Germanium Abstracts 2

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Inhibition of autoimmune disease and the generation of suppressor cells by spirogermanium: a biological profile similar to total lymphoid irradiation.
            (Badger et al., 1989) Download
Oral administration of spirogermanium (Sg), inhibits the development of immune-mediated hindpaw inflammation in the rat model of adjuvant arthritis (AA) and DTH responses to PPD (30 mg/kg/day). A similar dosing protocol inhibits hindleg paralysis in experimental autoimmune encephalomyelitis (EAE). The spleens of these animals and those of normal rats contain radiation resistant (2000 R) non-specific suppressor cells (SC) which bear some similarity to those generated following total lymphoid irradiation (TLI). These cells do not appear to be mature T cells, they are partially adherent to plastic, sephadex G10 and nylon wool, insensitive to indomethacin and are enriched in a 1.07 g/ml fraction of a Percoll density gradient.

Effect of organic germanium compound (Ge-132) on experimental osteoporosis in rats.
            (Fujii et al., 1993) Download
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.


 

Mutagenicity, carcinogenicity and teratogenicity of germanium compounds.
            (Gerber and Léonard, 1997) Download
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.

Cytotoxic effects and biological activity of 2-aza-8-germanspiro[4,5]-decane-2-propanamine-8,8-diethyl-N,N-dimethyl dichloride (NSC 192965; spirogermanium) in vitro.
            (Hill et al., 1982) Download
Lethal and other biological effects of 2-aza-8-germanspiro[4,5]decane-2-propanamine-8,8-diethyl-N,N-dimethyl dichloride (NSC 192965; spirogermanium), representing a new chemical class of compound exhibiting antitumor activity, have been studied in vitro. Survival curves for NIL 8 hamster cells were exponential with greater kill occurring with increasing drug concentrations and longer exposure times. Cytotoxicity was temperature dependent. "Quiescent" cultures were significantly less sensitive to spirogermanium than were logarithmically growing cells. These lethal effects showed no phase specificity. There was no evidence of progression delay through the cycle following spirogermanium treatment. When spirogermanium was tested against a range of human cell lines, the consistency of the values for the drug concentration required to reduce survival by 50% on the exponential part of the survival curve, derived from colony-forming assays, was most marked. The survival curves, characterized by an initial shoulder, were steep and exponential with measurements possible over only a narrow concentration range since complete cell lysis occurred at levels causing a greater than 2-log kill. Cell membrane damage by spirogermanium, as judged by dye exclusion, was progressive with time and increasing drug concentrations. Protein synthesis proved most susceptible to the drug. Spirogermanium concentrations cytotoxic to tumor cells were also toxic to cultured rat neurons, confirming the clinical neurological toxicity encountered. The precise mode of action of spirogermanium remains to be established, and these data further illustrate its apparent lack of specificity.


 

Prevention and reversible solubilization of advanced glycation and products (AGE) by organic germanium compounds as derivatives of amino acids.
            (Nakamura et al., 1991) Download
The amino-carbonyl reaction (The Maillard reaction) of bovine lens crystallin, serum albumin or skin collagen with glucose was investigated to find effective means to prevent the formation of Advanced Glycation End Products (AGE) and induce the reversible solubilization of polymerized glycated proteins. The organic germanium compounds (Ge-132, 373, 385), derivatives of amino acids containing germanium as the linker of framework, were combined by the box titration method to determine the dose that would be most effective, compared with Aminoguanidine-HCl (AMG),α-tocopherol (VE), and pirenoxine (Catalin-K, CK). Although AMG suppressed the formation of AGE, effective concentrations were higher than 20 mM. Ge-385, when administered by itself at a low dose, induced the reversible solubilization of AGE made from crystallin, and albumin. The addition of any two reagents such as AMG, VE, CK and Ge-132 or 385 together to proteins lessened the effective range, and the peaks of smaller molecules in the profiles of HPLC and PAGE were quite remarkable. Examination was made of the effects of Ge-132 on the eyes of SAM mice, which show senescence accelerated cataracts at a relatively young age. The prevention of cataract-genesis and induction of reversible transparency of turbid lenses became evident following the administration of Ge-132 to the eyes 4 times a day. The mode of action of organic germanium compounds was demonstrated quite capable of disconnecting the sugar-parts from AGE by decarbonylation, resulting in the formation of glucosone and amino residues, and further leading subsequently to fewer AGE.

A Review on the Radioprotective Activity of organogermanium and Organosilicon Compounds.
            (Rima et al., 1999) Download
The present review describes the work carried out during the last 20 years in the field of the radioprotective activity and toxicity of several classes of organosilicon and organogermanium compounds (i.e. metallathiazolidines, metalladithioacetals, metallatranes and germathianes).

Studies of the metabolism of germanium.
            (Rosenfeld, 1954) Download
Metabolic’ studies have been conducted of the absorption, transport, distribution, storage, and excretion of inorganic germanium (GeOz) in albino rats. The analytical data demonstrate that germanium is rapidly absorbed after oral, subcutaneous, intramuscular, or intraperitoneal administration. When injected directly into the systemic circulation or absorbed following oral or parenteral administration, it is transported unbound by plasma proteins and is rapidly eliminated from the blood stream. Germanium is not deposited selectively but is widely distributed among all the organs. It is not retained or stored by any tissue even after many weekly doses,but is rapidly excreted via the urine and feces, the kidney being the main excretory organ. A survey of the tissues of untreated rats did not indicate the normal occurrence of germanium as a microconstituent. The biochemical data support the view that germanium is relatively inert metabolically, and are consonant with its remarkably low toxicity.

Dietary germanium supplements.
            (Stricker, 1991) Download
In our report on a patient who had ingested germanium lactate/citrate capsules daily from early, 1986, to November, 1988, the cumulative dose was estimated at 10-8 g over two years. The patient showed u s 33 m g capsules of which, she said, she took two every day. However, we later learned from the community pharmacy that she had mostly ingested 250mg capsules and that at least 32 g germanium had been taken between July, 1987, and November, 1988. We apologise for this error, but the higher cumulative dose endorses our conclusions, especially now that similar cases have been published.

Dangers of dietary germanium supplements.
            (van der Spoel et al., 1990) Download
A 57-year-old woman with a diagnosis of breast cancer in 1984 had been successfully treated since 1986 with 30 m g tamoxifen daily because of bone and lung metastases. She did not use other prescribed drugs. At that time renal and hepatic function were normal. Since early 1986 she had been taking 66 mg germanium lactate citrate (12 mg germanium) and 0-2 mg selenium daily because she thought that this would improve her medical condition. In October, 1988, she was admitted to hospital with deteriorating renal function. We conclude that the irreversible renal damage in this patient was caused by germanium and would endorse the warning issued by the Department of Health in the UK.

Propagermanium reduces atherosclerosis in apolipoprotein E knockout mice via inhibition of macrophage infiltration.
            (Yamashita et al., 2002)  Download
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.

 


References

Badger, AM, et al. (1989), ‘Inhibition of autoimmune disease and the generation of suppressor cells by spirogermanium: a biological profile similar to total lymphoid irradiation.’, Agents Actions, 27 (3-4), 335-37. PubMed: 2529742
Fujii, A, et al. (1993), ‘Effect of organic germanium compound (Ge-132) on experimental osteoporosis in rats.’, Gen Pharmacol, 24 (6), 1527-32. PubMed: 8112531
Gerber, GB and A Léonard (1997), ‘Mutagenicity, carcinogenicity and teratogenicity of germanium compounds.’, Mutat Res, 387 (3), 141-46. PubMed: 9439710
Hill, BT, et al. (1982), ‘Cytotoxic effects and biological activity of 2-aza-8-germanspiro[4,5]-decane-2-propanamine-8,8-diethyl-N,N-dimethyl dichloride (NSC 192965; spirogermanium) in vitro.’, Cancer Res, 42 (7), 2852-56. PubMed: 7200828
Nakamura, K, et al. (1991), ‘Prevention and reversible solubilization of advanced glycation and products (AGE) by organic germanium compounds as derivatives of amino acids.’, Amino Acids, 1 (2), 263-78. PubMed: 24194112
Rima, G, et al. (1999), ‘A Review on the Radioprotective Activity of organogermanium and Organosilicon Compounds.’, Met Based Drugs, 6 (1), 49-60. PubMed: 18475880
Rosenfeld, G (1954), ‘Studies of the metabolism of germanium.’, Arch Biochem Biophys, 48 (1), 84-94. PubMed: 13125574
Stricker, BH (1991), ‘Dietary germanium supplements.’, Lancet, 337 (8745), 864. PubMed: 1672960
van der Spoel, JI, et al. (1990), ‘Dangers of dietary germanium supplements.’, Lancet, 336 (8707), 117. PubMed: 1975298
Yamashita, T, et al. (2002), ‘Propagermanium reduces atherosclerosis in apolipoprotein E knockout mice via inhibition of macrophage infiltration.’, Arterioscler Thromb Vasc Biol, 22 (6), 969-74. PubMed: 12067906