement Med. 2004 Apr;10(2):345-8.
Kaplan BJ, Andrus GM, Parish WW.
Departments of Paediatrics, and Community Health Sciences, Faculty of Medicine, University of Calgary, and Alberta Children's Hospital, Calgary, Alberta, Canada. kaplan@ucalgary.ca
The preceding paper reviewed the anticancer properties and safety of bis (2-carboxyethylgermanium) sesquioxide (CEGS). An examination of those data leads one to question why this information has not stimulated clinical trials in patients with cancer. The answer is discussed in this paper, which traces the history to an error published in the scientific literature in 1987. The reliance by subsequent authors on secondary sources, citing only the error and not the correction published in 1988, constitutes part of the explanation of why CEGS has been neglected. A second factor is also considered: careless reporting about any germanium-based compound as if the many thousands of germanium compounds were all the same. This combination of a publication error, careless writing, and the reliance on secondary sources appears to be responsible for the neglect of the potential clinical use of this unique germanium compound.
Reviews, History, Cancer,
Germane facts about germanium sesquioxide: I. Chemistry and anticancer properties. J Altern Complement Med. 2004 Apr;10(2):337-44.
Kaplan BJ, Parish WW, Andrus GM, Simpson JS, Field CJ.
This paper reviews the history, chemistry, safety, toxicity, and anticancer effects of the organogermanium compound bis (2-carboxyethylgermanium) sesquioxide (CEGS). A companion review follows, discussing the inaccuracies in the scientific record that have prematurely terminated research on clinical uses of CEGS. CEGS is a unique organogermanium compound first made by Mironov and coworkers in Russia and, shortly thereafter, popularized by Asai and his colleagues in Japan. Low concentrations of germanium occur in nearly all soils, plants and animal life; natural occurrence of the CEGS form is postulated but not yet demonstrated. The literature demonstrating its anticancer effect is particularly strong: CEGS induces interferon-gamma (IFN-gamma), enhances natural killer cell activity, and inhibits tumor and metastatic growth--effects often detectable after a single oral dose. In addition, oral consumption of CEGS is readily assimilated and rapidly cleared from the body without evidence of toxicity. Given these findings, the absence of human clinical trials of CEGS is unexpected. Possible explanations of why the convincing findings from animal research have not been used to support clinical trials are discussed. Clinical trials on CEGS are recommended.
Free Radical Scavenging
Studies on the hydroxyl free radical-scavenging effect of combined selenium and germanium. Wei Sheng Yan Jiu. 2001 Jul;30(4):208-10.
Wu Z, Chen X, Yang K, Xia T.
Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
The effect of selenium, carboxyethyl-germanium sesquioxide (Ge-132) and the combination of selenium and Ge-132 on the production of hydroxyl free radical in liver microsomes of rats treated with Fe2SO4-NADPH system was studied with electron spin resonance technique (ESR). The results showed that the production of hydroxyl free radical was decreased significantly by adding selenium, Ge-132 and combined selenium and Ge-132, indicating a direct scavenging effect on hydroxyl free radical. It was also observed a enhanced scavenging effect at the low concentration of combined selenium and Ge-132.
An observation of antiproliferative effect of germanium-132 on cultured pterygium fibroblasts. Zhonghua Yan Ke Za Zhi. 2000 Jul;36(4):263-6, 16.
Liu Y, Sun X, Li B, Wang J.
Beijing Institute of Ophthalmology, Beijing 100005, China.
OBJECTIVE: To detect the antiproliferation of carboxyethyl germanium sesquioxide (Ge-132) on fibroblasts of pterygium in vitro and try to find a potentially effective agent for treatment of primary pterygium and prevention of its postoperative recurrence. METHODS: Primary culture and subculture of pterygium fibroblasts were established in vitro. Different concentrations of Ge-132 (39 - 5,000 mg/L) or mitomycin-C (3.13 - 4.00 mg/L, the control) were added to the fibroblast culture of the third or forth passage respectively. The inhibitory effect was determined by MTT (tetrazolium bromide) method. The influence of addition of Ge-132 on the growth curve of fibroblasts was observed, and the changing expression of proliferating cell nuclear antigen (PCNA) in fibroblasts was studied by immunohistochemical method. RESULTS: The addition of Ge-132 in the culture caused significant inhibition of the fibroblast proliferation in dose dependent manner (625 - 50,000 mg/L) without cytotoxicity (IC(50) = 3,000 mg/L), the marked descent of growth curve and suppression of the expression of PCNA in cultured cells (P < 0.01). CONCLUSION: Ge-132 can inhibit the proliferation of pterygium fibroblast in vitro significantly.
Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium. J Korean Med Sci. 2001 Dec; 16 Suppl:S42-53.
Bespalov VG, Alexandrov VA, Limarenko AY, Voytenkov BO, Okulov VB, Kabulov MK, Peresunko AP, Slepyan LI, Davydov VV.
Group of Cancer Chemoprevention, N.N. Petrov, Research Institute of Oncology of the Ministry of Health of the Russian Federation, St. Petersburg, Russia.
The anticarcinogenic effects and mechanisms of the biotechnological drugs of Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, were studied. Bioginseng was produced from a tissue culture of ginseng root cultured on standard medium, whereas panaxel and panaxel-5 were produced from ginseng tissue root cultures using standard mediums enriched with 2-carboxyethylgermanium sesquioxide and 1-hydroxygermatran-monohydrate respectively. All three ginseng drugs inhibited the development of mammary tumors induced by intramammary injections of N-methyl-N-nitrosourea (MNU) in rats, the development of the brain and spinal cord tumors induced by transplacental administration of N-ethyl-N-nitrosourea (ENU) in rats, and the development of uterine, cervical and vaginal tumors induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene (DMBA) in mice. The ginseng drugs induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs exposed to cyclophosphamide, and stimulated the production of thyroid hormones in rats. These mechanisms may contribute to the anticarcinogenic action of the ginseng drugs. The organic germanium compounds present in panaxel and panaxel-5 did not potentiate the anticarcinogenic or immuno- stimulatory effects as much as biogeinseng. Preliminary clinical trials with panaxel and bioginseng were carried out in patients with precancerous lesions of the esophagus and endometrium. Panaxel was found to have a strong therapeutic effect in patients suffering from chronic erosive esophagitis. Bioginseng induced the regression of adenomatous-cystic hyperplasia of the endometrium in some patients. Thus, we conclude that the drugs of ginseng appear to hold considerable promise for future cancer chemoprevention.
Effect of germanium-132 on low-density lipoprotein oxidation and atherosclerosis in Kurosawa and Kusanagi hypercholesterolemic rabbits. Biosci Biotechnol Biochem. 2001 Aug;65(8):1893-6.
Wakabayashi Y.
Department of Medicine, University of Kitasato Medical School, Sagamihara, Japan. yasiwaka@med.kitasato-u.ac.jp
Germanium-132 (Ge-132) was given at 200 mg/kg of body weight to 8-week-old Kurosawa and Kusanagi hypercholesterolemic (KHC) rabbits. Thirty-six weeks later, the susceptibility of plasma low-density lipoprotein to oxidation and the morphology of atherosclerosis in the aorta and coronary artery were investigated. Treatment with Ge-132 resulted in decreases in the oxidation rate and in the formation rate of thiobarbituric acid-reactive substances following copper-induced oxidation of LDL. Ge-132 is suggested to possess antioxidative properties, but this did not lead to any attenuation of atherosclerotic progression in the KHC rabbits.
Complete remission of pulmonary spindle cell carcinoma after treatment with oral germanium sesquioxide. Chest. 2000 Feb;117(2):591-3.
Mainwaring MG, Poor C, Zander DS, Harman E.
Department of Medicine, Divisions of Hematology and Oncology, University of Florida College of Medicine and Veterinary Affairs Medical Center, Gainesville, FL 32610, USA. mainwmg@medicine.ufl.edu
Spindle cell carcinoma (SCC) is a rare form of lung cancer representing 0.2 to 0.3% of all primary pulmonary malignancies. Even with combined surgery, chemotherapy, and radiation therapy, these tumors are associated with a poor prognosis and only 10% of patients survive 2 years after diagnosis. We describe a patient with an unresectable SCC who, following no response to conventional treatment with combined modality therapy, chose to medicate herself with daily doses of germanium obtained in a health food store. She noted prompt symptomatic improvement and remains clinically and radiographically free of disease 42 months after starting her alternative therapy.
Antioxidant, Liver
Protective role of germanium-132 against paraquat-induced oxidative stress in the livers of senescence-accelerated mice.
J Toxicol Environ Health A. 1999 Nov 12;58(5):289-97.
Yang MK, Kim YG.
Department of Biological Science, College of Natural Sciences, Chosun University, Dong-ku, Kwangju, Korea.
The effects of the synthetic antioxidant germanium (Ge-132) were studied on liver oxidant damage induced by paraquat (PQ) in senescence-accelerated mice (SAM). PQ administered intravenously to SAM-P/8 (susceptible) or SAM-R/1 (resistant) mice increased liver DNA strand breakage and malondialdehyde (MDA) levels, indicators of oxidant damage. Ge-132 effectively blocked the PQ-induced effects on liver DNA strand breaks and MDA levels. In addition, Ge-132 significantly elevated the activities of hepatic superoxide dismutase (SOD) and catalase following PQ pretreatment. Histopathologically, Ge-132 inhibited PQ-induced hepatic mitochondrial injury in both strains, but more effectively in the susceptible strain. Data suggest that Ge-132 may be useful as an antioxidant in view of its ability to prevent PQ-induced hepatic oxidant injury.
Pharmacokinetics of germanium after po beta-carboxyethylgermanium sesquioxide in 24 Chinese volunteers. Zhongguo Yao Li Xue Bao. 1996 Sep;17(5):415-8.
Long QC, Zeng GX, Zhao XL.
Department of Clinical Pharmacology, Sun Yat-Sen University of Medical Sciences, Guangzhou, China.
AIM: To compare the pharmacokinetics after po different doses of beta-carboxyethylgermanium sesquioxide (Ge-132). METHODS: An atomic absorption spectrophotometric system was used to measure germanium concentrations in plasma and urine samples after po Ge-132 1 (low dose, LD), 2.5 (medium dose, MD), and 4 (high dose, HD) g.m-2 in 24 healthy volunteers (one dose per 8 subjects). RESULTS: T1/2 alpha (LD, 1.2 +/- 0.7 h; MD, 1.1 +/- 0.6 h; HD, 1.2 +/- 0.5 h), T1/2 beta (LD, 5.2 +/- 1.2 h; MD, 5.8 +/- 2.5 h; HD, 5.5 +/- 1.4 h) and Cl/F (LD, 33 +/- 12 L.h-1; MD, 35 +/- 10 L.h-1; HD, 33 +/- 11 L.h-1) were not dose-related. Tmax was between 0.75 h and 2 h. Cmax (LD, 5.3 +/- 2.2 mg.L-1; MD, 13 +/- 5 mg.L-1; HD 18 +/- 8 mg.L-1, HD) and AUC (LD, 31 +/- 13 mg.h.L-1; MD, 60 +/- 16 mg.h.L-1; HD, 79 +/- 42 mg.h.L-1) were positive correlation to the dose of Ge-132. Urine-eliminated germanium within 24 h accounted for 11 +/- 3% of LD, 9 +/- 3% of MD, and 6 +/- 5% of HD (calculated from Ge/F) and showed a negative correlation to the dose. CONCLUSION: 1) Intracorporal process of Ge after po Ge-132 coincided with the first-order absorption and elimination with two-compartment kinetic model; 2) The amount of germanium eliminated in urine was below 11%.
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[Effect of dietary selenium and germanium on the precancerous lesion in rat glandular stomach induced by N-methyl-N'-nitro-N-nitrosoguanidine] Zhonghua Wai Ke Za Zhi. 1996 Apr;34(4):221-3.
Ming X, Yin H, Zhu Z.
Department of Surgery, Ruijin Hospital Shanghai Second Medical University.
N-Methyl-N'-nitrosoguanidine (MNNG) was administered (100 mg/L) in drinking water in 100 Wistar rats for 24 weeks to induce the precancerous lesion in glandular stomach. 77 rats with the precancerous lesion in glandular stomach were divided into 3 groups randomly at the 25 thweek. Yeast selenium (Yse, 4 mg/L) and carboxyethyl germanium sesquioxide (Ge-132, 600 mg/L) in drinking water were administered respectively in the corresponding treatment groups: 100 ml/MNNG in drinking water was administered in the treatment group, and 100 ml/MNN in drinking water was administered in the treatment group and control group for another 5 weeks. The experiment ended at the end of the 37th week. The results showed that the incidence of glandular stomach cancer in the Yse group was significantly lower than that in the control group; the infiltrating depth of glandular stomach cancer in the Yse group and the Ge-132 group was remarkably shallower than that in the control group. These findings suggest that Yse and Ge-132 have some preventive effect on the precancerous lesion in rat glandular stomach induced by MNNG.
Effect of pretreatment of germanium-132 on Na(+)-K(+)-ATPase and galactose cataracts. Curr Eye Res. 1997 Aug;16(8):832-7.
Unakar NJ, Tsui J, Johnson M.
Department of Biological Sciences, Oakland University, Rochester, MI, USA.
PURPOSE: Recently, we reported that topical administration of 2-carboxyethyl germanium sesquioxide (Ge-132) concurrently with 50% galactose feeding delayed the establishment of mature cataracts and reduced advance glycation product. This study was to determine the effect of pretreatment of Ge-132 on galactose associated morphological changes and Na(+)-K(+)-ATPase activity. METHODS: Young Sprague Dawley rats received topical eye drops four times a day of either saline or Ge-132 seven days prior to the 50% galactose diet and during galactose feeding. At desired intervals the lenses were extracted, photographed and processed for either light microscopy, scanning electron microscopy or the determination of Na(+)-K(+)-ATPase activity. RESULTS: In Ge-132 pretreated lenses as compared to saline pretreated lenses the following results were observed: (a) the galactose-induced morphological alterations in the majority of lenses were delayed and (b) Na(+)-K(+)-ATPase activity was protected. CONCLUSIONS: Our previous and current studies show that in addition to osmotic stress post-translational protein modification, such as glycation, including enzymes may play a role in initiating changes that lead to cataract development. The inhibition of protein glycation by antiglycating compounds, such as Ge-132, delays sugar cataract formation. Currently, we are investigating the status of protein glycation and advanced glycation end products following pretreatment with Ge-132 and the role of Ge-132 on the activities of enzymes such as aldose reductase and Na(+)-K(+)-ATPase.
Hazard assessment of germanium supplements. Regul Toxicol Pharmacol. 1997 Jun;25(3):211-9.
Tao SH, Bolger PM.
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204, USA.
Germanium-containing dietary supplements became popular in the 1970s in Japan and later in other countries, as elixirs for certain diseases (e.g., cancer and AIDS). Germanium is not an essential element. Its acute toxicity is low. However, at least 31 reported human cases linked prolonged intake of germanium products with renal failure and even death. Signs of kidney dysfunction, kidney tubular degeneration, and germanium accumulation were observed. Other adverse effects were anemia, muscle weakness, and peripheral neuropathy. Recovery of renal function is slow and incomplete even long after germanium intake was stopped. The total dose of ingested germanium (as dioxide, carboxyethyl germanium sesquioxide, germanium-lactate-citrate, or unspecified forms) varied from 15 to over 300 g; the exposure duration varied from 2 to 36 months. In laboratory animals, elevated germanium in tissues and impaired kidney and liver function were observed in a life-time drinking water (5 ppm germanium) study. Other toxicities associated with ingested germanium products in human cases were also demonstrated in animal studies with germanium dioxide and sometimes other germanium compounds. Based on the evidence of persistent renal toxicity associated with germanium dioxide, the lack of conclusive findings of differential nephrotoxicity of organic germanium compounds, and the possibility of contamination of the organic germanium products with inorganic germanium, it is clear that germanium products present a potential human health hazard.
Study on the analysis of organogermanium compounds by ion chromatography Se Pu. 1997 May;15(3):240-2.
Chen Q, Mou S, Hou X, Ni Z.
Research Center for Eco-Environmental Sciences, the Chinese Academy of Sciences, Beijing, 100085.
A new high performance ion exchange chromatographic method for separation and determination of three organogermanium compounds beta-carboxyethylgermanium sesquioxide (I), beta-(alpha-methyl) carboxyethylgermanium sesquioxide (II) and di-(beta-carboxyethyl) germanium hydroxide (III) has been developed. A Dionex DX-300 Ion Chromatograph equipped with a Dionex PED-II pulsed electrochemical detector (conductivity mode), a Dionex AMMS-1 anion micromembrane suppressor, and a Dionex ACI advanced computer interface coupled with AI-450 chromatographic software was employed. The separation was achieved by using a Dionex IonPac AS4A-SC column as analytical column, sodium tetraborate solution as eluent, and sulfuric acid solution as regenerant. For reducing run time, a gradient program was chosen. The detection limits (S/N = 3, expressed as germanium) for the three compounds were 0.038mg/L (I), 0.035mg/L (II) and 0.025mg/L (III), respectively. The method has been applied to the analysis of two tonic oral drinks, and the average recoveries for the three compounds ranged from 95%-101%. The results obtained were in agreement with those of hydride generation atomic fluorescence spectrometry (HG-AFS).
2-Carboxyethylgermanium sesquioxide, a synthetic organogermanium compound, as an inducer of contrasuppressor T cells. Experientia. 1996 Feb 15;52(2):159-66.
Ikemoto K, Kobayashi M, Fukumoto T, Morimatsu M, Pollard RB, Suzuki F.
Department of Neurology, Yamaguchi University of Medical School, Japan.
2-Carboxyethylgermanium sesquioxide (Ge-132), a synthesized organogermanium compound with immunomodulating activities, was shown to be an inducer of anti-suppressor T cells in normal mice. The suppressor cell activity of T6S cells, a clone of burn-induced CD8+ IL-4-producing suppressor T cells, was clearly inhibited when a mixed lymphocyte-tumor cell reaction of the clone was conducted with splenic mononuclear cells from mice treated orally with a 100 mg/kg dose of Ge-132. The activity of anit-suppressor cells was demonstrated in spleens of mice 2 days after treatment with Ge-132 and reached its peak on day 3. The anti-suppressor cells induced by the compound were of a contrasuppressor T cell-linage, because they were characterized as CD4+ CD28+ TCRalpha/beta+ Vicia villosa lectin-adherent T cells. These cells produced IFN-gamma but did not produce IL-2, IL-4, IL-6 or IL-10 in their culture fluids. CD4+ anti-suppressor T cells induced by Ge-132 may be different from other subsets of CD4+ T cells because Th1 and Th2 cells generated in our laboratory did not adhere to Vicia villosa lectin-coated petri dishes, and each produced specific cytokines. Th1 cells produced IFN-gamma and IL-2 while Th2 cells produce IL-4 and IL-10 in vitro. These results suggest that Ge-132 may be useful as an inducer of contrasuppressor T cells in immunocompromised individuals bearing suppressor T cells. To eliminate suppressor T cells from immunocompromised hosts may result in improved resistance from various opportunistic infections.
Effect of germanium-132 on galactose cataracts and glycation in rats. Exp Eye Res. 1995 Aug;61(2):155-64.
Unakar NJ, Johnson M, Tsui J, Cherian M, Abraham EC.
Department of Biological Sciences, Oakland University, Rochester, MI 48309-4401, USA.
Germanium compounds have been shown to be effective in preventing the formation of advanced glycation end-products and for reversible solubilization of glycated proteins. As protein glycation has been proposed to play a role in lens opacification, we initiated studies to evaluate the effects of 2-carboxyethyl germanium sesquioxide (germanium compound 132 or Ge-132) on galactose-induced cataractogenesis. For this study young Sprague-Dawley rats were fed a 50% galactose diet. One group of rats received topical saline and another group was administered Ge-132 in saline four times a day. The lenses were periodically examined with an ophthalmoscope and at desired intervals processed for light and scanning electron microscopy. Our observations, beginning at 3 days and continuing to 21 days of galactose feeding, exhibited the characteristic galactose-induced morphological alterations, which include the formation of vacuoles, cysts, membrane disruption and swelling of fibers and epithelial cells as well as disorganization of the bow in lenses of rats in both groups. However, in the majority of rats administered Ge-132 these alterations were delayed as compared to the lenses of rats administered saline. Our findings show that, although the initiation, progression and pattern of lens opacification in rats receiving saline and Ge-132 were similar, in the majority of lenses the progression and establishment of mature cataracts in the Ge-132 group of rats were delayed. Analysis of the water-soluble and water-insoluble lens-protein fractions for glycated proteins showed increased levels of the Amadori products and advanced glycation related fluorescent products in galactosemic rats treated with saline eye drops. In rats receiving the topical Ge-132 treatment the levels of these glycation products were substantially reduced to levels lower than control values. Prevention of glycation seems to be a mechanism by which cataract progression is delayed.
Physiology, Bioavilability
[Absolute and relative bioavailability of germanium in the rabbit] J Pharm Belg. 1994 Sep-Oct;49(5):395-401. [Article in French]
Anger FS, Anger JP, Sado PA, Chevanne F.
Laboratoire de Toxicologie, Faculte des Sciences Pharmaceutiques et Biologiques, Rennes.
The debated consumption of germanium suggested the authors to compare biopharmaceutical parameters of germanium oxide and germanium sesquioxide. A first evaluation, in rabbit, has been based on Germanium blood levels determined by atomic absorption spectrometry, after cross administration of both products by the I.V. and oral routes. When given orally, the apparent oxide bioavailability is very low (about 10%) but better than that of the sesquioxide. That difference could result from differences of disposition parameters of both products, which have to be studied late.
Effects of 2-carboxythylgerumanium sesquioxide (Ge-132) as an immunological modifier of post-surgical immunosuppression in dogs. J Vet Med Sci. 1993 Oct;55(5):795-9.
Nakada Y, Kosaka T, Kuwabara M, Tanaka S, Sato K, Koide F.
Department of Veterinary Radiology, College of Agriculture and Veterinary Medicine, Nihon University, Kanagawa, Japan.
The effect of 2-carboxythylgerumanium sesquioxide (Ge-132) as an interferon-gamma (IFN-gamma) inducer on post-surgical immunosuppression was evaluated from the immunological response augmented in canine neutrophils, macrophages and peripheral blood lymphocytes (PBL) using the chemiluminescence technique. Experimental gastrotomy was performed on dogs in two groups; one group was subjected to sham-surgery without any medication, and the other was treated by Ge-132 administration at 24 hr before operation. Although the phagocytic activities of neutrophils, macrophages and PBL in the sham-operated group were depressed transiently after surgery, those in the Ge-132-administered group (Ge-132 group) were enhanced for a long time after surgery. It appeared that the generated free radical, which blocked the phagocytosis of macrophages and PBL, was activated by IFN-gamma. These results suggest that Ge-132 pre-treatment may be efficacious and useful in preventing the multifaceted clinical symptoms induced by post-operative immunosuppression in dogs.
Immunothermotherapy and related TNS induction in mice. J Vet Med Sci. 1993 Jun;55(3):471-3.
Kuwabara M.
Induction of tumor necrosis factor in sera (TNS) as a multidisciplinary cancer therapy by the administration of a combination of 2-carboxyethylgermanium sesquioxide (Ge-132) and lipopolysaccharide (LPS) on Meth-A sarcoma-bearing mice was attempted. In addition to the above TNS induction therapy (TNS therapy) per se, the potential on the above parameters by employing a multidisciplinary cancer therapy (immunothermotherapy), in which TNS therapy was coupled with regional hyperthermia treatment, was investigated. This immunothermotherapy enhanced the antitumor effects produced by the above TNS therapy.
Questionable methods of cancer management: hydrogen peroxide and other 'hyperoxygenation' therapies. CA Cancer J Clin. 1993 Jan-Feb;43(1):47-56.
"Hyperoxygenation" therapy--also called "oxymedicine," "bio-oxidative therapy," "oxidative therapy," and "oxidology"--is a method of cancer management based on the erroneous concept that cancer is caused by oxygen deficiency and can be cured by exposing cancer cells to more oxygen than they can tolerate. The most highly touted "hyperoxygenating" agents are hydrogen peroxide, germanium sesquioxide, and ozone. Although these compounds have been the subject of legitimate research, there is little or no evidence that they are effective for the treatment of any serious disease, and each has demonstrated potential for harm. Therefore, the American Cancer Society recommends that individuals with cancer not seek treatment from individuals promoting any form of hyperoxygenation therapy as an "alternative" to proven medical modalities.
Decreased plasma superoxide scavenging activity in immunological disorders--carboxyethylgermanium sesquioxide (Ge-132) as a promoter of prednisolone. Biotherapy. 1992;4(1):1-8.
Pronai L, Arimori S.
Fourth Department of Internal Medicine, Tokai University School of Medicine, Kanagawa-ken, Japan.
We investigated so-called superoxide scavenging activity (SSA) of plasma in patients with several immunological disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), polymyo-dermatomyositis (PM), progressive systemic sclerosis (PSS), myasthenia gravis (MG) and autoimmune thyroid disease (AT), using the electron paramagnetic resonance/spin trapping technique. Since carboxyethylgermanium sesquioxide, Ge-132, has been reported to modulate both the immune response and leukocyte functions, we have studied in vivo effect of Ge-132 on plasma SSA and other laboratory parameters in these disorders. The plasma SSA was significantly lower in RA, SLE, PM and PSS, but not in MG and AT, as compared with that in healthy controls. An inverse correlation was observed between plasma SSA and parameters such as erythrocytes sedimentation rates, absolute number of leukocytes, C-reactive protein and serum globulin levels. Furthermore, plasma SSA was significantly decreased in rheumatoid factor-positive patients as compared to negative patients. No correlation was observed between plasma SSA and factors such as ages, sex of patients or the other laboratory parameters, such as serum albumin, triglyceride, cholesterol, hemoglobin and serum iron levels. Patients treated with prednisolone, especially ones with RA, showed an increase of plasma SSA. It appears that Ge-132 promotes prednisolone effects. Our results indicate that a decrease in plasma SSA is not disease specific, but inversely correlates with the severity and activity of inflammation. The methodology to measure plasma SSA presented in this work provides a helpful tool for determining the actual activity of the diseases as well as in vivo studies of antiinflammatory agents.
Preventive effect of a synthetic immunomodulator, 2-carboxyethylgermanium sesquioxide, on the generation of suppressor macrophages in mice immunized with allogeneic lymphocytes. Immunopharmacol Immunotoxicol. 1992;14(4):841-64.
Kobayashi H, Aso H, Ishida N, Maeda H, Schmitt DA, Pollard RB, Suzuki F.
Asai Germanium Research Institute, Tokyo, Japan.
The effect of 2-carboxyethylgermanium sesquioxide (Ge-132) on the generation of splenic suppressor macrophages (S-M phi) in C3H/He mice (H-2k) immunized with allogeneic spleen cells from C57Bl/6 mice (H-2b) was investigated. We have previously demonstrated that S-M phi expressing I-J antigen, which appeared during alloimmunization, inhibited cytotoxic T lymphocyte (CTL) generation in the MLR and the elimination of these S-M phi before subjection to the MLR resulted in more effective generation of CTL. The CTL activity, which was determined in vivo by the Winn's test, was markedly enhanced when immunized mice received a 100 mg/kg dose of Ge-132. The compound was found to be the most efficacious when injected simultaneously with the immunization. The activity of allospecific CTL co-cultured with M phi fractions obtained from immunized mice in a 4-h 51Cr-release assay was shown to be 31% lysis of the target cells as compared with 90% lysis of the target cells in effector cells co-cultured with normal M phi fractions. In contrast, effector cells co-cultured with M phi fractions from Ge-132-treated immunized mice lysed 95% of the target cells. Analysis of the level of I-J antigen expression on macrophages (M phi) obtained from mice 7 days after immunization revealed a > 2.5-fold increase, whereas I-A antigen expression remained constant when compared with splenic M phi from naive mice. In contrast, the opposite effect on I-J and I-A antigen expression was observed in splenic M phi from alloimmunized mice treated with Ge-132. These results suggest that Ge-132 could regulate CTL generation in alloimmunized mice by preventing the generation of I-J+ S-M phi.
Effect of carboxyethylgermanium sesquioxide on cultured normal neonatal rat myocardial cells and cells injured by isoproterenol. Yao Xue Xue Bao. 1992;27(7):481-5.
Chen YQ, Tian B, Li XM, Chen YJ, Xie SH.
Department of Pathophysiology, Xian Medical University.
The effect of carboxyethylgermanium sesquioxide (Ge-132) on cultured neonatal rat myocytes and isoproterenol injured myocytes was studied. The results showed that Ge-132 (0.01 mmol.L-1 and 1 mmol.L-1) increased the incorporation of both [3H]-TdR and [14C]-UR, reduced the membrane lipid fluidity and inhibited the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Exposure of the myocytes to isoproterenol 0.5 mmol.L-1 for 6 hours resulted in 5-fold release of LDH compared with the control. All myocytes ceased beating. Ultrastructurally, severe sarcolemmal and mitochondrial damage was evident. When the cells were pretreated with Ge-132 before the addition of isoproterenol, the increased LDH release was inhibited significantly, and preservation of beat and ultrastructure of myocytes was observed. In addition, the activity of superoxide dismutase (SOD) was elevated by Ge-132. All the effects of Ge-132 were dose-related. The results indicate that Ge-132 may improve the metabolism of cultured neonatal rat myocytes and protect myocytes from isoproterenol-induced injury.
[Subacute and subchronic oral toxicity of beta-bis carboxyethyl sesquioxide of germanium in the rat] J Toxicol Clin Exp. 1991 Dec;11(7-8):421-36.
Anger F, Anger JP, Guillou L, Sado PA, Papillon A.
Laboratoire de Toxicologie, UFR des Sciences Pharmaceutiques et Biologiques, Rennes, France.
After a brief recall of toxicological data about germanium compounds, the authors relate subacute and subchronic oral toxicities of beta bis carboxyethyl-germanium sesquioxide in rats. During 28 days and six months, male and female animals have received 1 mg/kg/day. No particular toxic symptoms, no behaviour trouble except a small decrease of body weight, in male rats, at the end of the 6-month experimentation, were observed. A light decrease of erythropoiesis and a general stimulation of cellular metabolism has been noticed after 28 days. The only marked effect was a moderate renal deficiency characterized by a tubular disease with presence of cylinders, swelling of tubulus cells and floculus amounts after 6 months. Germanium urinary excretion was constant and linked to the received dose. Six months later, no preferential accumulation in organs was observed.
Chronic tubulointerstitial changes induced by germanium dioxide in comparison with carboxyethylgermanium sesquioxide.
Kidney Int. 1991 Nov;40(5):882-90.
Sanai T, Okuda S, Onoyama K, Oochi N, Takaichi S, Mizuhira V, Fujishima M.
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Chronic nephrotoxicity was investigated in rats orally administered germanium dioxide (GeO2) and carboxyethylgermanium sesquioxide (Ge-132) for 24 weeks. Increased BUN and serum phosphate as well as decreased creatinine clearance, weight loss, anemia and liver dysfunction were apparent at week 24 only in the GeO2 treated group. Vacuolar degeneration and granular depositions were observed by light microscope in the degenerated renal distal tubules in the rats of this group, with the semiquantitative scores of tubular degeneration being 95 +/- 9% in the GeO2 group, 3 +/- 1% in the Ge-132 group and 1 +/- 1% in the control group, respectively. Electron microscopy revealed electron-dense inclusions in the swollen mitochondrial matrix of the distal tubular epithelium in the GeO2 group. Although systemic toxicities were reduced after GeO2 was discontinued at week 24, renal tubulointerstitial fibrosis became prominent even at week 40 (16 weeks after discontinuation). A Ge.K alpha X-ray spectrum was clearly demonstrated in the mitochondrial matrix of the distal tubular epithelium in the GeO2 group with the help of electron probe X-ray microanalysis. On the other hand, neither toxic effects nor renal histological abnormalities were manifested in either the Ge-132 or the control group. The renal tissue content of germanium was high at weeks 24 and 40 in the GeO2 group. From these results, it is concluded that GeO2 causes characteristic nephropathy while Ge-132 does not. In addition, it appears that residual GeO2 remains for a considerably long time even after the cessation of GeO2 intake.
Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide.
Biol Trace Elem Res. 1991 Jun;29(3):267-80.
Schauss AG.
Life Sciences Division, American Institute for Biosocial Research, Inc., Tacoma, WA 98401.
There is no known biological requirement for germanium (Ge), germanates, or any organogermanium compound. Ge deficiency has not been demonstrated in any animal. The estimated average dietary intake of Ge in humans is 1.5 mg/d. Ge is widely distributed in edible foods, all of which, with few exceptions, contain less than 5 ppm Ge, since higher levels are toxic to most plants. Ingestion of Ge compounds has been shown to produce toxic effects in experimental animals. In recent years inorganic germanium salts and novel organogermanium compounds, such as carboxyethyl germanium sesquioxide (Ge-132) and lactate-citrate-germanate (Ge lactate citrate) have been sold as "nutritional supplements" in some countries for their purported immunomodulatory effects or as health-producing elixirs, resulting in intakes of Ge significantly exceeding the estimated average dietary intake. Since 1982, there have been 18 reported cases of acute renal dysfunction or failure, including two deaths, linked to oral intake of Ge elixirs containing germanium dioxide (GeO2) or Ge-132. In these cases, biopsies show vacuolar degeneration in renal tubular epithelial cells, without proteinuria or hematuria, in the absence of glomerular changes. Serum creatinine levels have been well above 400 mumol/L in such patients. In 17 of 18 cases, accumulated elemental Ge intakes reportedly ranged between 16 to 328 g over a 4-36 mo period, or between 100 to 2000 times the average estimated dietary intake for human. In surviving patients, renal function improved after discontinuation of Ge supplementation. However, in no case was recovery complete. One organogermanium compound, an azaspiran organogermanium compound, 2-aza-8-germanspiro[4,5] decane-2-propamine-8,8-diethyl-N,N-dimethyl dichloride (spirogermanium), has been found to cause both neurotoxicity and pulmonary toxicity in phase I and II studies examining its chemotherapeutic potential as an antitumor drug in the treatment of various malignancies. In cancer patients given the drug spirogermanium, 40% experienced marked, yet transient neurotoxicity. Two patients suffered from pulmonary toxicity. Results of phases I and II human cancer trials for spirogermanium have not been favorable, with the exception of moderate benefits for three types of malignancies. It is recommended that patients exposed to long-term (greater than 3 mo) Ge supplementation at levels well above the estimated daily intake be medically supervised and monitored for potential renal-, pulmonary- or neurotoxicity. Further study regarding the mechanism of Ge-induced nephrotoxicity in human is warranted.
Modifying responses of allyl sulfide, indole-3-carbinol and germanium in a rat multi-organ carcinogenesis model. Carcinogenesis. 1991 Apr;12(4):691-5.
Jang JJ, Cho KJ, Lee YS, Bae JH.
Department of Anatomical Pathology, Korea Cancer Center Hospital, Seoul.
The modifying potential of allyl sulfide (AS), indole-3-carbinol (I3C) and carboxyethylgermanium sesquioxide (GE) on lesion development was examined in a wide-spectrum initiation model. Groups 1-4 were treated sequentially with diethylnitrosamine (DEN) (100 mg/kg, i.p., single dose), N-methylnitrosourea (MNU) (20 mg/kg, i.p., four doses at days 2, 5, 8 and 11), and N,N-dibutylnitrosamine (DBN) (0.05% in drinking water during weeks 3 and 4). Groups 5-7 received vehicles without carcinogens during the initiation period. Group 8 served as the untreated control. After this initiating procedure, groups 2-7 were administered a diet containing 0.5% AS or I3C and 0.05% GE. All surviving animals were killed 40 weeks after the beginning of the experiment and the target organs were examined. The induction of GST-P+ hepatic foci in rats treated with carcinogens was significantly inhibited by treatment with all three compounds. AS treatment significantly decreased the incidence of hepatic hyperplastic nodules, adenoma of the lung and thyroid, and papillary or nodular hyperplasia of the urinary bladder. Administration of GE also significantly inhibited the development of hepatic nodules and adenoma of the lung and thyroid. However, I3C only inhibited the hyperplastic nodules of the liver. These results demonstrated that this multi-organ initiation model could be useful in confirming organ-specific modification potential and, in addition, the inhibitory effect of AS, I3C and GE on liver, lung, thyroid and urinary bladder carcinogenesis.
Nephrotoxicity in humans by the ultratrace element germanium. Ren Fail. 1991;13(1):1-4.
Life Sciences Division, American Institute for Biosocial Research, Inc., Tacoma, Washington 98401.
Acute renal failure (ARF) or renal dysfunction (RD) associated with germanium-induced nephrotoxicity has been reported in 18 patients since 1982. In 2 of these cases the patients died of acute renal and cardiogenic failure. In 17 of 18 cases biopsies showed vacuolar degeneration in renal tubular epithelial cells in the absence of glomerular changes, without proteinuria or hematuria. Accumulated elemental Ge intake in 17 patients over a period of 4 to 36 months ranged between 16 and 328 g, or more than 100 to 2000 times the average estimated dietary intake of Ge for man (1.5 mg/d; range 0.40 to 3.40 mg/d). The biological half-life of Ge is 4.5 days for kidneys, the highest retention level of any organ. The mean concentration of Ge in healthy adult kidneys is 9.0 mg/kg wet weight. In 3 patients studied with Ge-induced RD or ARF, urinary Ge excretion was 9, 15, and 60 ng/mL, compared to greater than 5 ng/mL in healthy controls, and remained elevated even 12 months after discontinuing supplemental Ge intake. The mechanism for Ge-induced nephrotoxicity remains unknown, although the suspected cause is the inorganic Ge salts, such as germanium dioxide. Sufficient evidence for a role of organogermanium compounds, such as carboxyethyl germanium sesquioxide or citrate-lactate germanate, in Ge-induced nephrotoxicity remains lacking. The recent introduction of over-the-counter Ge "nutritional" supplements in some countries increases the risk of additional cases of Ge-induced nephrotoxicity, especially if appreciable levels of inorganic Ge salts are present and consumed for long periods (greater than 3 months) at levels above the average daily estimated dietary intake for Ge.(ABSTRACT TRUNCATED AT 250 WORDS)
Germanium dioxide-induced nephropathy: a new type of renal disease. Nephron. 1990;54(1):53-60.
Sanai T, Okuda S, Onoyama K, Oochi N, Oh Y, Kobayashi K, Shimamatsu K, Fujimi S, Fujishima M.
Chronic renal failure developed in 5 patients who were taking germanium dioxide (GeO2)-containing compounds. Renal functional deterioration was slow but progressive and dialysis treatment was necessitated temporarily in 2 patients. After the discontinuation of GeO2, the impaired renal function tended to improve but remained abnormal for an observation period of 10-40 months. The lack of proteinuria and hematuria was characterized as the clinical manifestations. Renal biopsy specimens revealed the tubular epithelial cell degeneration containing hematoxylin-positive fine granules on light microscopy, and electron-dense inclusions in the swollen mitochondria on electron microscopy. These findings localized mainly in distal segment of the tubules. In the rats given GeO2 orally for 10 weeks, similar histological lesions were evident, as manifested by marked weight loss, anemia, azotemia, and negative proteinuria. In the rats given carboxyethylgermanium sesquioxide, these changes were not observed and Ge concentration of kidney was significantly lower than in the rats given GeO2. The present study indicates that chronic GeO2 intake causes progressive renal dysfunction characterized by the degeneration of distal tubules.
Effects of organogermanium compound 2-carboxyethyl germanium sesquioxide on cardiovascular function and motor activity in rats. Pharmacology. 1990;41(5):286-91.
Ho CC, Chern YF, Lin MT.
Department of Physiology, China Medical College, Taichung, Taiwan.
In rats anesthetized with urethane, intraperitoneal administration of a water-soluble organogermanium compound 2-carboxyethyl germanium sesquioxide (Ge-132) produced a dose-related reduction in either the mean arterial pressure or the heart rate. Both hypotension and bradycardia responses induced by Ge-132 injection were significantly inhibited by pretreatment of the animals with either spinal transection or bilateral vagotomy. The data indicate that Ge-132 induces both hypotension and bradycardia by promoting an activation of the parasympathetic efferent mechanisms and an inhibition of the sympathetic efferent mechanisms. On the other hand, following intraperitoneal injection of Ge-132, increased grooming and head swaying (as shown by an enhancement in fine movements monitored by an electronic activity counter) were provoked. Furthermore, the amphet-amine-induced enhancement in fine movements was potentiated by pretreatment of the animals with Ge-132. Thus, it appears that Ge-132 acts through the catecholaminergic mechanisms in the brain to induce locomotor stimulation in rats.
Effect of potential antidotes on the acute toxicity, tissue disposition and elimination of selenium in rats. Res Commun Chem Pathol Pharmacol. 1989 Dec;66(3):441-50.
Paul M, Mason R, Edwards R.
Toxicology Research Unit (Medical Research Council of New Zealand), University of Otago Medical School, Dunedin.
Treatment of male Wistar rats with sodium selenate (2.24 mg Se/kg, s.c.) inhibited their body weight gain for 24 hr, after which the animals recovered. Intraperitoneal injections of sodium-2,3-dimercaptopropane-1-sulphonic acid (60 mg/kg), meso-2,3-dimercaptosuccinic acid (50.9 mg/kg) and calcium disodium ethylenediamine-tetraacetate (500 mg/kg) 15 min after Se had no protective effect, whilst 2,3-dimercaptopropanol (15 mg/kg) inhibited the recovery of the Se-treated animal. Sodium diethyldithiocarbamate (DDTC, 70 mg/kg, i.p.) reduced the Se-induced loss of body weight but had no effect on the tissue disposition of 75Se when injected 15 min, 3 hr or 6 hr after a s.c. injection of sodium [75Se] selenite (50 microCi, 17.4 micrograms Se/kg). The citrate salts of bismuth (2.5 and 5 mg Bi/kg, s.c.), antimony (1.5 and 3 mg Sb/kg, s.c.) and germanium (40 mg Ge/kg, s.c.) also reduced the selenate-induced loss of body weight, whilst germanium citrate (40 mg Ge/kg) and bis-carboxyethyl germanium sesquioxide (80, 200 and 400 mg Ge/kg) promoted significant dose-related increases in the 24 hr urinary excretion of 75Se when given 15 min after sodium [75Se] selenite (30 microCi, 0.5 mg Se/kg, s.c.).
Antiviral activity of carboxyethylgermanium sesquioxide (Ge-132) in mice infected with influenza virus. J Biol Response Mod. 1989 Apr;8(2):180-9.
Aso H, Suzuki F, Ebina T, Ishida N.
Department of Bacteriology, Tohoku University School of Medicine, Sendai, Japan.
The protective effect of carboxyethylgermanium sesquioxide (Ge-132) in mice infected with a mouse-adapted strain of influenza virus (H2N2) was investigated. When mice were exposed to a 10 LD50 dose of influenza virus via aerosol and were treated orally with 20 or 100 mg/kg of Ge-132 daily for 6 consecutive days, a significant protective effect was demonstrated. The antiviral effect of Ge-132 was indicated by an increase of survivors, a prolongation of mean survival days, an inhibition of the development of lung consolidation, and a decrease of virus titer in lung tissues, as compared to infected control mice treated with phosphate-buffered saline. Natural killer (NK) cell activity in the spleens and lungs of the infected mice was also significantly augmented after the oral administration of Ge-132. In addition, NK cells stimulated with Ge-132 in vivo showed killing activity against NK-insensitive Meth-A cells infected with influenza virus. Because no virucidal or virustatic activities of Ge-132 on the virus were found in vitro, this protective effect in mice against influenza virus infection may be displayed through immunomodulating activities of this compound such as the augmentation of NK cell activity.
Cancer, Immune System
Antitumor mechanisms of carboxyethyl-germanium sesquioxide (Ge-132) in mice bearing Ehrlich ascites tumors. Gan To Kagaku Ryoho. 1987 Jan;14(1):127-34.
Suzuki F.
The administration of IFN-containing sera (Ge-sera) obtained from Ge-132-treated mice (Ge-mice) or the passive transfer of macrophages (M phi) to mice bearing ascites tumors resulted in the inhibition of tumor growth. The cooperative role of Ge-sera and Ge-M phi in the display of Ge-132-antitumor activity was studied. When mice were pretreated with antimouse IFN gamma antiserum, no IFN-inducing or antitumor activities of the compound were detected. Cytotoxic activities were detected in peritoneal M phi of mice treated with Ge-sera, and passive transfer of these M phi to tumor-bearing mice resulted in the inhibition of tumor growth. When tumor-bearing mice were pretreated with substances toxic to M phi, no antitumor activity of Ge-sera was observed. However, Ge-132 antitumor activity was observed in mice depleted of T-cells, even though the antitumor effects of the compound itself were not demonstrable in T-cell-depleted mice. Therefore, a part of the antitumor activity of Ge-132 appears to be expressed as follows: Ge-132 stimulates T-cells to produce circulating lymphokine(s) which are inactivated by anti-IFN gamma treatment; activated M phi are generated from resting M phi by these lymphokine(s); the transplanted tumors are inhibited by these M phi.
Inhibitory effects of Ge-132 (carboxyethyl germanium sesquioxide) derivatives on enkephalin-degrading enzymes. Biotechnol Appl Biochem. 1986 Oct;8(5):379-86.
Komuro T, Kakimoto N, Katayama T, Hazato T.
Twenty-eight species of carboxyethyl germanium sesquioxide (Ge-132) derivatives were examined for their inhibitory effects on enkephalin-degrading enzymes that were purified from monkey brain, the longitudinal muscle layer of bovine small intestine, and human cerebrospinal fluid (CSF). A series of the sulfurized Ge-132 derivatives showed strong inhibition of these purified enzymes. The most effective ones were Ge-014 and Ge-107, which showed IC50 values of 60 and 100 micrograms/ml, respectively, for dipeptidylcarboxypeptidase from the longitudinal muscle layer. They also exhibited inhibitory activity against aminopeptidase from human CSF, the IC50 values being 450 and 440 micrograms/ml, respectively. Furthermore, these compounds showed inhibition of dipeptidylaminopeptidase from monkey brain and the longitudinal muscle layer of bovine small intestine. These compounds are expected to have analgesic effects due to their inhibition of the degradation of endogenous opioid peptides.
Cooperation of lymphokine(s) and macrophages in expression of antitumor activity of carboxyethylgermanium sesquioxide (Ge-132). Anticancer Res. 1986 Mar-Apr;6(2):177-82.
Suzuki F, Brutkiewicz RR, Pollard RB.
The administration of IFN containing sera (Ge-sera) obtained from Ge-132-treated mice (Ge-mice) or the passive transfer of macrophages (M phi) to mice bearing ascites tumors resulted in the inhibition of tumor growth. The cooperative role of Ge-sera and Ge-M phi in the display of Ge-132-antitumor activity was studied. When mice were pretreated with antimouse IFN gamma antiserum, no IFN-inducing and antitumor activities of the compound were detected. Cytotoxic activities were detected on peritoneal M phi of mice treated with Ge-sera, and passive transfer of these M phi to tumor-bearing mice resulted in the inhibition of tumor growth. When tumor-bearing mice were pretreated with substances toxic to M phi, there was no antitumor activity of Ge-sera observed. However, there was antitumor activity of Ge-sera in mice depleted of T-cells, even though the antitumor effects of the compound itself were not demonstrable in T-cell depleted mice. Therefore, a part of the antitumor activity of Ge-132 may appear to be expressed as follows: (1) Ge-132 stimulated T-cells to produce circulating lymphokine(s) which were inactivated by anti-IFN gamma treatment; (2) activated M phi were generated from resting M phi by such lymphokine(s); (3) the transplanted tumors were inhibited by these M phi.
[Antitumor effect in mice of an organic germanium compound (Ge-132) when different administration methods are used] Gan To Kagaku Ryoho. 1985 Dec;12(12):2345-51.
Aso H, Shibuya E, Suzuki F, Nakamura T, Inoue H, Ebina T, Ishida N.
The antitumor effect of an organic germanium compound, carboxyethylgermanium sesquioxide (Ge-132), was examined in mice using two systems: one, the ascitic form of Ehrlich carcinoma in DDI mice, and the other, the solid form of Meth-A fibrosarcoma in BALB/c mice. In the mice with Ehrlich ascitic tumors, a remarkable prolongation in life span was observed after intraperitoneal (i.p.) or per oral (p.o.) administration of Ge-132 (300 mg/kg), but not after intravenous (i.v.) injection of the same compound. Following i.p. or p.o. administration, cytotoxic macrophages (Mo) were induced in the peritoneal cavity after 48 h. although this was not the case after i.v. injections. When the in vivo effect of these in vitro active Mo was examined after adoptive transfer to mice bearing Ehrlich ascitic tumor cells, a significant antitumor effect was noted. In the mice bearing solid Meth-A tumors, i.v. injections of Ge-132 (100 mg/kg) were found to inhibit tumor growth remarkably, although i.p. and p.o. administrations did not have the same result. This inhibitory effect of Ge-132 by i.v. administration was explained by the continued augmentation of NK activity in peripheral blood, which was followed by the induction of specific killer cells appearing in the spleen. When the mice which had recovered from Meth-A tumor growth, following i.v. injections of Ge-132, were challenged with the same tumor on day 30, all mice were able to tolerate the challenge, but not a challenge of RL male 1 tumor cells. These observations may indicate that the differing antitumor effects of Ge-132 produced when different administration methods are used can be explained by the variation in effector cells induced by such different administration routes.
[Suppression of tumor growth by peritoneal macrophages isolated from mice treated with carboxyethylgermanium sesquioxide (Ge-132)] Gan To Kagaku Ryoho. 1985 Nov;12(11):2122-8.
In a murine model it has been shown that the antitumor activity of carboxyethylgermanium sesquioxide (Ge-132) can be depleted by administration of macrophage (M phi) blockers. In the present study, the role that M phi play in the antitumor activity of the compound was investigated. Oral administration of Ge-132 in mice was demonstrated to be effective in activating M phi (Ge-132-cytotoxic M phi), and the cytotoxic activity of these M phi appeared in the peritoneal cavity of mice 48 hours after the oral administration of the compound. Co-cultivation of RL male-1 leukemia or Ehrlich carcinoma cells with Ge-132-cytotoxic M phi in vitro resulted in marked suppression of the growth of tumor cells. The transfer of peritoneal exudate cells (PEC), or purified M phi fractions of PEC from Ge-132-treated mice to mice bearing Ehrlich or RL male-1 ascites tumors resulted in significant protection. However, when the cytotoxic M phi were depleted by carbonyl-iron treatment in vitro, no antitumor effect was demonstrated in mice bearing Ehrlich or RL male-1 ascites tumors. Macrophage fractions obtained from PEC of Ge-132-treated mice exhibited an inhibitory effect against certain tumors both in vivo and in vitro suggesting that the antitumor effect of Ge-132 observed in vivo resulted from the activation of M phi.
Importance of T-cells and macrophages in the antitumor activity of carboxyethylgermanium sesquioxide (Ge-132). Anticancer Res. 1985 Sep-Oct;5(5):479-83.
The purpose of this study was to investigate the effective mechanisms of Ge-132, an organogermanium compound with immunomodulatory activity, on experimental murine ascites tumors. The antitumor effects of Ge-132 were observed when mice inoculated with Ehrlich carcinoma (allogeneic) or RL male 1 leukemia (syngeneic) cells were treated orally. However, Ge-132 had no activity on EL-4 lymphoma (syngeneic) or Meth A fibrosarcoma (syngeneic). The antitumor activity of Ge-132 was not observed when tumor-bearing mice were treated with trypan blue, carrageenan, or monoclonal anti-Thy 1.2 antibody. However, when natural killer (NK) cells were eliminated from mice bearing RL male 1 or Ehrlich ascites tumors by treatment with anti-asialo GM1 antiserum, the antitumor activity of the compound was unchanged. This suggests that Ge-132 was effective against certain ascites tumors regardless of whether the tumor was syngeneic or allogeneic. Furthermore, its effect might be expressed through host defense mechanisms, including macrophages and/or T-cells.
Inhibition of tumor growth and metastasis in association with modification of immune response by novel organic germanium compounds. J Biol Response Mod. 1985 Apr;4(2):159-68.
Sato I, Yuan BD, Nishimura T, Tanaka N.
The effects of two novel organic germanium compounds, 1-phenyl-2-carbamoylethylgermanium sesquisulfide (PCAGeS) and 1-phenyl-2-carbamoylethylgermanium sequioxide (PCAGeO), on transplantable murine tumors and immune responses were studied. Both drugs showed low toxicity for mice. In culture, neither substance displayed significant cytotoxicity against murine tumor cells L1210 leukemia, L5178Y lymphoma, or IMC carcinoma. Growth of subcutaneously transplanted IMC carcinoma or Meth-A fibrosarcoma was markedly reduced by oral administration of PCAGeS. PCAGeO exhibited a similar but smaller effect on the tumor growth. Pulmonary metastasis of Lewis lung carcinoma was inhibited by oral or intraperitoneal treatment with PCAGeS. The activity of cyclophosphamide or Adriamycin against L1210 leukemia was significantly potentiated by oral administration of PCAGeS. PCAGeS enhanced the delayed-type hypersensitivity response to sheep red blood cells (SRBC) of mice or restored the response suppressed by ascitic IMC carcinoma, but did not significantly affect the formation of antibody to SRBC. PCAGeO similarly stimulated the DTH reaction. Phagocytic activity of peritoneal macrophages was enhanced by oral treatment of mice with PCAGeS. The results suggest that PCAGeS and PCAGeO display tumor-inhibitory activity by modification of the immune mechanism.
Analgesic effect of novel organogermanium compound, GE-132. J Pharmacobiodyn. 1983 Nov;6(11):814-20.
Hachisu M, Takahashi H, Koeda T, Sekizawa Y.
A novel organogermanium compound, Ge-132, carboxyethylgermanium sesquioxide, showed enhancement of 0.5 mg/kg morphine analgesia in both administration routes of oral administration (p.o.) and intraperitoneal injection (i.p.) in the Tail-Flick test, and the effect was completely abolished by 0.5 mg/kg Naloxone, stereospecific opiate antagonist. Ge-132 alone, 250 mg/kg i.p., did not show any antinociceptive action by assessing the Tail-Flick test and the Hot-Plate test. By the intracerebral injection of Ge-132, 100-1000 micrograms, prolongation of Tail-Flick latency was observed and the action was abolished by 50 micrograms CaCl2 injection. Although bestatin which is reported to enhance the morphine analgesia inhibits enkephalinase and enkephalin aminopeptidase, Ge-132 did not show any inhibition on both enkephalin degrading enzymes. The possibility for the mode of action of Ge-132 was discussed.
Effect of carboxyethylgermanium sesquioxide on the methylcholanthrene-induced tumorigenesis in mice. Sci Rep Res Inst Tohoku Univ [Med]. 1978 Dec;25(3-4):89-95.
Kumano N, Nakai Y, Ishikawa T, Koinumaru S, Suzuki S, Konno K
752926&query_hl=2&itool=pubmed_DocSum
Antiviral, Immune System
Immunological control of methicillin-resistant Staphylococcus aureus (MRSA) infection in an immunodeficient murine model of thermal injuries. Clin Exp Immunol. 2005 Dec;142(3):419-25.
Katakura T, Yoshida T, Kobayashi M, Herndon DN, Suzuki F.
Department of Internal Medicine, The University of Texas Medical Branch, Galveston 77555-0435, USA.
Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a major cause of sepsis in patients who are immunosuppressed by their burns. In this study, an immunological regulation of MRSA infection was attempted in a mouse model of thermal injury. SCIDbg mice were resistant to MRSA infection, while SCIDbgMN mice (SCIDbg mice depleted of neutrophils and macrophages (Mphi)) were susceptible to the same infection. Also, thermally injured SCIDbg mice were shown to be susceptible to MRSA infection. On the other hand, the resistance of SCIDbgMN mice to the infection was completely recovered after an inoculation with Mphi from normal mice. However, anti-MRSA resistance was not shown in SCIDbgMN mice inoculated with Mphi from thermally injured mice. Mphi from MRSA-infected thermally injured mice were identified as alternatively activated Mphi, and Mphi from MRSA-infected unburned mice were characterized as classically activated Mphi. Mphi from thermally injured SCIDbg mice previously treated with 2-carboxyethylgermanium sesquioxide (Ge-132) protected SCIDbgMN mice against MRSA infection. Ge-132 has been described as an inhibitor of alternatively activated Mphi generation. These results suggest that MRSA infection in thermally injured patients is controlled immunologically through the induction of anti-MRSA effector cells and elimination of burn-associated alternatively activated Mphi, which are cells that inhibit the generation of classically activated Mphi.
16297152&query_hl=48&itool=pubmed_docsum
DNA binding specificity and cytotoxicity of novel antitumor agent Ge132 derivatives. Bioorg Med Chem Lett. 2005 Jun 15;15(12):2962-5.
Shangguan G, Xing F, Qu X, Mao J, Zhao D, Zhao X, Ren J.
Division of Biological Inorganic Chemistry, Key Laboratory of Rare Earth Chemistry and Physics, Graduate School of the Chinese Academy of Sciences, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
A series of Ge132 derivatives have shown enhanced antitumor activity. Previous studies suggest that DNA can be their primary target. Here we show direct evidence that two newly synthesized Ge132 derivatives can intercalate into DNA. Unexpected methyl substitution effect of the novel derivatives on DNA sequence selectivity and cytotoxicity was observed.
Immune System, Cancer
Effectiveness of propagermanium treatment in multiple myeloma patients. Eur J Haematol. 2004 Dec;73(6):397-401.
Tsutsumi Y, Tanaka J, Kanamori H, Musashi M, Minami H, Fukushima A, Yamato H, Ehira N, Kawamura T, Obara S, Ogura N, Asaka M, Imamura M, Masauzi N.
Department of Internal Medicine, Hakodate Municipal Hospital, Hakodate, Japan. rtsutsu@nyc.odn.ne.jp
Interferon (IFN) is one of several drugs effective in treating multiple myeloma (MM), and propagermanium is an IFN inducer. We report on 10 MM patients who were treated with propagermanium at doses from 10 to 40 mg. Two patients achieved complete remission (CR), two patients achieved partial remission (PR), and the condition of four patients was stable (stable disease, SD). After discontinuation of propagermanium, the status of MM progressed in two patients who were in SD and in two patients who had achieved PR. The administration of propagermanium was restarted in one patient resulting in a decrease in her paraprotein.
Blockade of CCR2 ameliorates progressive fibrosis in kidney.
Am J Pathol. 2004 Jul;165(1):237-46.
Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, Asano M, Takeya M, Kuziel WA, Matsushima K, Mukaida N, Yokoyama H.
Department of Gastroenterology and Nephrology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Fibrosis is a hallmark of progressive organ diseases. Monocyte chemoattractant protein (MCP)-1, also termed as macrophage chemotactic and activating factor (MCAF/CCL2) and its receptor, CCR2 are presumed to contribute to progressive fibrosis. However, the therapeutic efficacy of MCP-1/CCR2 blockade in progressive fibrosis remains to be investigated. We hypothesized that blockade of CCR2 may lead to the improvement of fibrosis. To achieve this goal, we investigated renal interstitial fibrosis induced by a unilateral ureteral obstruction in CCR2 gene-targeted mice and mice treated with propagermanium or RS-504393, CCR2 inhibitors. Cell infiltrations, most of which were F4/80-positive, were reduced in CCR2 knockout mice. In addition, dual staining revealed that CCR2-positive cells were mainly F4/80-positive macrophages. Importantly, CCR2 blockade reduced renal interstitial fibrosis relative to wild-type mice. Concomitantly, renal transcripts and protein of MCP-1, transforming growth factor-beta, and type I collagen were decreased in CCR2-null mice. Further, this CCR2-dependent loop for renal fibrosis was confirmed by treatment with CCR2 antagonists in a unilateral ureteral obstruction model. These findings suggest that the therapeutic strategy of blocking CCR2 may prove beneficial for progressive fibrosis via the decrease in infiltration and activation of macrophages in the diseased kidneys.
Immune System, Liver
Propagermanium: a nonspecific immune modulator for chronic hepatitis B. J Gastroenterol. 2003;38(6):525-32.
Hirayama C, Suzuki H, Ito M, Okumura M, Oda T.
Second Department of Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.
Although antiviral agents have been adopted for the management of chronic hepatitis B, they have only limited efficacy because of the underlying impaired immune status. Propagermanium, a hydrophilic polymer of 3-oxygermyl propionate, has been reported to have potent immune modulatory activity associated with antiinflammatory and antineoplastic properties. For example, propagermanium augments lymphocyte functions in CD4 and CD8 cells, and in natural killer (NK) cells, and induces the production of several cytokines. A controlled pilot study of 16-week treatment with propagermanium for chronic hepatitis B (of moderate and mild grades on hepatic histology) revealed a sustained clearance of hepatitis B e (HBe) antigen and a favorable biochemical response at week 16 of treatment and at week 48 post-treatment. An open study also supported the clearance of hepatitis B virus from the blood and the possible improvement of histologic grading in the liver. There were few adverse events. A postmarketing survey, however, revealed the occurrence of moderate to severe liver damage after the treatment in about 4% of patients. Despite the exact nature of the liver damage being unclear, a putative cause is the swift removal of virus-infected hepatocytes by an immune reaction through the treatment. A subtle balance between host and viral conditions is the factor which most determines hepatitis B virus persistence. The rationale for a nonspecific immune modulator for the treatment of chronic hepatitis B will be the restoration of cellular immune responsiveness to viral infection. Although the cellular immunity for hepatitis B virus prior to the treatment should be studied, adequate observation of hepatic functions and viral markers in the recipients is clinically useful to predict liver failure during the treatment. In summary, the propagermanium regimen offers a potent and safe approach that is cost-effective for appropriate chronic hepatitis B patients with reserve hepatic capacity, and will provide new perspectives for immune therapy in chronic hepatitis B.
Propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in pigs in vivo.
J Cardiovasc Pharmacol. 2003 Mar;41(3):372-80.
Shimokawa H, Eto Y, Miyata K, Morishige K, Kandabashi T, Matsushima K, Takeshita A.
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. shimo@cardiol.med.kyushu-u.ac.jp
Although the importance of monocytes/macrophages in the pathogenesis of arteriosclerosis is widely accepted, effective and safe treatment to inhibit those inflammatory cells remains to be developed. It was recently found that propagermanium, which is clinically used for the treatment of chronic hepatitis type B in Japan, markedly suppresses monocyte chemotaxis in response to macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor, C-C chemokine receptor 2, in vitro. This prompted examination of whether propagermanium suppresses the macrophage-mediated formation of coronary arteriosclerotic lesions in our porcine model in vivo. It was first confirmed that propagermanium inhibited the migration of porcine monocytes in response to MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two groups; one group was orally treated with propagermanium (1 mg/kg, three times/day) and another group served as a control (n = 6 each). Porcine coronary segment was treated from the adventitia with MCP-1 and oxidized low-density lipoprotein for 2 weeks. In the control group, this treatment resulted in the development of stenotic coronary lesions with hyperconstrictive responses to serotonin where arteriosclerotic lesions (neointimal formation and constrictive remodeling) were developed. Immunohistochemical analysis demonstrated the macrophage accumulation in the adventitia and the media. By contrast, in the propagermanium group, angiographic coronary stenosis, hyperconstrictive responses, histologic changes, and macrophage accumulation were all significantly suppressed. These results indicate that propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its potential usefulness for the treatment of arteriosclerotic vascular diseases.
Long-term treatment with propagermanium suppresses atherosclerosis in WHHL rabbits. J Cardiovasc Pharmacol. 2003 Feb;41(2):171-7.
Eto Y, Shimokawa H, Tanaka E, Morishige K, Fuchigami M, Ishiwata Y, Matsushima K, Takeshita A.
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Macrophages play an important role in the pathogenesis of atherosclerosis, for which monocyte chemoattractant protein (MCP)-1 and CCR2 chemokine receptors may be involved. The authors have recently demonstrated that propagermanium exerts inhibitory effect on the CCR2 receptors. In the current study, the authors examined whether the organic germanium suppresses the MCP-1-induced monocyte migration in vitro and the development of atherosclerosis in WHHL rabbits in vivo. In the in vitro experiment, propagermanium concentration-dependently suppressed the MCP-1-induced migration of THP-1 cells. In the in vivo experiment, 20 WHHL rabbits were randomly divided into two groups; one group was treated with oral administration with propagermanium (9 mg/kg/day) for 3 months, and another group served as a control (n = 10 each). After 3 months, the aorta was isolated and stained with oil red O staining, and neointimal formation was quantified. Macrophage accumulation in the aorta was also evaluated by immunostaining. Long-term treatment with propagermanium did not affect the serum lipid profiles. However, the treatment significantly suppressed the oil red O-positive area of the total aorta (p < 0.05). Similarly, propagermanium significantly suppressed the intimal lesions (maximal intimal thickness and intimal area) and macrophage staining-positive area (all p < 0.05). A significant positive correlation was noted between macrophage staining-positive area and intimal lesions (p < 0.0001). These results indicate that long-term treatment with propagermanium suppresses the development of atherosclerosis in WHHL rabbits, suggesting its usefulness for the treatment of atherosclerotic vascular disease in humans.
Propagermanium reduces atherosclerosis in apolipoprotein E knockout mice via inhibition of macrophage infiltration.
Arterioscler Thromb Vasc Biol. 2002 Jun 1;22(6):969-74.
Yamashita T, Kawashima S, Ozaki M, Namiki M, Inoue N, Hirata K, Yokoyama M.
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Monocyte chemoattractant protein-1 (MCP-1), which binds to C-C chemokine receptor 2, has been implicated as the primary source of monocyte chemoattractant function in the early stages of atherosclerosis. Recently, propagermanium, a drug used clinically for the treatment of chronic hepatitis in Japan, has been shown to inhibit C-C chemokine receptor 2 function and suppress monocyte/macrophage infiltration in vitro and in vivo. Given the importance of monocyte infiltration in atherogenesis, the inhibition of it by propagermanium might prevent atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were fed an atherogenic high cholesterol diet with or without 0.005% propagermanium for 8 or 12 weeks. Although the plasma lipid levels were unchanged by the drug treatment, atherosclerotic lesion area in the aortic root was reduced by 50% in the drug-treated apoE-KO mice compared with the nontreated apoE-KO mice after 8 weeks of cholesterol feeding (0.62+/-0.12 versus 1.27+/-0.07 mm2, respectively; P<0.01). Moreover, the accumulation of macrophages in the lesions was markedly reduced in the drug-treated group (macrophage positive area, 0.23+/-0.06 mm2 [drug-treated group] versus 0.67+/-0.07 mm2 [control group]; P<0.01). After 12 weeks of cholesterol feeding, atherosclerotic lesion formation in the aortic root and in the descending thoracic aorta was significantly reduced in the drug-treated group. Inhibition of macrophage infiltration by propagermanium prevented the formation of atherosclerotic lesions in apoE-KO mice. This drug may serve as a therapeutic tool for the treatment of atherosclerosis.
An anti-inflammatory drug, propagermanium, may target GPI-anchored proteins associated with an MCP-1 receptor, CCR2. J Interferon Cytokine Res. 2001 Jun;21(6):389-98.
Yokochi S, Hashimoto H, Ishiwata Y, Shimokawa H, Haino M, Terashima Y, Matsushima K.
Central Research Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Hokusei-cho, Inabe-gun, Mie 511-0406, Japan.
Monocyte chemoattractant protein-1 (MCP-1) promotes the migration and activation of monocytes and plays a pivotal role in the development of chronic inflammation. Propagermanium (3-oxygermylpropionic acid polymer) has been used as a therapeutic agent against chronic hepatitis B in Japan. We report here that propagermanium specifically inhibits in vitro chemotactic migration of monocytes by MCP-1. Propagermanium did not inhibit binding of MCP-1 to a human monocytic cell line, THP-1 cells, or affect intracellular Ca(2+) mobilization or the cAMP concentration in MCP-1-treated THP-1 cells. The effect of propagermanium seems to require glycosylphosphatidylinositol (GPI)-anchored proteins, as cleavage of GPI anchors by phosphatidylinositol-phospholipase C (PI-PLC) eliminated the inhibitory activity of propagermanium. Anti-GPI-anchored protein antibodies, such as anti-CD55 and anti-CD59, reduced staining of C-C chemokine receptor 2 (CCR2) with an anti-CCR2 antibody against the N-terminus of CCR2 in a flow cytometric analysis, and these antibodies also selectively inhibited MCP-1-induced migration of THP-1 cells. Furthermore, under fluorescence microscopy, GPI-anchored proteins colocalized with CCR2 on THP-1 cells. These results suggest that propagermanium may target GPI-anchored proteins that are closely associated with CCR2 to selectively inhibit the MCP-1-induced chemotaxis, thus providing a mechanistic basis for the anti-inflammatory effects of the drug.
Protection against concanavalin A-induced murine liver injury by the organic germanium compound, propagermanium. Scand J Immunol. 1998 Dec;48(6):605-14.
Ishiwata Y, Yokochi S, Hashimoto H, Ninomiya F, Suzuki T.
Developmental Research Department, Sanwa Kagaku Kenkyusho Co. Ltd, Mie, Japan.
Propagermanium (3-oxygermylpropionic acid polymer) is an organic germanium compound that activates the immune system. In this study, we investigated the action of propagermanium on T-cell-mediated murine hepatic injury induced by concanavalin A (Con A). Oral administration of propagermanium inhibited the development of liver injury about 10 h after ConA injection. Histological analysis demonstrated that propagermanium attenuated the extent of liver damage compared with controls, reducing infiltration by leucocytes, especially CD11b-positive cells. Infiltration by CD4-positive cells was not affected. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma are crucial for the development of hepatitis in this model. Propagermanium treatment induced significant inhibition of subsequent TNF-alpha production about 10 h after Con A injection, without affecting IFN-gamma, interleukin (IL)-10, IL-4 and IL-12 production. This effect on TNF-production coincided with the inhibition of aminotransferase activity late in the progression of Con A-induced liver injury. These facts suggest that this compound affects the macrophages (Mphi) function in the liver sinusoid. Therefore, Mphi were cultured with liver sinusoidal endothelial cells (SEC) and the effect of propagermanium on TNF-alpha production in the presence of IFN-gamma was determined. TNF-alpha production was reduced significantly in the coculture of Mphi and SEC when Mphi was treated with propagermanium. These results might explain the mechanisms by which propagermanium inhibits Con-A-induced liver injury. That is, propagermanium improves hepatitis through mechanisms including the reduced production of TNF-alpha, without modification of Th1- and Th2-cell function.
9874494&query_hl=48&itool=pubmed_docsum
Effectiveness of Ge-132 to relieve pain and smooth home care administration for the terminal cancer patient Gan To Kagaku Ryoho. 1996 Dec;23 Suppl 3:291-5.
Dozono H, Ikeda K, Onishi T.
Ikeda Radiation Clinic.
Measures to alleviate pain are the most important issue in care of the cancer patient. In the present study, we investigated whether the use of narcotics could be reduced in the use of Ge-132 (Repargermanium) when used alone or together with a narcotic as a means to facilitate pain management in home care. The patients have died at home over the past 2 years with various types of cancer under our hospital supervision. Five were cases of bone metastasis, 6 of ascites. All cases had been given Ge-132, 750 approximately 2,500 mg/day (mean 1,000 mg) either orally or by IV. For pain control the first choice was MS Contin, and when the need arose the route used was intravenous or by suppository. We investigated the rate of narcotic usage and the dosage of same. Narcotics were used in 7 of the 16 patients (44%) who died at home, and the daily dose was 20 approximately 240 mg (mean 60 mg). By using Ge-132 as a pain killer the rate of narcotics use and the dosage were decreased, resulting in less side effects from the narcotics. Thus, Ge-132 proved effective in relieving the pain of the terminal cancer patient receiving home care, and since it has no side effects it assures smooth home treatment.
Interference of selenium germanium and calcium in carcinogenesis of colon cancer. Zhonghua Wai Ke Za Zhi. 1995 Mar;33(3):167-9.
Yu B, Wu J, Zhou X.
Ruijin Hospital, Shanghai Second Medical University.
We studied DMH induced colon cancer in 120 wistar rats, which were divided into 8 groups based on different diets. They were killed and autopsied on 4 weeks after the last injection of DMH. The tumors in various organs including its characteristics, number, site, histological types and ultrastructural changes were observed. The results showed that high fat diet has a significant effect on DMH induced colon cancer. Selenium and calcium can inhibit the effect of DMH and decrease the incidence of colon cancer. Selenium can also interfere the effect of high fat diet but germanium has no effect on colon carcinogenesis.
Safety, Kidneys
Influence of propagermanium (SK-818) on chemically induced renal lesions in rats. J Toxicol Sci. 1994 Oct;19 Suppl 2:131-43.
Asano K, Yamano M, Haruyama K, Ikawa E, Nakano K, Kurono M, Wada O.
Department of Pharmacology, Mie Research Laboratory, Sanwa Kagaku Kenkyusho Co. Ltd., Japan.
A histopathological study was performed to examine the influence of propagermanium and germanium dioxide (GeO2) on chemically induced renal lesions in rats. Animals were treated with adriamycin or mercuric chloride to induce glomerular or proximal tubular damage, and then given drinking water containing propagermanium (480 or 2,400 ppm solution) or GeO2 (300 or 1,500 ppm solution: equivalent to propagermanium in terms of germanium contents). The distal tubular epithelium after 8 weeks dosage with the 1,500 ppm solution of GeO2 was characterized by vacuolization and deposits of PAS-positive material not only in adriamycin-treated rats, but also in normal rats. In contrast, propagermanium administration was not associated with any alternation in the changes induced by adriamycin or mercuric chloride. We previously clarified that propagermanium had no biochemical influence on the renal function of these renal injured rats. The histological demonstration that this compound does not exert renal toxicity, even when given at a high dosage to renal injured rats, further indicates that it would not exacerbate renal dysfunction already present. This confirms that propagermanium may be a safe compound for use in individuals with compromised kidneys.
Immune System, Antiviral
Studies on the antiviral activity of propagermanium with immunostimulating action. Arzneimittelforschung. 1994 Mar;44(3):357-61.
Ishiwata Y, Suzuki E, Yokochi S, Otsuka T, Tasaka F, Usuda H, Mitani T.
Mie Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Japan.
The effects of propagermanium (3-oxygermylpropionic acid polymer) on various virus-infected mice were investigated. Propagermanium did not inhibit the multiplication of various DNA or RNA viruses in vitro. Oral administration of propagermanium in mice infected with herpes simplex virus type I (HSV-1) significantly prolonged the mean survival days. The efficacy of propagermanium at doses of 1 and 10 mg/kg daily was 13.4 +/- 2.3 and 14.2 +/- 2.3 mean survival days in comparison with 7.7 +/- 0.5 mean survival days at control group. In vaccinia virus-infected mice, oral doses of propagermanium ranging from 0.2 to 10 mg/kg suppressed the number of pocks on the tail which induced by the virus. Propagermanium (0.5-10 mg/kg) orally given to HSV-1-infected mice induced cytotoxic T lymphocytes (CTL) against HSV-1 antigen. In addition, propagermanium (1-10 mg/kg) enhanced interferon-gamma (IFN-gamma) induction in mice treated with Mycobacterium bovis (BCG). In mice spleen cells cultured with Concanavalin A, 0.1 to 10 micrograms/ml of propagermanium stimulated interleukin 2 (IL-2) production. It seems likely that the antiviral activity of propagermanium was exerted via enhancement of host immune resistance against viral infection.
Effect of organic germanium compound (Ge-132) on experimental osteoporosis in rats. Gen Pharmacol. 1993 Nov;24(6):1527-32.
Fujii A, Kuboyama N, Yamane J, Nakao S, Furukawa Y.
Department of Pharmacology, Nihon University School of Dentistry, Chiba, Japan.
1. The therapeutic effect of organic germanium compound, 2-carboxyethylgermaniumsesquioxide (Ge-132), for experimental osteoporosis was studied using ovariectomized rats maintained on a low calcium containing diet. 2. Serum calcitonin (sCT) level was decreased and serum parathyroid hormone (sPTH) level was increased by ovariectomy and the decrement and increment rates, respectively, were reduced by administration of Ge-132. Thus, the sCT/sPTH ratio was greater in the groups given Ge-132, indicating that the resorption was somehow inhibited by Ge-132. 3. The transverse strength of femur bone was significantly enhanced by Ge-132. 4. A trend was found in the group given Ge-132 for a larger femur cortical bone index. 5. The relative femur bone wet weight was greater in the group given Ge-132. 6. These results indicate that Ge-132 prevents decreased bone strength, and affects the femur cortical bone index, and bone mineral mass caused by osteoporosis.
Protective effect of carboxyethylgermanium sesquioxide (Ge-132) on superoxide generation by 60Co-irradiated leukocytes. Biotherapy. 1991;3(3):273-9.
Second Department of Internal Medicine, Semmelweis University Medical School, Budapest, Hungary.
The carboxyethylgermanium sesquioxide, Ge-132, is an organogermanium compound which has been shown to modulate leukocyte functions. In this study, we examined the effect of Ge-132 on the generation of superoxide radicals (O2-) either from leukocytes or in cell-free system, employing the highly sensitive 2-methyl-6-[p-methoxy-phenyl]-3,7-dihydroimidazo[1,2-alpha]pyra zin-3-one (MCLA)-dependent chemiluminescence method and the specific electron spin resonance/spin trapping method, respectively. In addition, the in vitro protective effect of Ge-132 on the leukocytes irradiated with 60Co was studied. The incubation with Ge-132 resulted in an increase in basal O2- release of intact leukocytes, but had no effect on O2- generation from leukocytes stimulated with phorbol myristate acetate (PMA). Irradiation with 60Co decreased the O2- generation from leukocytes in a dose-dependent manner. Ge-132 had no effect on basal O2- release from 60Co-irradiated leukocytes, but it prevented the decrease in PMA-stimulated O2- generation by irradiated leukocytes. Ge-132 itself had no superoxide scavenging activity in cell-free system. On the other hand, higher concentrations of Ge-132 had decreasing effects on both basal O2- release and PMA-stimulated O2- generation from leukocytes, but they did not affect leukocyte viability. Above results indicate that 1) Ge-132 can stimulate the basal O2- release from leukocytes, 2) Ge-132 can prevent the decrease of O2- generation by 60Co-irradiated leukocytes, 3) in higher concentrations, Ge-132 may have a membrane stabilizing effect.
Effects of proxigermanium on interferon production and 2',5'-oligoadenylate synthetase activity in the lung of influenza virus-infected mice and in virus-infected human peripheral blood mononuclear cell cultures. Arzneimittelforschung. 1990 Aug;40(8):896-9.
Ishiwata Y, Yokochi S, Suzuki E, Michishita H, Tashita A, Asano K, Mitani T, Kurono M.
Mie Laboratory, Sanwa Kagaku Kenkyusho Co. Ltd., Japan.
Proxigermanium (SK-818) is a synthesized organic germanium compound having various biological activities. The effects of proxigermanium on interferon (IFN) production in mice infected with influenza virus and virus-infected human peripheral blood mononuclear cells (hPBMC) were investigated. Proxigermanium alone did not induce IFN production in normal mice or in hPBMC without viral infection. On the other hand, proxigermanium enhanced alpha/beta IFN production in viral-infected mice and hPBMC. Since proxigermanium is known to have antiviral activity in vivo but not in vitro, it is likely that the IFN production augumenting activity of proxigermanium is involved in its antiviral activities.
Immune System, Cancer, Physiology
Biological activities and antitumor mechanism of an immunopotentiating organogermanium compound, Ge-132 (review). In Vivo. 1987 Jul-Aug;1(4):189-203.
Brutkiewicz RR, Suzuki F.
Department of Internal Medicine, University of Texas Medical Branch, Galveston 77550.
The biological activities and antitumor mechanism of an immunopotentiator, Ge-132, is reviewed herein. Ge-132 exhibited antitumor activity against certain syngeneic and allogeneic experimental tumors. It was shown that T-cells and macrophages were involved when tumor-bearing mice were protected by the compound. This protective effect could be transferred to tumor-bearing mice, not treated with the compound, by a macrophage fraction and serum specimens obtained from Ge-132-treated mice. Interferon gamma (IFN gamma) was detected in the circulation of Ge-132-treated mice and when sera obtained from Ge-132-treated mice were treated with anti-IFN gamma antiserum in vitro, the antitumor activity was abolished. On the other hand, in mice treated with anti-IFN gamma antiserum, Ge-132 did not induce serum IFN and failed to protect against death due to ascites tumor progression. The in vivo administration of monoclonal anti-Thy 1.2 antibody prevented the expression of the antitumor activity of Ge-132. However, serum specimens obtained from Ge-132-treated mice effectively inhibited the tumor growth of T-cell-depleted mice bearing ascites tumors. Since it has been reported that T-lymphocytes produce IFN gamma, this suggested that Ge-132 may first stimulate T-cells to produce IFN gamma in the expression of the observed antitumor efficacy. In addition, sera obtained from Ge-132-treated mice did not show any antitumor activity in mice depleted of macrophage functions. Additionally, passive transfer of macrophages from mice treated with these serum specimens to tumor-bearing mice also resulted in the inhibition of tumor growth. Pretreatment of these serum specimens with anti-IFN gamma antiserum effectively prevented the generation of cytotoxic macrophages. Also, tumor-bearing mice treated exogenously with this antiserum did not differ significantly in survival as compared to controls, despite the administration of Ge-132. Furthermore, the antitumor activity of Ge-132 was detected in NK cell-depleted mice. Therefore, the antitumor mechanism of Ge-132 in the murine ascites tumor system may be expressed as follows: (a) Ge-132 stimulates T-cells to induce IFN gamma when mice are treated orally with the compound, (b) IFN gamma activates macrophages to become cytotoxic, and (c) the cytotoxic macrophages eliminate tumor cells.
Induction of interferon production by natural killer cells by organogermanium compound, Ge132. J Interferon Res. 1987 Feb;7(1):69-76.
Munakata T, Arai S, Kuwano K, Furukawa M, Tomita Y.
Interferon (IFN)-inducing activity of the organogermanium compound Ge132 in human peripheral mononuclear cells was investigated. By using Percoll discontinuous density gradient centrifugation, peripheral blood nonphagocytic and nonadherent mononuclear cells were divided into the low-and high-density fractions. Natural killer (NK)-enriched low-density fractions, but not the T-cell-enriched high-density fractions, showed IFN production by the stimulation of Ge132. The maximal titer of IFN by NK-enriched fractions (F1 + F2) was observed after a 74-h cultivation in the presence of 200 micrograms/ml Ge132. IFN production by the NK-enriched fractions was abrogated by treatment of the cells with monoclonal antibody against human NK cells in the presence of complement. The treatment with antiserum-neutralizing human IFN-gamma resulted in a marked reduction, indicating that a major part of IFN was IFN-gamma. These results suggested that Ge132 might possess affinity to NK cells, inducing IFN production by NK cells.
Ability of sera from mice treated with Ge-132, an organo-germanium compound, to inhibit experimental murine ascites tumors. Gan To Kagaku Ryoho. 1985 Dec;12(12):2314-21.
Serum specimens from mice treated orally with Ge-132 (100 mg/kg) exhibited antitumor activity against Ehrlich (allogeneic) and RL 1 (syngeneic) ascites tumors in BALB/c mice. Sera obtained from mice 24 hours after Ge-132 administration displayed the highest antitumor effect and the antitumor activity was dose-dependent. Sera prepared from mice 12, 36 or 48 hours after Ge-132 treatment had no protective effect. Circulating interferon (IFN) was induced at 24 hours after administration. The antiviral activity of serum from Ge-132-treated mice was inactivated by treatment with trypsin, low pH, and anti-IFN-gamma antiserum. The inactivated preparations of serum IFN induced by Ge-132 did not show antitumor activity when administered to mice bearing Ehrlich ascites tumors. These results suggest that the antitumor activity in the sera of Ge-132-treated mice may have been expressed through IFN-gamma which was induced by Ge-132.
Role for macrophage metalloelastase in glomerular basement membrane damage associated with alport syndrome. Am J Pathol. 2006 Jul;169(1):32-46.
Rao VH, Meehan DT, Delimont D, Nakajima M, Wada T, Gratton MA, Cosgrove D.
Boys Town National Research Hospital, 555 No. 30th St., Omaha, NE 68131, USA.
Alport syndrome is a glomerular basement membrane (GBM) disease caused by mutations in type IV collagen genes. A unique irregular thickening and thinning of the GBM characterizes the progressive glomerular pathology. The metabolic imbalances responsible for these GBM irregularities are not known. Here we show that macrophage metalloelastase (MMP-12) expression is >40-fold induced in glomeruli from Alport mice and is markedly induced in glomeruli of both humans and dogs with Alport syndrome. Treatment of Alport mice with MMI270 (CGS27023A), a broad spectrum MMP inhibitor that blocks MMP-12 activity, results in largely restored GBM ultrastructure and function. Treatment with BAY-129566, a broad spectrum MMP inhibitor that does not inhibit MMP-12, had no effect. We show that inhibition of CC chemokine receptor 2 (CCR2) receptor signaling with propagermanium blocks induction of MMP-12 mRNA and prevents GBM damage. CCR2 receptor is expressed in glomerular podocytes of Alport mice, suggesting MCP-1 activation of CCR2 on podocytes may underlie induction of MMP-12. These data indicate that the irregular GBM that characterizes Alport syndrome may be mediated, in part, by focal degradation of the GBM due to MMP dysregulation, in particular, MMP-12. Thus, MMP-12/CCR2 inhibitors may provide a novel and effective therapeutic stra-tegy for Alport glomerular disease. PMID: 16816359 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=
Formulating for fast efficacy
J Cosmet Sci. 2006 Mar-Apr;57(2):191-2.
Wiechers JW, Kelley CL, Blease TG, Dederen JC.
Uniqema Applied Research, The Netherlands. PMID: 16758562 [PubMed - indexed for MEDLINE]
CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol. 2003 Oct;14(10):2503-15.
Furuichi K, Wada T, Iwata Y, Kitagawa K, Kobayashi K, Hashimoto H, Ishiwata Y, Asano M, Wang H, Matsushima K, Takeya M, Kuziel WA, Mukaida N, Yokoyama H.
Department of Gastroenterology and Nephrology and Division of Blood Purification, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Examined were CCR2-deficient mice to clarify the contribution of macrophages via monocyte chemoattractant protein 1 (MCP-1 or CCL2)/CCR2 signaling to the pathogenesis of renal ischemia-reperfusion injury. Also evaluated was the therapeutic effects via the inhibition of MCP-1/CCR2 signaling with propagermanium (3-oxygermylpropionic acid polymer) and RS-504393. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury was observed. Ischemia-reperfusion induced the expression of MCP-1 mRNA and protein in injured kidneys, followed by CCR2-positive macrophages in interstitium in wild-type mice. The expression of MCP-1 was decreased in CCR2-deficient mice compared with wild-type mice. The number of interstitial infiltrated macrophages was markedly smaller in the CCR2-deficient mice after ischemia-reperfusion. CCR2-deficient mice decreased the number of interstitial inducible nitric oxide synthase-positive cells after ischemia-reperfusion. The area of tubular necrosis in CCR2-deficient mice was significantly lower than that of wild-type mice after ischemia-reperfusion. In addition, CCR2-deficient mice diminished KC, macrophage inflammatory protein 2, epithelial cell-derived neutrophil-activating peptide 78, and neutrophil-activating peptide 2 expression compared with wild-type mice accompanied with the reduction of interstitial granulocyte infiltration. Similarly, propagermanium and RS-504393 reduced the number of interstitial infiltrated cells and tubular necrosis up to 96 h after ischemia-reperfusion injury. These results revealed that MCP-1 via CCR2 signaling plays a key role in the pathogenesis of renal ischemia-reperfusion injury through infiltration and activation of macrophages, and it offers a therapeutic target for ischemia-reperfusion. PMID: 14514728 [PubMed - indexed for MEDLINE]
Liver, Antiviral
New management of hepatitis B virus. Nippon Naika Gakkai Zasshi. 1999 Apr 10;88(4):713-7.
Sata M, Kumashiro R.
PMID: 10341661 [PubMed - indexed for MEDLINE
Hepatoprotective effect of propagermanium on Corynebacterium parvum and lipopolysaccharide-induced liver injury in mice. Scand J Immunol. 1998 Aug;48(2):183-91.
Yokochi S, Ishiwata Y, Hashimoto H, Ninomiya F, Suzuki T.
Developmental Research Department, Sanwa Kagaku Kenkyusho Co., Ltd, Mie, Japan.
Propagermanium is an organic germanium compound with immunopotentiating activity. We examined the hepatoprotective effect of propagermanium and its mechanism in an experimental animal model of acute liver injury induced with Corynebacterium parvum (C. parvum) and lipopolysaccharide (LPS) injection. Oral pretreatment with propagermanium decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in a dose-dependent manner. Significant attenuation of ALT and AST activity was obtained at a dose of 3 mg/kg. Administration of propagermanium also inhibited the infiltration of mononuclear cells into the liver of mice induced by C. parvum/LPS. Immunohistochemical examination revealed infiltration of the liver by CD4-, CD8-, CD11b- and Gr-1-positive cells. Propagermanium prevented CD4- and CD11b-positive cells from infiltrating the liver. In this animal model, blood cytokine levels increased rapidly after LPS injection, causing severe hepatitis. Notably, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are important mediators of the progress of liver injury. We demonstrated that propagermanium reduced IFN-gamma production by 53% at a dose of 3 mg/kg and also significantly inhibited the production of interleukin-12 (IL-12). These results indicate that propagermanium inhibits cell infiltration in the liver and cytokine production, and improves massive liver injury in C. parvum/LPS mice. PMID: 9716110 [PubMed - indexed for MEDLINE
Advances in the research of germanium
Sheng Li Ke Xue Jin Zhan. 1996 Apr;27(2):173-5.
Kong XR.
PMID: 9592247 [PubMed - indexed for MEDLINE]
Free Radical Scavenging, Antioxidant
Effects of selenium and germanium on lipid peroxidation in rats fed with low-selenium grain. Zhonghua Yu Fang Yi Xue Za Zhi. 1996 Mar;30(2):88-90.
Xie W, Chen X, Yang K.
Department of Environmental Health Tongji Medical University, Wuhan.
Rats were fed with grain produced in the area prevalent of Keshan disease for 12 weeks, by adding certain amount of sodium selenite (Na2SeO3) and carboxylethylgermanium (Ge-132) to study the combined effects of selenium and germanium on lipid peroxidation and metabolism of free radicals in their bodies. Results showed selenium and germanium added to the grain could reduce the content of free radicals in rats' liver and kidney tissues, and that of lipid peroxide in their heart, liver and kidney, and increase the activities of glutathione peroxidase (GSH-Px) in their blood, in a synergic way. PMID: 8758855 [PubMed - indexed for MEDLINE]
Multidisciplinary treatment of head and neck cancer using BCG, OK-432, and GE-132 as biologic response modifiers. Head Neck. 1994 Jan-Feb;16(1):30-8.
Fukazawa H, Ohashi Y, Sekiyama S, Hoshi H, Abe M, Takahashi M, Sato T.
2nd Department of Oral and Maxillofacial Surgery, Niigata University, School of Dentistry, Japan.
Since 1979, we have performed multidisciplinary treatment using intensive immunotherapy with biologic response modifiers (BRM) in combination with surgical treatment of oral cancer. Chemotherapy and radiotherapy were also included as part of the therapy. A historic control study was performed. Adjuvant therapy was administered by standardized methods, and the distribution of patients at various stages was similar between groups. The immunotherapy group showed a shorter treatment period, lower rates of recurrence, metastases, and side effects, greater histologic effects at the end of the first treatment, and a higher survival rate than the nonimmunotherapy group. Immunologically, immunotherapy tended to promote positive immune reactions and inhibit negative immune reactions. PMID: 7510275 [PubMed - indexed for MEDLINE]
Experimental study on prevention of the colorectal cancer by China medical stone and the organgermanium compound. Zhonghua Yu Fang Yi Xue Za Zhi. 1993 Sep;27(5):286-9.
Song WS.
Pearl River Hospital, First Medical University of PLA, Guangzhou.
To compare the effect of cancer prevention of China medical stone (CMS) and Ge-132, rats were subcutaneously injected with dimethylhydrazine for 15 weeks and orally administered with 10% china medical stone soak and Ge-132 for 27 weeks. Colorectal cancer incidence in CMS was found significantly lower than in Ge-132 and controls (P < 0.05-0.01). In Ge-132 only the mean cancer foci and the mean cancer volumes/rat were found significantly less than controls (P < 0.01). It was shown by endoscopy that a precancerous lesion of the bowel resulted from carcinogen was more mild in CMS and Ge-132 than in controls. Serum gamma-interferon titer and NK activity of spleen cells were significantly elevated in CMS and Ge-132. Researches explained that the effect of cancer prevention of CMS was better than that of Ge-132. PMID: 8137660 [PubMed - indexed for MEDLINE]
Cancer, Physiology, Safety
Organic germanium: its toxic effect and function in medical care. Zhonghua Yi Xue Za Zhi. 1993 Aug;73(8):454-6.
Kong X.
Protective effect of an organic germanium compound on warm ischemia and prolonged kidney preservation. Transplant Proc. 1989 Feb;21(1 Pt 2):1250-1.
Masaki Y, Kumano K, Iwamura M, Endo T, Sakai T, Koshiba K, Nakamura K, Yokota K, Sato K, Uchida H, et al.
Department of Animal Experiment, Kitasato University School of Medicine, Kanagawa, Japan.
Heart, Physiology
Effects of dicarboxyethenylgermanium sesquioxide on electrical and mechanical activity in isolated guinea pig and rabbit heart. Yao Xue Xue Bao. 1989 Jan;24(1):63-6.
Ma FJ, Zhao GS, Li XG.
The effects of dicarboxyethenylgermanium sesquioxide (DCG) on electrical and mechanical activity in isolated guinea pig papillary muscles and rabbit sinus node were studied by intracellular capillary glass electrode. The effects of DCG on slow action potential and contractile force (Fc) of preparations in which the fast Na+ channels were inactive by partial depolarization by increasing the concentration of K+ 25.4 mmol/L were observed. DCG (0.5 mol/L) increased Vmax and APA of fast action potential of guinea pig papillary muscles, but its Fc decreased from 105 +/- 12% of control to 80 +/- 16%. DCG prolonged the spontaneous cycle length (SCL) and APD90 of rabbit sinus node, but the slope of phase 4(SP4) was lowered. The functional refractory period (FRP) of rabbit left atria was determined by the paired stimulus method. In experiments involving one drug, the drug was added until equilibrium had been reached. It has been demonstrated by experiments that the administration of DCG resulted in an increase of atrial FRP. These findings suggest that the Ca2+ inward currents and the K+ outward current may be inhibited by DCG. PMID: 2801126 [PubMed - indexed for MEDLINE]
Cancer, Lung
Effect of combination immunochemotherapy with an organogermanium compound, Ge-132, and antitumor agents on C57BL/6 mice bearing Lewis lung carcinoma (3LL). Gan To Kagaku Ryoho. 1986 Aug;13(8):2588-93.
Kobayashi H, Komuro T, Furue H.
The antitumor effect of combination immunochemotherapy with Ge-132 and antitumor agent was studied using C57BL/6 mice bearing Lewis lung carcinoma (3LL). Ge-132 was administered orally at a daily dose of 100 mg/kg. Antitumor agents were administered intraperitoneally once a week. Initially, the effect of combination immunochemotherapy with Ge-132 and 5-fluorouracil (5-FU) was studied on 3LL local tumor growth, pulmonary metastases, survival, delayed type hypersensitivity (DTH) and body weight in tumor-bearing mice, and the following results were obtained: Inhibition of tumor growth in the combined group; Enhanced anti-metastatic effect; Prolonged survival time, and; Recovery of loss of both DTH and body weight as a result of combination therapy. These antitumor effects were also obtained by adoptive transfer of Ge-132-stimulated splenocytes in 5-FU-treated mice bearing 3LL. These results therefore suggest that the effects of Ge-132 were expressed through modification of immunocytes. Furthermore, Ge-132 enhanced the antitumor activity of bleomycin as well as that of 5-FU. These facts suggested that Ge-132 is useful for antitumor combination immunochemotherapy. PMID: 2427032 [PubMed - indexed for MEDLINE]
Antitumor activity of Ge-132, a new organogermanium compound, in mice is expressed through the functions of macrophages and T lymphocytes. Gan To Kagaku Ryoho. 1985 Jul;12(7):1445-52.
The antitumor activity of Ge-132 against a variety of allogeneic and syngeneic murine ascites tumors was first evaluated. The antitumor effects of Ge-132 were observed when mice inoculated with Ehrlich carcinoma (allogeneic) or RL male 1 leukemia (syngeneic) cells were treated orally. However, Ge-132 had no activity on a T-cell lymphoma (EL 4, syngeneic) or a methylcholanthrene-induced fibrosarcoma (Meth-A, syngeneic). The antitumor effect of Ge-132 in mice was related to the dose administered as well as the administration schedule. The antitumor activity of Ge-132 was next studied in mice pretreated with some blockers against immunocompetent cells. The antitumor efficacy of Ge-132 was not observed when tumor-bearing mice were treated with trypan blue and carrageenan or monoclonal anti-Thy 1.2 antibody. However, when natural killer cells were eliminated from mice bearing RL male 1 or Ehrlich ascites tumors by treatment with anti-asialo GM 1 antiserum, the antitumor efficacy of the compound was unchanged. These results suggest that Ge-132 is effective against certain ascites tumors regardless of whether the tumor is syngeneic or allogeneic. Further, its effect might be expressed through host defense mechanisms, including macrophages and/or T lymphocytes. PMID: 3874600 [PubMed - indexed for MEDLINE]
Antitumor effect of the organogermanium compound Ge-132 on the Lewis lung carcinoma (3LL) in C57BL/6 (B6) mice. Tohoku J Exp Med. 1985 May;146(1):97-104.
Kumano N, Ishikawa T, Koinumaru S, Kikumoto T, Suzuki S, Nakai Y, Konno K.
Effects of the organogermanium compound Ge-132 (i.p.) were examined on the 3LL local tumor (1 X 10(5)/mouse, s.c.) and its pulmonary metastases in B6 mice. A characteristic feature of its action was the preferential antimetastatic effect under strictly defined conditions. Either inhibition or facilitation was observed depending on the treatment schedules; 7 daily doses of 100 mg/kg yielded the inhibition ratio 49% when started from day 1, whereas the treatment from day 8 resulted in the ratio -99%. The maximum inhibition was obtained at 100 mg/kg. The postsurgical-adjuvant treatment with Ge-132 was of no beneficial effect. The local tumor growth was affected only marginally and temporarily. When inoculum size was minimized (1 X 10(4)), a single dose of 300 mg/kg on day 1, but not on day 8, was effective in prolonging the latency before tumor take. The antitumor action of Ge-132 was discussed with reference to its interferon (IFN)-inducing activity. PMID: 4024087 [PubMed - indexed for MEDLINE]
Induction of interferon and activation of NK cells and macrophages in mice by oral administration of Ge-132, an organic germanium compound. Microbiol Immunol. 1985;29(1):65-74.
Aso H, Suzuki F, Yamaguchi T, Hayashi Y, Ebina T, Ishida N.
After oral administration of an organic germanium compound, Ge-132 (300 mg/kg), a significant level of interferon (IFN) activity was detected in the sera of mice at 20 hr and it reached a maximum of 320 U/ml at 24 hr. This IFN activity was lost after heat- or acid-treatment, suggesting that the induced IFN is of gamma-nature. The molecular weight of this IFN was estimated to be 50,000 daltons by gel filtration. The NK activity of spleen cells was increased 24 hr after the oral administration of Ge-132, and cytotoxic macrophages were induced in the peritoneal cavity by 48 hr. In the mice receiving an intraperitoneal (ip) injection of trypan blue or carrageenan 2 days before oral administration of Ge-132, neither induction of IFN nor augmentation of NK activity occurred, and X-ray irradiation of mice also rendered the mice incapable of producing IFN, all indicating that both macrophages and lymphocytes are required for this IFN induction. Both NK and cytotoxic macrophages appeared 18 hr after ip administration of the induced IFN with a titer as low as 20 U/ml. These facts suggest that both the augmentation of NK activity and activation of macrophages in mice after oral administration of Ge-132 are mediated by the induced IFN. PMID: 2581116 [PubMed - indexed for MEDLINE]
Effects of interferon and its inducers on neutrophil chemiluminescence. Gan To Kagaku Ryoho. 1984 Jul;11(7):1439-43. [Article in Japanese]
Takahashi I, Fukumoto M, Inagaki N, Ueda I, Nishimura M, Aoyama S, Oda Y, Ohmoto E, Takaoka K, Lai M, et al.
In order to evaluate effects of interferon (IFN) and its inducers on neutrophil functions, neutrophil chemiluminescence (ChL) was assayed in 12 patients treated with IFN (human lymphoblastoid interferon, 3.0 X 10(6) units/day i.m. daily) or Ge-132 (2,250 mg/day p.o. daily). The peak levels of neutrophil ChL, assayed one week after the initiation of treatment, were increased in comparison to those before treatment, but one month after treatment they were decreased to pretreatment levels in spite of the daily administration of the agent. On the basis of these results, it was concluded that IFN and Ge-132 enhanced the host defence mechanism including the activation of neutrophils, which appeared at the early phase of the host reaction. PMID: 6588923 [PubMed - indexed for MEDLINE]
Augmentation of NK activity in peripheral blood lymphocytes of cancer patients by intermittent GE-132 administration. Gan To Kagaku Ryoho. 1984 Jun;11(6):1303-6. [Article in Japanese]
Tanaka N, Ohida J, Ono M, Yoshiwara H, Beika T, Terasawa A, Yamada J, Morioka S, Mannami T, Orita K.
The natural killer (NK) activity of peripheral blood lymphocytes from 18 cancer patients was studied prior to and after multiple administration of organo-germanium compound (Ge-132). In successive oral administration of Ge-132 at a dose of 1000 mg/day for 10 days, NK-activity of patients was augmented at 3 days, but by 10 days, depression of NK activity was observed in all cases. In intermittent oral administration of Ge-132, however, more than half of the patients with augmented NK activity at day 3 maintained the high activity level at day 10. This result suggests the superiority of intermittent administration of Ge-132 for clinical use. PMID: 6732257 [PubMed - indexed for MEDLINE]
Prevention of suppressed interferon gamma production in thermally injured mice by administration of a novel organogermanium compound, Ge-132. J Interferon Res. 1984 Spring;4(2):223-33.
Suzuki F, Pollard RB.
As reported previously, gamma interferon (IFN-gamma) production was selectively decreased in thermally injured mice (TI-Mice) and spleen cell cultures from the mice following stimulation with various IFN inducers. The decrease in IFN production was associated with splenic suppressor macrophages. The present study demonstrated that TI-Mice treated with Ge-132 (TGe-Mice) produced IFN following stimulation with IFN-gamma inducers. The level of IFN activity detected in the sera of TGe-Mice approximated that of controls. Similar results were obtained when spleen cells prepared from TGe-Mice were stimulated with IFN-gamma inducers in vitro. While transfer of spleen cells from TI-Mice resulted in the suppression of IFN production in normal mice (N-Mice) stimulated with IFN-gamma inducers, the transfer of spleen cells derived from TGe-Mice did not induce suppression of IFN production in N-Mice. Mononuclear cells (MNC) prepared from N-Mice produced IFN following concanavalin A (Con A) stimulation when they were co-cultured with macrophage-enriched populations (PAC) obtained from the spleens of TGe-Mice. In contrast, MNC stimulated with Con A did not produce IFN activity when they were co-cultured with PAC of TI-Mice. These results suggest that the generation of suppressor macrophages in TI-Mice may be altered by the administration of Ge-132. PMID: 6431019 [PubMed - indexed for MEDLINE]
Antimutagenic effect of Ge-132 on gamma-ray-induced mutations in Escherichia coli B/r WP2 trp-. Int J Radiat Biol Relat Stud Phys Chem Med. 1982 Dec;42(6):653-9.
Mochizuki H, Kada T.
Effect of NK-421 (Bestatin) and Ge-132 on the cytotoxicity of spleen cells obtained from the tumor-bearing mice. Gan To Kagaku Ryoho. 1982 Oct;9(10):1771-7.
Ono M, Oka T, Yoshihara H, Tanaka N, Miwa H, Mannami T, Konaga E, Orita K.
The effect of NK-421(Bestatin) and Ge-132 (an organic germanium compound) on the ADCC and natural killing (NK) activities of the spleen cells of MH-134 tumor-bearing mice were studied. In the tumor-bearing mice, the ADCC activity was enhanced, and NK activity was reduced in accordance with the progress of the tumor. By oral administration of Bestatin at doses of 5, 10 and 50 mg/kg, ADCC activity was potentiated, and at a dose of 10 mg/kg, NK activity was significantly increased. Intraperitoneal administration of Ge-132 at 50 mg/kg potentiated the ADCC activity of tumor-bearing mice. A higher activity was observed in the plastic dish adherent fraction. Ge-132 also potentiated the reduced NK activity of tumor-bearing mice to higher level than normal mice. The elevated activities of ADCC and NK following Bestatin and Ge-132 administration were decreased with anti-Thy-1 antibody and complement; however, the percent reduction was lower compared to that of the control cancer animals. This result indicates that Bestatin and Ge-132 may act on non-T cells and augment ADCC and NK activities. PMID: 7184374 [PubMed - indexed for MEDLINE]
Liver, Immune System
Endogenous gamma interferon production may protect against hepatic cirrhosis and administration of exogenous gamma interferon may protect individuals prone to cirrhosis. Med Hypotheses. 1987 Apr;22(4):415-9.
Sharpe RJ.
Hepatic cirrhosis is characterized by the replacement of normal liver parenchyma by collagenous fibrous tissue. Although hepatocytes in the adult retain the ability to divide, under certain circumstances hepatocyte death leads to replacement with fibroblasts and collagen. Whether a particular form of hepatocyte injury leads to cirrhosis is dependent upon the stimulus for the injury and is also highly variable between individuals. It has recently been shown that gamma interferon inhibits collagen synthesis in vitro and fibrosis in vivo. I suggest that individuals who are prone to hepatic cirrhosis from a given stimulus are low producers of gamma interferon while high gamma interferon producers are relatively protected from cirrhosis. I also hypothesize that exogenous gamma interferon administration may halt or slow the progression of cirrhosis in patients with early progressive cirrhosis. Alternatively, endogenous gamma interferon production could be stimulated in these patients with progressive cirrhosis. One agent which may be useful for inducing endogenous gamma interferon is GE-132, an organogermanium. PMID: 3108636 [PubMed - indexed for MEDLINE]
Antimutagenic, DNA Repair
Organogermanium compounds as inhibitors of the activity of direct acting mutagens in Salmonella typhimurium. Arzneimittelforschung. 1997 Dec;47(12):1398-402.
Schimmer O, Eschelbach H, Breitinger DK, Grutzner T, Wick H.
Institut fur Botanik und Pharmazeutische Biologie, Universitat Erlangen-Nurnberg, Erlangen, Germany.
The organogermanium compounds bis(D,L-lactato)germanium(IV), bis(L-lactato)germanium(IV), bis (thiolactato)germanium(IV) and bis(thioglycolato)germanium(IV) were tested for their antimutagenic activity in Salmonella typhimurium strains TA98 and TA100. Each compound showed moderate activity against the mutagenic effect of nitroaromatic compounds and weak effects against the mutagenic activity of ethylmethane sulfonate. No inhibition of mutagenicity was observed against the indirect acting promutagens benzo(a)pyrene and 2-aminoanthracene. The compounds differed only quantitatively in their antimutagenicity spectrum. It is concluded from these results that an intracellular mechanism is involved in the inhibition of ethylmethane sulfonate-induced mutagenicity. The effect is probably produced, at least partially, at the level of DNA repair. Frameshift mutations seem to be prevented with higher efficiency than base pair substitutions. PMID: 9450171 [PubMed - indexed for MEDLINE]
Cancer, Cervix, Uterus
The inhibition of the development of experimental tumors of the cervix uteri and vagina by using tinctures of the cultured-cell biomass of the ginseng root and its germanium-selective stocks. Biull Eksp Biol Med. 1993 Nov;116(11):534-6.
Bespalov VG, Davydov VV, Limarenko AIu, Slepian LI, Aleksandrov VA.
The anticarcinogenic effects of bioginseng and two germanium-selective drugs produced by cultivating cells of ginseng radix (Panax ginseng C. A. Mey) in a conventional medium or in media containing organogermanium compounds were studied. Squamous-cell carcinomas of the uterus cervix and vagina were induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene in mice. The drugs of ginseng were used orally or intravaginally during a long period of time of the postinitiation stage of carcinogenesis. All the drugs used locally effectively inhibited the development of induced carcinomas of the uterus cervix and vagina. When orally used, the drugs of ginseng exhibited only an insignificant tendency to inhibit the carcinogenesis of uterus cervix and vagina. The anticarcinogenic effects of the compared drugs were similar. PMID: 8312554 [PubMed - indexed for MEDLINE]
A new inducer of immune interferon in human leukocytes--the organogermanium compound MOP-11. Vopr Virusol. 1991 Jan-Feb;36(1):63-4.
Khusainov RM, Ignatenko MA, Gritsenko LI, Frolova IS, Babaiants AA, Kuznetsov VP, Amchenkova AM, Narovlianskii AN, Pokidysheva LN, Barteneva NS, et al.
Restoration of impaired immunoresponse by germanium in mice. Int Arch Allergy Appl Immunol. 1980;63(3):338-9
Mizushima Y, Shoji Y, Kaneko K.
An organogermanium was given to young and aged C3H/HeJ mice sensitized by sheep red blood cells, and plaque-forming cells (PFC) in the spleens from the animals were measured. PFC decreased markedly in the aged mice. The organogermanium at an appropriate dose significantly increased the PFC in the aged mice, whereas it did not increase PFC in the young mice. Thus, germanium is considered to restore to some extent the impaired immunoresponses in aged mice. PMID: 7419294 [PubMed - indexed for MEDLINE]
Inhibition of glutathione-S-aryltransferase from rat liver by organogermanium, lead and tin compounds. Biochem Pharmacol. 1976 Oct 15;25(20):2291-5.
Henry RA, Byington KH.
PMID: 985560 [PubMed - indexed for MEDLINE]
Antimicrobial activity of organogermanium derivatives. Nature. 1964 Feb 15;201:736.
Sijpesteijn AK, Rijkens F, Van Der Kerk GJ, Manten A.
PMID: 14134741 [PubMed - OLDMEDLINE]
Anti-inflammatory, Pain Management
Anti-inflammatory effect of germanium-concentrated yeast against paw oedema is related to the inhibition of arachidonic acid release and prostaglandin E production in RBL 2H3 cells. Auton Autacoid Pharmacol. 2005 Oct;25(4):129-34.
Lee JH, Kim KW, Yoon MY, Lee JY, Kim CJ, Sim SS.
Department of Pathophysiology, College of Pharmacy, Chung-Ang University, 221 Huksuk-dong, Dongjak-gu, Seoul 156-756, South Korea.
To investigate anti-inflammatory activity of organic germanium, we measured the effect of germanium-concentrated yeast on arachidonic acid release, prostaglandin E(2) (PGE(2)) production, histamine release, and intracellular H(2)O(2) or hydroperoxide generation in RBL 2H3 cells, and carrageenan-induced paw oedema in rats. 2 Germanium-concentrated yeast dose-dependently inhibited carrageenan-induced paw oedema, suggesting that germanium-concentrated yeast has anti-inflammatory activity in acute inflammation. 3 Germanium-concentrated yeast significantly inhibited melittin-induced arachidonic acid release and PGE(2) production in RBL 2H3 cells. 4 Germanium-concentrated yeast did not affect melittin-induced histamine release and silica-induced intracellular H(2)O(2) or hydroperoxide generation in RBL 2H3 cells. 5 These results suggest that anti-inflammatory activity of germanium-concentrated yeast appears partly to be related to the inhibition of arachidonic acid release and PGE(2) production in RBL 2H3 cells. PMID: 16176443 [PubMed - indexed for MEDLINE]
Safety, Toxicity
Oral single- and repeated-dose toxicity studies on Geranti Bio-Ge Yeast, organic germanium fortified yeasts, in dogs. J Toxicol Sci. 2004 Dec;29(5):555-69.
Lee JS, Park JI, Kim SH, Lee HY, Hwang ZZ, Park CB, Sohn TU, Shin S, Kang JK, Kim YB.
Biotoxtech Co., Ltd., Ochang Scientific and Industrial Complex, Cheongwon, Korea.
Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast, organic germanium fortified yeasts, were investigated in dogs. Both sexes of Beagle dogs were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test, no animal dead, moribund, or showing clinical signs or changes in body weight gain was found. In repeated-dose toxicity study, there were no considerable changes in ophthalmoscopy and urinalysis. Several alterations were observed in electrocardiography, hematology and blood biochemistry, including heart rate, R-R interval, QT correcting, reticulocytes, activated partial thromboplastin time and albumin/globulin ratio in only male dogs, but not in females, administered with Geranti Bio-Ge Yeast in a dose-independent manner. In gross findings, several cases of abnormal findings were observed in both control and treatment groups, showing diffuse dark brown to black discoloration of liver, in a dose-independent manner. In microscopic examination, mild lesions, including cholestasis and inflammatory cell foci in liver, kidneys and prostate, were found sporadically in both control and treatment groups. In spite of some alterations in electrocardiography, hematology, blood biochemistry, gross and microscopic findings, such effects were not considered to include toxicopathological significance, based on the marginal changes within normal ranges and lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast is considered to be 2,000 mg/kg in dogs, and that long-term treatment in clinical trials might not exert adverse effects. PMID: 15729010 [PubMed - indexed for MEDLINE]
Oral single- and repeated-dose toxicity studies on Geranti Bio-Ge yeast, organic germanium fortified yeasts, in rats. J Toxicol Sci. 2004 Dec;29(5):541-53.
Lee JS, Park JI, Kim SH, Park SH, Kang SK, Park CB, Sohn TU, Jang JY, Kang JK, Kim YB.
Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast, organic germanium fortified yeasts, were investigated in rats. Both sexes of Sprague-Dawley rats were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test to determine dose levels in repeated-dose toxicity study, the body weight gain was suppressed at 2,000 mg/kg, although no death, clinical signs and pathological findings related to the treatment were observed. In repeated-dose toxicity test, there were no clinical signs in animals administered up to 2,000 mg/kg, except one rat died due to a gavage error. In addition, no significant changes in feed consumption and body weight gain were obtained during the treatment period, in spite of week-to-week fluctuation of water consumption. There were no considerable changes in ophthalmoscopy, urinalysis, hematology and serum biochemistry, except a significant decrease in albumin/globulin ratio in males treated with 1,000 mg/kg. In contrast, a significant increase in relative heart weight was observed in both male and female rats treated with a high dose (2,000 mg/kg) of Geranti Bio-Ge Yeast. In microscopic examination, mild lesions were found sporadically in both control and treatment groups in a dose-independent manner. In spite of some alterations in water consumption, serum biochemistry and organ weights, such effects were not considered to include toxicopathological significance, based on the lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast is considered to be over 2,000 mg/kg in rats, and that long-term oral intake in humans might not exert adverse effects. PMID: 15729009 [PubMed - indexed for MEDLINE]
Determination of germanium in aloe vera by spectrophotometric method. Wei Sheng Yan Jiu. 2004 Nov;33(6):747-9. [Article in Chinese]
Hou D, Hui R, Chen B, Guo H, Li H.
Department of Chemistry, Anshan Normal University, Anshan 114005, China.
OBJECTIVE: To analyze the organic germanium in aloe vera from different localities. METHODS: The method was based on germanium forms a stable complex with phenylfluorone in the acidified solution and CTMAB as solubilization agent. The contents of the organic germanium in Aloe vera from different localities were determined by spectrophotometric methods. RESULTS: The linear range of determination is 0-0.7 microg/ml. The recovery is 98.1%-99.0% and the coefficient of variation is 1.8%. PMID: 15727195 [PubMed - indexed for MEDLINE]
Organotrichlorogermane synthesis by the reaction of elemental germanium, tetrachlorogermane and organic chloride via dichlorogermylene intermediate. Dalton Trans. 2004 Aug 7;(15):2372-6. Epub 2004 Jun 24.
Okamoto M, Asano T, Suzuki E.
Department of Applied Chemistry, Tokyo Institute of Technology, Ookayama, Meguro-ku, Tokyo 152-8552, Japan.
Organotrichlorogermanes were synthesized by the reaction of elemental germanium, tetrachlorogermane and organic chlorides, methyl, propyl, isopropyl and allyl chlorides. Dichlorogermylene formed by the reaction of elemental germanium with tetrachlorogermane was the reaction intermediate, which was inserted into the carbon-chlorine bond of the organic chloride to give organotrichlorogermane. When isopropyl or allyl chloride was used as an organic chloride, organotrichlorogermane was formed also in the absence of tetrachlorogermane. These chlorides were converted to hydrogen chloride, which subsequently reacted with elemental germanium to give the dichlorogermylene intermediate. The reaction of elemental germanium, tetrachlorogermane and organic chlorides provides a simple and easy method for synthesizing organotrichlorogermanes, and all the raw materials are easily available. PMID: 15278133 [PubMed]
Determination of germanium in human specimens: comparative study of atomic absorption spectrometry and microwave-induced plasma mass spectrometry. J Anal Toxicol. 1999 Nov-Dec;23(7):625-31.
Shinohara A, Chiba M, Inaba Y.
Department of Epidemiology and Environmental Health, Juntendo University School of Medicine, Tokyo, Japan.
The determination methods of germanium (Ge) in biological specimens such as blood plasma, erythrocytes, urine, hair, nail, and other organs were established using graphite furnace atomic absorption spectrometry (GFAAS) and microwave-induced plasma mass spectrometry (MIP-MS). The detection limits of Ge standard solution were 3 ng/mL with GFAAS and 0.05 ng/mL with MIP-MS. The detection limits in organ samples depended on the type of samples and sampling amounts: 3-30 ng/g by GFAAS and 0.05-0.5 ng/g by MIP-MS. The sensitivity of GFAAS was lower than that of MIP-MS; however, it was adequate for determining Ge concentrations in specimens from patients who had ingested Ge. Samples were digested by a simple wet-ashing procedure using nitric acid and perchloric acid. To avoid the interfering effects of coexisting elements and perchloric acid residue, an extraction method using organic solvent was tried. When using MIP-MS, extraction was not necessary; however, both dilution and addition of an internal standard were needed. Special attention was required for iron-rich samples because a molecular ion of 56Fe16O was observed at nm/z72 where 2Ge was monitored. The results of Ge concentrations in human samples obtained by these methods agreed well. Interfering effects of perchloric acid, which was used for digestion and which remained in samples, were observed in both methods. Hair and nail samples from people who had ingested Ge were useful for monitoring Ge in the body. Hair samples were useful for determining past exposure to Ge when the distribution patterns from the scalp to the end of the strand were analyzed. In control subjects, Ge concentrations in the listed specimens and organs were lower than 0.1 microg/g or mL, and these low levels of Ge were able to be determined by MIP-MS in combination with the extraction method. PMID: 10595851 [PubMed - indexed for MEDLINE]
Safety, Toxicity, Mutagenicity
Mutagenicity, carcinogenicity and teratogenicity of germanium compounds. Mutat Res. 1997 Dec;387(3):141-6.
Gerber GB, Leonard A.
Teratogenicity and Mutagenicity Unit, Catholic University of Louvain, Brussels, Belgium.
The metalloid germanium has found widespread application in electronics, nuclear sciences and in medicine. General toxicity of germanium is low, except for the tetrahydride germane, and few observations on toxicity of germanium in man exist. Germanium is not carcinogenic and even appears to inhibit cancer development and, in the form of the organic germanium compound, spirogermanium, to destroy cancer cells. Germanium compounds have no mutagenic activity and may, under certain conditions, inhibit the mutagenic activity of other substances. High doses of germanium may result in an increased embryonic resorption, but possible malformations have been reported only after administration of dimethyl germanium oxide to pregnant animals. Germanium may thus be considered an element of rather low risk to man. PMID: 9439710 [PubMed - indexed for MEDLINE]
Safety, Toxicity, Cancer
Cancer risks for humans from exposure to the semiconductor metals. Scand J Work Environ Health. 1993;19 Suppl 1:101-3.
Fowler BA, Yamauchi H, Conner EA, Akkerman M.
Program in Toxicology, University of Maryland, Baltimore 21227.
Of the semiconductor metals, only arsenic has been extensively studied as a human carcinogen and systemic toxicant. Recent studies have shown, however, that gallium, arsenic, and indium are capable of producing marked alterations in cellular gene products. After acute in vivo administration indium and thallium have been shown to produce decreases in the activity of some drug-metabolizing enzymes dependent on cytochrome P-450; therefore these metals would be capable of interfering with the metabolism of organic carcinogens. Selenium is essential for the activity of the enzyme glutathione peroxidase, which modulates the active intermediates generated by drug-metabolizing enzyme systems. Germanium produces toxicity in a number of organ systems. Antimony produces lung and circulatory system effects. Overall, available data suggest that these metals or metalloids are capable of biologically altering several cellular defense mechanisms involved in the carcinogenic process and that further studies are needed to determine the associated risks. PMID: 8159952 [PubMed - indexed for MEDLINE]
Safety, Toxicity, Hazards, Physiology
Toxicity of an organic Germanium compound: deleterious consequences of a "natural remedy". Schweiz Med Wochenschr. 1992 Jan 8;122(1-2):11-3.
Raisin J, Hess B, Blatter M, Zimmermann A, Descoeudres C, Horber FF, Jaeger P.
Medizinische Universitatspoliklinik, Inselspital, Bern.
Reports mainly from Japan, recommend germanium (Ge)-containing compounds as "anti-cancer" and "immunostimulatory" remedies. We report on a 25-tear-old woman with stage II HIV disease who consumed a total of 47 g Ge as Ge-lactate-citrate 18%. She developed severe renal insufficiency (creatinine clearance 7 ml/min/1.73 m2, proteinuria 0.28 g/d) and hepatomegaly. Biopsies revealed tubulointerstitial nephropathy with vacuolar degeneration, mainly of distal tubular epithelia, and severe liver steatosis. Tissue Ge content in kidney and liver biopsy specimens was increased 68-and 140 fold respectively. In agreement with previous reports, renal dysfunction persisted 9 months later (creatinine clearance 11 ml/min/1.73 m2). PMID: 1594900 [PubMed - indexed for MEDLINE]
Cancer, Antimutagenic
Effect of germanium on 1,2-dimethylhydrazine-induced intestinal cancer in rats. Dis Colon Rectum. 1990 Feb;33(2):99-104.
Jao SW, Lee W, Ho YS.
Department of Surgery, National Defense Medical Center, Taipei, Taiwan,Republic of China.
Through recent research, the trace element, germanium, was found to have an anticancer effect. The purpose of this research was to determine the effect of germanium on 1,2-dimethylhydrazine-induced intestinal cancer in rats. Ninety-six 8-week-old Sprague-Dawley male rats were divided into 4 groups, with 24 rats in each group. All received dimethylhydrazine, 20 mg/kg body weight, subcutaneously, once a week for 20 weeks. Except for one control group, the other three groups were subdivided into six groups and administered three different kinds of germanium (inorganic germanium, organic germanium, and natural organic germanium) one month before and during dimethylhydrazine treatment, and during dimethylhydrazine treatment, respectively. Twenty-four weeks after carcinogen exposure, all surviving animals were sacrificed and examined for intestinal tumors. The number and location of the tumors were recorded and the pathology examined. The incidence of intestinal cancer in the control group (dimethylhydrazine only) was 91 percent; in groups provided with inorganic germanium one month before and during dimethylhydrazine treatment, and during dimethylhydrazine treatment only, it was 91 and 78 percent; in groups provided with organic germanium one month before and during dimethylhydrazine treatment, and during dimethylhydrazine treatment only, it was 64 and 64 percent; in groups provided with natural organic germanium one month before and during dimethylhydrazine treatment and during dimethylhydrazine treatment only, it was 50 and 45 percent. From these results, the authors conclude that natural organic germanium has the best prevention effect for intestinal cancer in this animal model (P less than 0.01), followed by organic germanium (P less than 0.05). Inorganic germanium has no effect. However, there is no difference in the cancer prevention effect of germanium provided one month before and during dimethylhydrazine treatment, and during dimethylhydrazine treatment only. PMID: 2153512 [PubMed - indexed for MEDLINE]
Cancer, Immune System, Antiviral, Arthritis, Osteoporosis
Therapeutic effects of organic germanium. Med Hypotheses. 1988 Jul;26(3):207-15.
Goodman S.
International Inst. of Symbiotic Studies, Brighton, Sussex, U.K.
Germanium is present in all living plant and animal matter in micro-trace quantities. Its therapeutic attributes include immuno-enhancement, oxygen enrichment, free radical scavenging, analgesia and heavy metal detoxification. Toxicological studies document Germanium's rapid absorption and elimination from the body, and its safety. Clinical trials and use in private practices for more than a decade have demonstrated Germanium's efficacy in treating a wide range of serious afflictions, including cancer, arthritis and senile osteoporosis. Germanium's anti-viral and immunological properties, including the induction of interferon, macrophages, T-suppressor cells and augmentation of natural killer cell activity, suggest its possible efficacy in treating and/or preventing AIDS. PMID: 3043151 [PubMed - indexed for MEDLINE]
Cancer, Lung, Immune System
Prevention of pulmonary metastasis of Lewis lung carcinoma and activation of murine macrophages by a novel organic germanium compound, PCAGeS. J Biol Response Mod. 1988 Feb;7(1):1-5.
Sato I, Nishimura T, Kakimoto N, Suzuki H, Tanaka N.
Institute of Applied Microbiology, University of Tokyo, Japan.
The pulmonary metastasis of Lewis lung carcinoma was strongly blocked by daily intraperitoneal (i.p.) treatment with 0.5 mg of PCAGeS/kg/day for 7 days after tumor implantation. The metastasis-preventive activity of PCAGeS was markedly reduced when mice were treated with carrageenan, a macrophage blocker. On the other hand, treatment with antiasialo GM1 antiserum did not significantly affect the percentage of inhibition of metastasis by the compound. These results suggest that macrophages rather than natural killer (NK) cells play an important role in the suppression of metastasis by PCAGeS. PCAGeS induced tumoristatic and tumoricidal activities in the peritoneal macrophages of mice by oral administration. The activity of NK cells was also augmented by i.p. treatment with the compound. These results suggest that PCAGeS is a useful substance for preventing pulmonary metastasis. PMID: 3373232 [PubMed - indexed for MEDLINE]
Elemental-organic combinations in medicine. Pharmazie. 1987 Dec;42(12):793-9.
Bohm R.
Sektion Pharmazie, Martin-Luther-Universitat Halle-Wittenberg, Wissenschaftsbereich Pharmazeutische Chemie. PMID: 3328203 [PubMed - indexed for MEDLINE]
Safety, Hazards, Physiology
Accumulation of germanium in the tissues of a long-term user of germanium preparation died of acute renal failure. J Toxicol Sci. 1985 Nov;10(4):333-41.
Nagata N, Yoneyama T, Yanagida K, Ushio K, Yanagihara S, Matsubara O, Eishi Y.
Acute renal failure developed in a patient accompanied by systemic manifestations such as myopathy and skin rash. The patient, a middle aged house wife, had been taking 600 mg of germanium (Ge) preparation daily for 18 months as an elixir. The main component of the preparation was GeO2 and some organic compound was also present. Histological study of the kidney post mortem showed foamy cell transformation of glomerular epithelia, degeneration of tubular epithelia with red blood cell casts and urate crystals, and a mild proliferation of mesangial matrix. Analysis of the tissue content of Ge, prompted by her history, revealed an increased accumulation of the metal. As compared to a non-user died of liver cirrhosis, the concentration of the metal was higher particularly in the spleen (183X), thyroid gland (175X), psoas muscle (93X), jejunum (76X), and renal cortex (69X). So far, neither accumulation of Ge in humal tissue nor systemic toxicity of the Ge in human has been reported. The relevance of massive accumulation of Ge to the renal failure as well as to other systemic manifestations the patient presented remains to be clarified. PMID: 3831368 [PubMed - indexed for MEDLINE]
Suppression and acceleration of experimental amyloidosis in mouse model. Acta Pathol Jpn. 1980 Jul;30(4):557-64.
Suzuki T, Ishikawa S, Motoyama T, Oboshi S.
Leupeptins, protease inhibitors, suppress the appearance of experimental amyloidosis in CBA mice induced by the injections with complete Freund's adjuvant. This substance, however, should be administered continuously from 1 week prior to amyloid induction to the end of the experiment. On the other hand, Trypan blue, inhibitors of lysosomal enzymes, accelerates experimental amyloidosis in the mouse model above-mentioned. Trypan blue is effective when given either prior to or at the same time of the initiation of amyloid induction. Organic Germanium has not been confirmed to be a potent suppressor of experimental murine amyloidosis but the experimental group administered this substance continuously from 1 week prior to the induction shows a rather low incidence of amyloidosis, and the average number of amyloidotic organs per affected mouse is about half of that of the control group. The suppression and acceleration of experimental murine amyloidosis presented here are a useful tool for investigating the pathogenesis of amyloidosis. PMID: 7415838 [PubMed - indexed for MEDLINE]
Inhibition of senile amyloidosis of mice by biscarboxyethyl germanium sesqui-oxide. Acta Pathol Jpn. 1976 Jan;26(1):63-71.
Kuga N, Oboshi S, Sato H, Sato R.
A mouse strain, ICR/SLC, was involved in spontaneous amyloidosis with high incidence. The amyloid deposition in this strain was seen mainly in the mucosal propria of duodenum and terminal ileum, liver, spleen, adrenal cortices, and renal glomeruli. The mice, orally administered more than 300 mg/kg of organic germanium for 22 months since 5 weeks old, did not develop amyloidosis. Half of the mice, given 30 mg/kg of organic germanium for 22 months developed amyloidosis. The mice given 5% carboxymethylcellulose, the solvent of organic germanium, were affected with systemic amyloidosis with high frequency. The results showed that the organic germanium successfully inhibited the occurrence of senile amyloidosis with dose response. The agent did not have any apparent relation to the incidence of hepatic cell carcinoma or pulmonary adenoma which is frequently combined with aged mice. Although the actual mechanism involved is not clear, the evidence of the inhibition of senile amyloidosis by organic germanium may give a light to elucidate the pathogenesis of amyloidosis. PMID: 1274578 [PubMed - indexed for MEDLINE]
Antiviral Activity of 3-oxygermylpropionic Acid Polymer (SK-818). Pharmacometrics 1990;39(4):385-388.
Haruhisa Fujita and Yoshiko Seto. Division of Chemotherapy, Pharmaceutical Institute, School of Medicine, Keio University, Shinanomachi, Shiinjyuku-ku, Tokyo 160, Japan
The antiviral effect of 3-oxygermylpropionic acid polymer (proxigermanium or SK-818) was examined in in vitro systems with DNA and RNA viruses and in mice infected with herpes simplex virus type 2. A multiple oral administration of the compound at doses of 10-100 mg/kg protected mice from virus infection. However, Proxigermanium itself has no direct action on virus particles or virus-infected cells in vitro. The ability of the compound to suppress infection of mice with herpes virus may be expressed through potentiation of the host's defense functions including an interferon production and an augmentation of natural killer (NK) cell activity. The interferon-inducing NK cell-stimulating and delayed type of hypersensitivity – augmenting activities of Proxigermanium (SK-818) have already been demonstrated in experimental animals.
Abuse of Germanium Associated With Fatal Lactic Acidosis
Nephron 1992; 62:351-356
Germanium compounds are marketed as nonprescription drugs in Europe and are recommended by the suppliers for AIDS and metastic cancer disease. We observed a patient with nonmetastactic breast cancer who died because of severe lactic acidosis (plasma lactate concentration = 27 mmol /l) after ingestion of 25 g of elemental germanium over a 2-months period. Renal failure and hepatotoxicity had newly developed during germanium intake. Postmortem examination revealed severe hydropic vacuolation of tubule cells and the presence of inclusion bodies predominately in straight proximal tubule cells with normal appearance of renal interstitium and glomeruli. The liver showed panlobular steatosis.Urnine, blood and tissue (kidney, liver, muscle, pancreas) levels of germanium were high. Lactic acidosis may have been caused by the combined, germanium-Induced renal and hepatic failure (underutilization), but it remains to be seen Whether germanium can affect lactate production and/or metabolism directly.
Effect of 3-oxygermylpropionic Acid Polymer (SK-818) on the Incidence of Spontaneous Leukemia in AKR Mice
Haruhisa Fujita, Masayasy Kurono, Shigeshi Toyoshima
Division of chemotherapy, Pharmaceutical Institute, School of Medicine, Keio University, Shinjyuku-ku, Tokyo 160, Japan and Sanwa Kagaku Kenkyusyo Co. Ltd.., Mie 511-04, Japan
The effects of 3-oxygermylpropionic acid polymer (proxigermanium, or SK-818) on the incidence of the spontaneous leukemia in AKR mice were examined. The occurrence of leukemia was indicated by a greater increase of weights of the spleen, thymus, and mesenteric lymph nodes in these mice than in non-leukemic C3H mice. Proxigermanium inhibited the increase of the organ weights accompanying leukemia. When administered at a dose of 10 mg/kg or 100 mg/kg orally twice a week for five months between 4 and 9 months of age, proxigermanium had a marked inhibitory effect on the increase of the organ weights in AKR mice. These results suggest that proxigermanium powerfully inhibits spontaneous leukemia from occurring in AKR mice.
Key words: Spontaneous leukemia/Proxigermanium compound/Inhibitory effect on the incidence of leukemia.
TREATING HYPERTENSION WITH GERMANIUM SESQUIOXIDE DERIVATIVES (Patent)
http://www.google.com/patents?vid=USPAT3793455&id=9notAAAAEBAJ&printsec=abstract&zoom=4&dq=
%22Kakimoto%22+%22TREATING+HYPERTENSION+WITH+G.+ERMANIUM+SESQUIOXIDE+...%22+
Tubulointerstitial nephropathy persisting 20 months after discontinuation of chronic intake of germanium lactate citrate. Am J Kidney Dis. 1993 May;21(5):548-52.
Hess B, Raisin J, Zimmermann A, Horber F, Bajo S, Wyttenbach A, Jaeger P.
Policlinic of Medicine, University Hospital, Berne, Switzerland.
Two young human immunodeficiency virus (HIV)-infected patients, a 25-year-old woman and a 26-year-old man, consumed large amounts of germanium lactate citrate 18% as an "immunostimulant" for 9 months. The woman, who had stage II HIV infection, developed severe renal dysfunction (creatinine clearance, 7 mL/min/1.73 m2) and slight proteinuria (0.28 g/d) after ingesting 260 g germanium lactate citrate 18%. Hepatomegaly with liver dysfunction (SGOT, 102 U/L; gamma-glutamyl transferase (GT), 159 U/L) and lactic acidosis (plasma lactate, 7.3 mmol/L) developed simultaneously. Renal biopsy revealed tubulointerstitial nephropathy with vacuolar cell degeneration and periodic acid-Schiff-positive intracellular deposits mainly in distal tubules. Liver biopsy disclosed severe hepatic steatosis; liver function tests returned to normal within 5 weeks. Since renal failure persisted for 2 years after ingestion of germanium (creatinine clearance, 14 mL/min/1.73 m2; proteinuria, 0.84 g/d), a second renal biopsy was performed, which showed marked but focal distal tubular atrophy and slight interstitial fibrosis. The male patient, who had stage III HIV infection, had ingested the same compound; he presented with a creatinine clearance of 43 mL/min/m2 and proteinuria of 0.36 g/d. Renal biopsy disclosed tubulointerstitial changes similar to those found in the female patient. After 9 months off germanium, creatinine clearance remained unchanged. Neutron activation analysis of all biopsy specimens in both cases documented germanium concentrations 10 to 70 times normal in renal tissue and 140 times normal in liver tissue. PMID: 8488824 [PubMed - indexed for MEDLINE]
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