Description
Propagermanium is an organic germanium compound. Germanium compounds are popular as nutritional supplements and proponents advertise beneficial effects on the course of a multiplicity of illnesses. Propagermanium is approved for the treatment of hepatitis B in Japan and is thought to have anticancer effects through induction of endogenous interferon-γ production and augmented NK cell activity.
Efficacy
There is not enough evidence from clinical trials to judge its efficacy in cancer treatment. Several cases of severe organ toxicity including acute renal failure after oral ingestion of germanium compounds have been documented. These cases were caused by inorganic germanium compounds. However, labelling of products containing germanium compounds is often misleading and even in scientific literature, substance as well as product names of germanium compounds have been confounded.
Safety
Given the risk of possible contamination with inorganic forms, organic germanium compounds, including propagermanium, should be avoided outside clinical trials.
Citation
Markus Horneber, Elke Wolf, CAM Cancer Collaboration. Propagermanium [online document], Sep 15, 2020.
Document history
Latest update: September 2020
Next update due: September 2023
Names
International Union of Pure and Applied Chemistry (IUPAC): 3-[(2-Carboxyethyl-oxogermyl)oxy-oxogermyl]propanoic acid.
International Nonproprietary Name (INN): Propagermanium.
Other names/brand names: 2-carboxyethylgermasesquioxane, Ge-132, SK-818, Serocion, germanium sesquioxide, proxigermanium, repagermanium, organic germanium.
History / chemical structure / properties
The element germanium was discovered by the German chemist Clemens Winkler in 18861. It is located in the fourth main group of the periodic table of elements and detectable as a trace element in soil, seawater, plants, animals and carbon2-5. Germanium is not considered an essential trace element as no vital biological functions and no syndromes of deficiency are known6.
The Russian chemist V.F. Mironov first published the synthesis of an organic germanium compound in April 19677. This compound was a polymer of subunits with the formula [(GeCH2CH2COOH)2O3]n which today has the international non-proprietary name propagermanium.
Propagermanium has been produced and branded over the years with a confusing number of names by various manufacturers (see above). However Kaplan et al. refer in their review that all of these substance represent polymorphic forms of propagermanium, which are identical in aqueous solution8.
Some other germanium compounds should not be confounded with propagermanium and are briefly addressed in the following.
Spirogermanium
In the late 70ies and 80ies, a completely different organic germanium compound was investigated for the use in cancer therapy: Spirogermanium (chemical name: 8,8-diethyl-N,N-dimethyl-3-aza-8-germaspiro[4,5]decane-2-propanamine). This substance was synthesized in 1974 and represents an azaspiran-germanium compound which was tested in various phase I/II trials to examine its antitumour effect.
Due to a markedly negative risk-benefit profile, in particular neurologic toxicity, spirogermanium was abandoned (reviewed by Kaplan et al.8).
Inorganic germanium compounds
Two inorganic germanium compounds have been associated with renal damage: germanium dioxide (GeO2), which was contained in germanium supplements and elixirs sold over the counter as ingredient or contamination9 and germanium lactate citrate, a chelated form of GeO2, sometimes erroneously referred to as organic germanium compound (reviewed by Kaplan et al.8).
Claims of efficacy / mechanism of action / claimed indication
Germanium compounds have been popular as nutritional supplement since the 70ies9-10. K. Asai, a Japanese scientist, first advertised beneficial effects on health in general and on the course of a multiplicity of illnesses, amongst others cancer2.
Present-day providers and proponents of propagermanium mostly refer to the theoretical concept of K. Asai, who marketed propagermanium, which he claimed to have first synthesized and regarded as “the fountain of life, which animates the entire universe” under the name “Ge-132”. In his concept, Asai proclaimed a lack of oxygen due to stress and wrong nutrition as common causes of all diseases. He deduced from the chemical structure of “Ge-132” an ability to enrich the body with oxygen and to reduce hydrogen radicals, thus effectuating a detoxification and normalization of a disturbed electric potential in diseased organs2.
These theories never have been proofed, however preclinical studies in animals and healthy humans suggested a dose-dependent induction of interferon γ and an activation of macrophages and NK cells11-15.
Pharmacological aspects
An absorption rate of about 30% after oral administration of Ge-132 and rapid urinary excretion in a largely unmetabolized state was observed in a pharmacokinetic study on a small group of healthy adults15.
Application
Propagermanium is usually sold as a powder or in capsules for oral administration. Dose recommendations vary highly among providers (100 to 6,000mg/day). In a case series doses of 30 mg/day16, in one clinical trial 3,500 mg/day were applied17.
Aspects of pharmaceutical drug and law regulations
In most countries propagermanium falls under the regulations of dietary supplements. An import alert on germanium products was imposed by the U.S. FDA in 1988, because of possible injury to health18. In Germany governmental institutions warned consumers of possibly fatal kidney damage19. In the UK supplements containing germanium were voluntarily withdrawn by the industry6. In Japan propagermanium is approved for the treatment of HBe positive chronic hepatitis B20.
Evidence concerning the efficacy of propagermanium comes from two clinical trials17, one review including seven case series21, a case series16 and one case report22.
The clinical trials were reported with fragmentary data and a few sentences in a conference report17. One of them was a controlled study comparing two concentrations of propagermanium in 35 lung cancer patients. Higher survival rates were alleged in patients who received a not further specified dose above 20 mg/kg/day. The other study was referred to as a placebo controlled trial in patients with lung cancer during chemotherapy. Higher response and survival rates after 3 months were alleged in the propagermanium group. The sparse data given in the conference report do not allow any serious judgement and a more complete publication was not traceable.
A 1987 review summarized results of seven case series in which propagermanium was given during chemotherapy or radiotherapy. According to the authors, the clinical courses suggested ”antitumour efficacy” and “a reduction of tumour-associated pain in several patients”21.
A further case series describes the outcome of 10 patients with multiple myeloma being treated with daily doses of 10 to 40 mg propagermanium. Authors refer complete or partial responses in four patients as measured by decreases or normalisations of paraprotein levels. In the two complete responders bone marrow biopsy showed also a reduction of plasma cells16. Time points of measuring were not reported and in three of the patients the interval to former chemotherapy treatment was rather short. Therefore it is debateable whether the effect was truly attributable to propagermanium.
A well documented complete remission of a rare form of lung cancer (spindle cell carcinoma) refractory to radiation therapy and various chemotherapies in a female 47-year-old patient was published in 2000. After 5 months of self-medication with propagermanium, the patient achieved complete remission, which at the time of the report had lasted more than four years22.
A review from 1997 reported on 31 cases of organ toxicity related to different germanium compounds, including GeO2, germanium-lactate-citrate and propagermanium (Ge-132), which were ingested over a period from two to 36 months. In the two cases of propagermanium intake contamination with GeO2 was detected9. All cases showed renal impairment in terms of chronic or acute renal failure, which caused death in nine cases. Other clinical findings were anaemia, which occurred in all cases, gastrointestinal disturbances, weight loss, myopathy and liver dysfunction9. If at all, renal function improved very slowly and remained impaired in some patients observed as long as 40 months23-24. As a consequence, governmental institutions of several countries imposed alerts because of possible injury to health.
According to data from animal studies, inorganic germanium compounds cause renal toxicity, whereas propagermanium does not25. However, French investigators found evidence that at least in rats, higher doses of propagermanium could also cause structural changes in the kidneys26.
Adverse effects
In a case series with 10 myeloma patients, depression was seen as an adverse effect attributed to propagermanium in two patients16. In a double-blind placebo-controlled trial on the treatment of chronic hepatitis B with daily doses of 30 mg propagermanium including 182 patients, no adverse events attributable to propagermanium were reported. A post-market survey including 32,700 patients with chronic hepatitis B reported liver enzyme flares in 4% of patients treated with propagermanium. As a consequence, severely impaired liver function is regarded a contraindication for the application of propagermanium in Japan20.
Quality problems
Germanium dioxide (GeO2) represents an intermediate product in the synthesis of organic germanium compounds9. Thus contamination of organic germanium compounds is possible if manufacturers do not safeguard the purity of their products.
- A new Element: Germanium. Lancet 127, 562 (1886).
- Asai, K. Organisches Germanium - Eine Hoffnung für viele Kranke. Semmelweis-Verlag, 27316 Hoya (2001).
- Schroeder, H. A. & Balassa, J. J. Abnormal trace metals in man: germanium. J Chronic Dis 20, 211-224 (1967). Accessed 15th of September 2020.
- Hara, S. et al. Determination of germanium in some plants and animals. Z Naturforsch [C] 45, 1250-1251 (1990). Accessed 15th of September 2020.
- Lewis, B. L., Frolich, P. N. & Andreae, M. O. Methylgermanium in natural waters. Nature 313, 303-305 (1985). Accessed 15th of September 2020.
- Expert Group on Vitamins and Minerals. Safe Upper Levels for Vitamins and Minerals: Risk assessment Propagermanium, 2003. p. 197. Accessed 15th of September 2020.
- Mironov, V. F., Berliner, E. M. & Gar, T. K. Reactions of Trichlorogermane with Acrylic Acid and its Derivatives. Zhurnal Obshchei Khimil 37 Nr. 4, 962. 1967.
- Kaplan, B. J., Parish, W. W., Andrus, G. M., Simpson, J. S. & Field, C. J. Germane facts about germanium sesquioxide: I. Chemistry and anticancer properties. J Altern Complement Med 10, 337-344 (2004). Accessed 15th of September 2020.
- Tao, S. H. & Bolger, P. M. Hazard assessment of germanium supplements. Regul Toxicol Pharmacol 25, 211-219 (1997). Accessed 15th of September 2020.
- Kaplan, B. J., Andrus, G. M. & Parish, W. W. Germane facts about germanium sesquioxide: II. Scientific error and misrepresentation. J Altern Complement Med 10, 345-348 (2004). Accessed 15th of September 2020.
- Suzuki, F., Brutkiewicz, R. R. & Pollard, R. B. Importance of T-cells and macrophages in the antitumor activity of carboxyethylgermanium sesquioxide (Ge-132). Anticancer Res 5, 479-483 (1985). Accessed 15th of September 2020.
- Suzuki, F., Brutkiewicz, R. R. & Pollard, R. B. Ability of sera from mice treated with Ge-132, an organic germanium compound, to inhibit experimental murine ascites tumours. Br J Cancer 52, 757-763 (1985). Accessed 15th of September 2020.
- Suzuki, F., Brutkiewicz, R. R. & Pollard, R. B. Cooperation of Lymphokine(s) and Macrophages in Expression of Antitumor Activity of Carboxyethylgermanium Sesquioxide (Ge-132). Anticancer Res 6, 177-182 (1986). Accessed 15th of September 2020.
- Aso, H. et al. Induction of interferon and activation of NK cells and macrophages in mice by oral administration of Ge-132, an organic germanium compound. Microbiol Immunol 29, 65-74 (1985). Accessed 15th of September 2020.
- Miyao, K., Onishi, T., Asai, K., Tomizawa, S. & Suzuki, F. Current Chemotherapy and Infectious diseases. Nelson, J. D. (ed.), pp. 1527-1529 (American society of Microbiology, Washington DC,1980).
- Tsutsumi, Y. et al. Effectiveness of propagermanium treatment in multiple myeloma patients. Eur J Haematol 73, 397-401 (2004). Accessed 15th of September 2020.
- Mizushima, Y., Satoh, H. & Miyao, K. Germanium in biologischen Systemen. Lekim, D. & Samochowiec, L. (eds.), pp. 189-210 (Semmelweis-Verlag, 27316 Hoya,2007).
- FDA-import alert no.54-07. FDA-import alert no.54-07. 10-2-2009. Ref Type: Electronic Citation
- Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin Warnung vor Germanium. Dtsch Ärztebl 97, 2418 (2000).
- Hirayama, C., Suzuki, H., Ito, M., Okumura, M. & Oda, T. Propagermanium: a nonspecific immune modulator for chronic hepatitis B. J Gastroenterol 38, 525-532 (2003). Accessed 15th of September 2020.
- Brutkiewicz, R. R. & Suzuki, F. Biological activities and antitumor mechanism of an immunopotentiating organogermanium compound, Ge-132 (review). In Vivo 1, 189-203 (1987). Accessed 15th of September 2020.
- Mainwaring, M. G., Poor, C., Zander, D. S. & Harman, E. Complete remission of pulmonary spindle cell carcinoma after treatment with oral germanium sesquioxide. Chest 117, 591-593 (2000). Accessed 15th of September 2020.
- Hess, B. et al. Tubulointerstitial nephropathy persisting 20 months after discontinuation of chronic intake of germanium lactate citrate. Am J Kidney Dis 21, 548-552 (1993). Accessed 15th of September 2020.
- Sanai, T. et al. Germanium dioxide-induced nephropathy: a new type of renal disease. Nephron 54, 53-60 (1990). Accessed 15th of September 2020.
- Sanai, T. et al. Chronic tubulointerstitial changes induced by germanium dioxide in comparison with carboxyethylgermanium sesquioxide. Kidney Int 40, 882-890 (1991). Accessed 15th of September 2020.
- Anger, F., Anger, J. P., Guillou, L., Sado, P. A. & Papillon, A. [Subacute and subchronic oral toxicity of beta-bis carboxyethyl sesquioxide of germanium in the rat]. J Toxicol Clin Exp 11, 421-436 (1991). Accessed 15th of September 2020.
