therapeutic effects of organic germanium...free radical scavenging, analgesia and heavy metal...

Medical Hypotheses (IYXK) 26. X17-215 8 Longman Group UK Lkt 148X

Therapeutic Effects of Organic Germanium

SANDRA GOODMAN

International Inst. of Symbiotic Studies. 5, Fairlight Place, Brighton, Sussex U.K.

Abstract - 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.

Introduction

Organic Germanium compounds have been used therapeutically within research and clinical practices for almost two decades, yet Germanium is not presently listed as a nutritional trace element, nor are its health-enhancing properties generally known. This report reviews the literature. with particular emphasis upon organic germanium’s therapeutic effects in cancer, which appear to be mediated by immuno-modulation, features which suggest its possible role in the treatment and/or prevention of AIDS.

Historical background, general features of germanium The element Germanium, atomic number 32, atomic weight 72.60, density 5.36, had been predicted by Mendeleev in his periodic table, but

it was not until 1886, that a German chemist, Clemens Winkler, isolated this trace element and named it Germanium. In 1948, it came to be used for its semiconductor properties by U.S. Bell Laboratories, and played a major role in the development of the semiconductor electronics industry. Also around this time. a Japanese scientist Kazuhiko Asai, isolated Germanium from coal, and subsequently demonstrated the existence, albeit in trace amounts, of Germa- nium in a wide spectrum of plants (1).

In 1967. Schroeder and Balassa (56) documented the presence of Germanium in all biom- aterial, plant and animal. Traces of Germanium are found in almost all nutrients, animal and vegetable, with the highest content observed in beans (4.67 ppm), oysters (2 ppm), tunny (2.3 ppm) and dry fish (3.63 ppm). The average daily human intake ranges from 0.9-3.2 mg.. on

207

208 MEDICAL HYPOTHESES

high protein, low carbohydrate and ovovege- evaluated by Smith, Kline & French Laborato- tarian diets, respectively. Asai had obtained ries. It is a member of a class of azaspirane higher Germanium amounts in some plants used compounds containing a N linked to dimethy- in ancient Chinese medicine, such as Ginseng laminopropyl substituent. and Shelf Fungus; however, Mino et al (42), using highly sensitive atomic absorption spectro- Safety of organo-germanium compounds in the photometric technology, found ultra-trace amounts body of Germanium in these herbs (below 5 ppb). The highest content was found in green tea (9 ppb).

Absorption, distribution and elimination of

Germanium thus joins a class of ultra-trace germanium. Organic Germanium compounds are

elements, average daily intake by man being less rapidly absorbed and eliminated from the body.

than 1 ppm. The criterion that the essentiality of In pharmacokinetic C 1Clabelled studies of absorption, excretion, distribution and metab_

an element must be proved by a deficiency ohsm of Ge-132 (43) Ge-132 administered orally, disease resulting from its withdrawal, is now giving way to the view that the metabolism of

was absorbed about 30%, distributed evenly, with almost no residual concentration after

silicon and germanium in living systems has a twelve hours. It was excreted, unchanged meta- role in limiting and regulating functions in the bolicahy, in the urine in 24 hours. In studies “carbon metabolism”, and can change and inhu- performed by Lekim & Kehlbeck, (35), after one ence the living cell over longer periods (68). hour, 50% of the Ge was shown to be in the However, we still know very little about germanium metabolism in living plants and animals.

gastrointestinal tract, which was reduced to only 5% after twelve hours. Germanium is resorbed

Properties of organo-germanium compounds via the vena portae. One hour after administration, 50% of Germanium is in the vena

Germanium belongs to the fourth group of the portae; after eight hours, this figure rises to periodic table with carbon, silicon, tin and lead. 85%, and by twelve hours, it is quasi complexed. It is intermediate in its chemical properties - Plasma levels reach a maximum two hours after oxidation states, affinity for electropositive administration. In eight hours, Germanium is elements, bond angles with oxygen and basicity reduced by 80% of the maximum. of nitrogen compounds - between carbon and The rate of elimination is also quite high. silicon. Its atomic number is 32, atomic weight Germanium is linearly eliminated at approxi- 72.60, specific gravity 5.33 g/cm3, and a melting mately 8% of the dose per hour during the first point of 937. eight hours. Ge is completely eliminated after

GE-132, carboxyethyl germanium sesquioxide three days, mainly via the kidneys (85%). was originally synthesized by Asai in Japan in Germanium is ubiquitously distributed in all 1967, by the hydrolysis of trihalogenopropionic organs - there are no specific target organs, and acid, followed by the addition of trihalogenoger- no differences detected between sexes. Germa- mane to acrylic acid. This organic germanium nium is soluble in the interstitial fluids, and is not compound forms a cubic structure with three protein-bound. Germanium does not accumulate negative oxygen ions at the base of a cubic in any organ - no Germanium can be found in triangle. Two cubic triangles whose bases face animals one week after their removal from each other form one molecule. The three-dimen- treatment. sional array composed of oxygen atoms linked A single report of Germanium accumulation to germanium form a layer network with no exists (46). A patient taking 600 mg. of Ge02 definite melting point, which is soluble in water daily as an elixir for 18 months died of acute at 1.19 mg/lOO ml at 31 C. Its solubility in renal failure. The relevance of Ge accumulation aqueous solution increases at pH = 7.4. Ge-132 to the renal failure remains to be clarified. is in a trihydroxyl form in solution.

Sanumgerman. chemical name lactate-citrate- Toxicity studies. Sanumgerman was investigated germanate, exists in a ‘quasi-crystalline’ struc- for acute and chronic toxicity in mice (CWF/Bog ture, and is soluble in aqueous solution. This strain) and Wistar rats (52). The LDso was compound is the registered trademark of Sanum- 275 mg/kg/24 hours, and 250 mg/kg/48 hours. Kehlbeck, West Germany. Taken orally, SG was nontoxic up to 3400 mg/kg

Spirogermanium, synthesized by Rice et al bodyweight. In studies of Sanumgerman for (50), is an organic germanium compound being chronic toxicity, after 24 weeks, O-50 mg/kg/day,

THERAPEUTIC EFFECTS OF ORGANIC GERMANIUM 209

no symptoms of disease were detected. Compared to the control group the general condition, appearance, behaviour and motor activity were all normal. Appetites were equal, body weight similar and biochemical assays of blood serum showed no abnormalities. There were no abnormalities in hemoglobin, red cells, leukocytes and platelets. The weight of internal organs was similar; there were no pathological changes or differences in macroscopic or microscopic appearance of internal organs. Respiration was unchanged. In orally administered SG, there was no effect on blood pressure: with intravenously administered SG, there was a decrease in the arterial blood pressure of 20-40 mg for 60-100 sec. In the isolated heart determination. there was an increased coronary outflow, but the amplitude and rate were unchanged. In the isolated intestine test, there was no effect on tonus and contractility. In summary, Sanum- german caused no toxic effects in mice and rats that could be detected by biochemical and morphological studies after prolonged administration.

For Spirogermanium the LDlO in mice (strain CDFI) was determined to be 105-147 mg/m’. The highest nontoxic dose in beagle dogs was 12.5 mg/m2, the lowest toxic dose was 25 mg/m’. and the lethal dose was 800 mg/m2 (54). Toxic effects included focal necrosis of lymph nodes, inflammation and necrosis of the gastrointestinal mucosa and abnormal liver function. There was no evidence of bone marrow toxicity. Following acute, subactute chronic toxicity and teratogenicity studies on mice, rats and rabbits, and a chronic study and reproductive study in beagle dogs, Ge-132 was found to be highly safe (43). The acute toxicology findings were as follows:

LDSO Orul (m&&d Intraperitoned Sub Cut.

Mice (ddN) $sp. 6300 4500 1800 Mice (ddY) HZO-M 12500 7550 ‘110 Mice (ddY) H20-F I 1400 8050 2230 Rats (Wist) H20-M 11700 > 16589 3500 Rats (Wist) H20-F 11000 > 16589 3200

Teratogenic studies. Teratogenic studies of an older formulation of Sanumgerman in rats was performed (11) according to the advices of WHO and the Canadian Ministry of Health. Malfor- mations were found in fetuses of pregnant rats. These were mainly skeleton malformations -

dificiencies or defects of bones of the skull and sternebrae. Results of teratogenic studies with the present Sanumgerman formulation are pending. The influence of SG on pregnant females was minimal. After a 136 mg/kg bw dose, administered after day 14 and 21 day of pregnancy, body weight diminished slightly. Sanumgerman showed practically no damaging effects on mothers.

Central nervous studies. The effects of Sanum- german on central nervous activity in mice were investigated (27. 28). The results indicated that Sanumgerman exerts a positive inhibiting effect (drive-depressant with hyperexcitability, antide- pressive) on the central nervous system of the mouse. The mechanism seems to be connected with a depression of the central catechoiami- nergic and a stimulation of the central iseroto- nergic neurons. These results explain, in part, the mechanism of the transient side-effects observed with Spirogermanium administration (54, 66) - slight lethargy, drowsiness. ataxia, defective vision. paresthesia, with an absence of nausea.

Oncostatic properties of germanium compounds Cytological evidence. The Allium Test (38) uses changes in the mitotic characteristics of plant meristematic cells, treated with potential cytostatic agents, as a measure of the oncostatic activity of these compounds. Although positive results in the Allium test cannot guarantee a compound’s oncostatic activity. all known potent cytostatics show an evident inhibitory or cytotoxic effect in the Allium test, making this a useful tool in prescreening potential cytostatic agents (29). Cytological preparations of Sanum- german-treated material were analyzed by the Allium procedure (19). The results - lowering of mitotic index values. and changes in other mitotic parameters - indicate that Sanum- german can be considered as a mitotically active compound.

In vitro. cytotoxicity studies of Spiroger- manium with Hela cells (54) and Chinese hamster cells (71) demonstrated highly significant inhibition of DNA, RNA and protein synthesis at micromolar concentrations, and Hill et al, (23) documented the cytotoxic activity of Spirogermanium in NIL 8 hamster cells and a wide range of human cancer lines. Synthesized germanium nucleosides inhibited HSV-1 replication in vitro. blocked 2-deoxyuridine incorpo-


ration into DNA of hepatoma 22A cells and thymidine incorporation into DNA of cancer ovarian cells (41). Various synergistic combinations of Spirogermanium with other drugs are being investigated in vitro (22).

Animal studies. The antitumour activity of Sanumgerman was tested on transplantable neoplasms in mice, according to methods and protocols of the’ National Cancer Institute, U.S.A. In this study Sanumgerman exhibited moderate antitumour activity against Sarcoma 180, Melanoma B16 and Lewis lung carcinoma (36).

In another study of the effect of Sanumgerman on tumour genesis in mice (5), SG significantly lowered the incidence of tumours from 50% after 4 months in the control group, to 20% after 4 months in the SG-treated group. These results were essentially identically reproduced by Lekim & Kehlbeck, (35) strongly indicating a protective influence of SG against fibrosarcoma. In addition, SG prolonged the survival time of mice with carcinoma of the colon (37).

In further studies of Sanumgerman’s antineoplastic activity in mice, Sanumgerman showed positive results against Carcinoma of the colon C-26, Madison’s lung cancer and Myeloma MP- 26a (36, 37).

In studies with rats, Spirogermanium was shown to be effective against Walker 256 Carci- nosarcoma, increasing the lifespan by 500%. and resulting in a 50% 45-day survival rate (69).

Ge-132 exhibited significant antitumour activity against a wide spectrum of tumours, including Walker 256, Ehrlick Ascites, BC47, Lewis lung, IMC carcinoma, AH 66, AH 43, MH 134 (43, 60, 34). The anti-ascites tumour (syngeneic or allogeneic) activity of Ge-132 appears to be expressed by activation of immune mechanisms, including macrophages and/or T Lymphocytes (53, 58, 59, 61, 62). The augmentation of natural killer (NK) activity and activation of macrophages in mice after oral administration of Ge- 132 are mediated by Ge-induced interferon (IFN) (2).

In one study, the administration of IFN- containing sera obtained from Ge-132-treated mice, or the passive transfer of macrophages from Ge-treated mice to mice bearing ascites tumours, resulted in the inhibition of tumour growth (63). The mechanism of Ge-132’s antitumour activity was elucidated as follows: 1) Ge- 132 stimulated T-cells to produce circulating

lymphokines(s); 2) activated macrophages were generated from resting macrophages by these lymphokine(s); 3) the transplanted tumours were inhibited by these macrophages. Studies using combination immunochemotherapy with Ge-132 and 5-fluorouracil demonstrated inhibition of tumour growth, enhanced anti-metastatic effect, prolonged survival time and recovery of loss of delayed type hypersensitivity and body weight in tumour-bearing mice (29).

Human clinical trials Ge-232 In 1978, a nation-wide organization in Japan was inaugurated to study germanium within research and medical institutions. Numerous controlled studies on Ge-132’s effect on cancer have been carried out (17, 43).

A phase I study with Ge-132 was performed with 23 healthy volunteers of both sexes (17). No significant hematological or biochemical changes were found, except for soft stool appearing in several cases. The maximum tolerated dose was between 50-100 mg/kg/day. The absorption and elimination pattern was similar to that in rats. Ge-132 was also observed to induce interferon in humans in a dose-dependent manner.

Clinical trials on lung cancer revealed a statistically significant effect of Ge-132 upon life prolongation, tumour regression in some cases and overall improvement in performance status and immunological parameters (43).

A double-blind controlled study for unresect- able lung cancer was commenced in 1980 with Ge-132. The patients were divided into 4 classes, Adenocarcinoma, Squamous, Small and Large Cell, according to the histological type of cancer. The treatments, over 3 months, consisted either of chemotherapy + Ge-132 or chemotherapy + placebo by means of double blind. Effects were evaluated by means of an X-ray assessment committee. Although the study was still ungoing at the time of writing, interim results were disclosed (43). In respect to tumour response, in stage IV patients, there was a significant difference between the placebo and Ge-132, that is, the proportion of partial and complete responses was significantly higher in Ge-132-treated subjects. The survival of Ge-132 patients tended to be longer than in placebo treatments; however the difference was not significant.

S&u.mgerman. A phase 1 clinical study of Sanumgerman’s effectiveness against ovarian malignancy was conducted (51) with 6 women,


aged ‘W-64, post-operative for malignant tumours of ovaries and uterus. The well-being of all these patients improved considerably, and pain allevi- ation was considerable. In five out of six patients, no exudate formation occurred in the abdominal or inner pelvic cavity; in the remaining patient. only a little exudate was observed. No toxic or side effects were observed.

Detailed patient case histories provide impres- sive yet anecdotal evidence of Sanumgerman’s therapeutic effects in cancer (31, 48, 51, 72).

Spirogermanium. A Phase I clinical trial comprising 35 patients with varying types of cancer, was conducted with Spirogermanium to define a tolerated dose and determine antitumour activity without myelosuppression (54, 70). All had been previously treated with chemotherapy to which their tumours were resistant. The Spiroger- manium was administered by intravenous injection, with an initial dose of 8 ms/m, ranging up to 32 mg/m. Several of the patients experienced mild and transient neurologic toxic side effects, such as dizziness. lethargy that lasted for a few minutes to several hours. All signs of neurotoxicity were completely resolved. There was no evidence of cumulative toxicity to the nervous system. There was no evidence of acute or cumulative toxicity, no evidence of bone marrow depression. One patient experienced pain at the injection site and nausea. In this trial one patient showed a partial response in the palpable lymph nodes for 2 months. (Partial response = <50% reduction in the sum of the tumour area). The conclusions drawn from this trial were that Spirogermanium is not toxic to bone marrow, there is no evidence of myelosuppression and no cumulative hematologic toxicity (55).

A Phase II trial for 18 patients with lympho- maproliferative disease - 14 non Hodgkin’s lymphoma, and 4 with Hodgkin’s disease was conducted (54). The results - out of 17 patients (one patient withdrew from the study after the first treatment for reasons unrelated to drug toxicity), 5 (30%) demonstrated an objective response, including 2 complete responses. In this study no hematologic toxicity was demonstrated. The conclusions reached were that due to its lack of bone marrow toxicity, Spirogermanium represents a therapeutic option as a single agent or in combination with myelosuppressive drugs for the treatment of lymphoma.

Smith Kline & French Laboratories and other oncology groups have conducted several clinical

trials with Spirogermanium as an anticancer therapeutic agent (4, 8, 66). In several Phase II trials with Spirogermanium, there was no hematologic, renal or hepatic toxicity, mild neurotoxicity, limited activity against malignant melanoma (13) and no demonstrated response in heavily pretreated patients with advanced malignant neoplasms and various cancers (5. 6. 9. 12, 14, 25, 33. 49. 56. 65, 66).

Imm~4nological effects of organic germanium compor4nds Interferon induction, macrophage, T-cell & NK augmentation. Organic Germanium compounds demonstrate significant immuno-modulating activities. These include interferon (IFN) induction, activation of macrophages, augmentation of natural killer (NK) cell activity and restoration of impaired immunoresponse (2, 53). As detailed above (see Animal Studies), the anti-tumour activity of Ge-132 appears to be mediated by the orchestrated stimulus and augmentation of various components of the immune system, mainly macrophages and T-suppressor cells (3, 53, 58, 59, 62, 63) and NK activity augmentation and macrophage activation appear to be mediated by IFN induced by Ge-132 (2). Admin- istration of Ge-132 to healthy volunteers was correlated by IFN induction and an augmentation of natural killer (NK) cells (61). In addition to its cell-mediated immunity effects, Ge-132 augments humoral immunity in aged mice with decreased immune response (44). Ge- 132 significantly increases plaque-forming cells (PFC) in aged mice and is considered to restore to some extent the impaired immunoresponses in aged mice.

Sanumgerman was shown, in vivo, to stimulate the cytolytic activity of natural killer (NK) cells by 27% and 33% in mice (18). There was a parallel elongation of time of the effect. The cytolytic value of the cells approached normal only on the 8th day. SG seems to stimulate the mechanism of immunological surveillance with NK cells. It is conceivable, however, that the increase of cytolytic activity of NK cells is secondary and takes place through interferon induction.

Leukemia. The influence of Sanumgerman (SG) upon experimentally induced leukemia was investigated in mice (18). The two higher doses of SG administered daily to AKR and DBA strain mice produced a statistically significant


prolongation of survival, 168 & 180 days, compared to the control group’s 127 days.

Effects of germanium treatment upon other diseases Senile osteoporosis. Clinical investigations have demonstrated the preventive and therapeutic effect of Ge-132 upon senile osteoporosis - (43). In a 12 month study with senile osteoporosis patients, the bone mass of control subjects tended to decrease, while those receiving Ge-132 demonstrated slightly increasing tendencies, with significant differences seen 1 to 3 months after initial treatment. Parathyroidhormone (PTH) levels are negatively correlated with bone mass, and Ge-132 significantly decreased PTH serum levels, thus pointing to the apparent mechanism of Germanium’s therapeutic’s effect on osteoporosis.

Arthritis. Oral administration of Spirogermanium to rats resulted in the generation of radiation- resistant (2000 Rad) T suppressor cells, which inhibited the proliferative response of normal spleen cells to Concanavatin A (3). Spiroger- manium decreased hindleg inflammatory lesions of adjuvant arthritic rats when administered orally before or after the development of the arthritic lesions (10). The lesions remained significantly suppressed for at least 2 weeks post- drug treatment. Spirogermanium treatment normalized some arthritic response parameters, such as interleukin (IL)-1 production by adherent spleen cells.

Malaria. Spirogermanium demonstrated significant in vitro activity against chloroquine-resistant (FCB, FTA, FVO) and sensitive (FSL, FUI, FH) strains of Plasmodium falciparum. (45). lnhibition of growth and maturation of parasites occurred after 36 hours’ exposure to concentrations ranging from 2.48 to 9.9 rim/ml.

Analgesia. Ge-132 demonstrated enhancement of morphine analgesia administered both orally and by intraperitoneal injection (20). Twenty-eight species of GE-132 derivatives were examined for inhibitory effects on enkephalin-degrading enzymes from monkey brain, the longitudinal muscle layer of bovine small intestine and human cerebrospinal fluid (CSF) (32). A series of these derivatives strongly inhibited these purified enzymes, particularly from the longitudinal muscle layer, human CSF, and monkey brain.

Mechanisms of action Organic Germanium compounds have been successful in treating a multiplicity of illnesses. The elucidation of germanium’s immunomodu- latory activities have started to shed light on these mechanics. But, clearly, there is something intrinsically unique to the element Germanium that facilitates its wide-ranging therapeutic effects.

Electronic structure. The electronic structure of organic germanium compounds may be a factor in its therapeutic properties. Germanium has 32 electrons, 4 of which are in the outer shell. These 4 outer shell electrons are negative charge carriers, and if approached by a foreign substance, one will be ejected out of its orbit. This is known as the positive-hole effect in electronics, because when one of these electrons is ejected, a positive-charge hole is created, and the three remaining electrons each seize electrons from other substances to maintain stability.

Germanium compounds function as free radical scavengers by virtue of electrons being available to interact with toxic, unpaired electrons. Germanium, in low doses raises Gluta- thione (reduced) GSH levels, affording protection against endogenously arising (free) radicals (21).

Oxygen enrichment, blood purification. Germa- nium compounds, complexed in lattice-network structures, bond with negatively charged oxygen atoms which are available to “capture” positively charged hydrogen ions, and heavy metals such as mercury and cadmium (1). Since the germanium compound binds and discharges hydrogen ions (H +), it frees up the body’s extant oxygen supply, and thereby effectively enriches the body’s own supply of oxygen (39). In oxygen multi-step therapy carried out with the administration of Germanium (Sanungerman), the arterial PO:! may rise 70-140 Torr during O2 inhalation (40). Germanium’s oxygen enrichment effects may partially explain its far- reaching therapeutic effects upon so many diverse conditions. Studies have linked oxygen deficiency with cancer; an increased provision of oxygen by germanium compounds may in part account for its positive oncogenic activity.

Possible effectiveness in AIDS?

Cancer, characterized by uncontrolled prolifera- tion of T cells, and AIDS, by destruction of T cells, seemingly diseases of opposite effects, are


both mediated by retroviruses (15, 16). Germa- nium compounds have shown effective anticancer activity, which appear to be mediated by the mobilization of host immune mechanisms. Recent reports indicate that T-suppressor cells play a role in modulating the appearance of the virus in the blood and the onset of AIDS symptoms (47, 67). There is no literature, known to this author, on the use of germanium to treat AIDS. However, germanium’s anti-viral and cytotoxic activities, along with its abilities to mobilize the immune system, make its suggested effectiveness against AIDS eminently plausible, Moreover, since germanium compounds are virtually nontoxic, there is minimal risk to AIDS patients, and a potential for its efficacy in strengthening AIDS victims’ immune systems.

Conclusions

Organic germanium have been shown to be virtually nontoxic and to possess wide-ranging therapeutic effects in cancer and other serious illnesses. The immuno-enhancement attributes of organic Germanium suggest its testing in AIDS patients.

References

1.

2.

3.

4.

5.

6.

7.

8.

Asai K. Miracle Cure: Organic Germanium. Japan Publications Inc. 1980. Aso H. Suzuki F. Yamaguchi T. Hayashi Y. Ebina T. lshida N. Induction of interferon and activation of NK cells and Macrophages in mice by oral administration of Ge-132. an organic germanium-compound. Microbial. lmmunol. 29. 65-74. 1985. Badger A M. Mirabelli C K. DiMartino hl. Generation of suppressor cells in normal rats by treatment with Spirogermanium. a novel heterocyclic anticancer drug. lmmunopharmacology IO. 201-7. 1985. Boros L. Tsiatis A A, Neiman R S, Mann R B. Glick J H. Phase 11 Eastern Cooperative Oncology Group Study of Spirogermanium in previously treated lymphoma. Cancer Treat. Rep. 70. 917-8. 1986. Brenner DE. Rosenshein N B, Dillon M, Jones H W. Forastiere A. Tipping S. Burnett L S. Greco F A. Wiernik P H. Phase 11 study of Spirogermanium in patients with advanced carcinoma of the cervix. Cancer Treat. Rep. 69, 457-8. 1985. Brenner D E. Jones H W, Rosenshein N B. Forastiere A. Dillon M. Grumbine F. Tipping S. Burnett L. Greco F A. Wiernik P H. Phase 11 evaluation of spirogermanium in advanced ovarian carcinoma. Cancer Treat Rep. 67. 193-4. 1983. Brodbeck J. Germanium in biological systems. In: 1st Int. Conf. on Germanium. Hanover. Oct. 1984. Lekim & Samochowiec. eds. Semmelweis-Verlag. 1985. Dexeus F H. Logothetis C. Samuels M L and Hossan B. Phase 11 study of Spirogermanium in metastatic prostate cancer. Cancer Treat Rep. 70(9). 1129-30. 1986.

Y.

IO.

II.

I?.

13.

14.

15.

16.

17. 18

19

20.

21.

22.

23.

24.

25.

26.

Dhingra H M, Unsawaski T, Chiuten D F, Murphy W K. Holoye P Y. Spitzer G. Valdivieso M. Phase 11 study of spirogermanium in advanced (extensive) non- small cell lung cancer. Cancer Treat. Rep. 70. 673-4. 1986. DiMartino M J, Lee J C, Badger A M. Muirhead K A, Mirabelli C K. & Hanna N. Antiarthritic and immunor- egulatory activity of spirogermanium. J. Pharmacol. Exp. Ther. 236. 103-10. 1986. Dluzniewski A. Gastol-Lewinska L, Buczynska B, Monicqewski A. Teratogenic effects of Sanumgerman in rats. In: 1st lnt. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samochowiec, eds. Semmelweis-Verlag. 198.5. Eisenhauer E. Quirt 1. Connors J M, Maroun J. Skillings J. A phase Jl study of Spirogermanium as second line therady in patients.with poor-prognosis lymphoma. An NC1 Canada Clinical Trials Grout Studv. Invest New Drugs 3. 307-10. 1985. Eisenhauer E. Kerr I. Bodurtha A, lscoe N. McCullock P. Pritchard K. Quirt 1. A phase 11 study of spirogermanium in patients with metastatic malignant melonama. An NC1 Canada Clinical Trials Group Study. Invest New Drugs. 3. 303-5. 1985. Falkson G. & Falkson H C. Phase 11 trial of spirogermanium for treatment of advanced breast cancer. Cancer Treat. Rep. 67, 189-90. 1983. Gallo R C. The AIDS virus. Scientific American 256 (Jan). 38-61. 1987. Gallo R C. The first human retrovirus. Scientific Amer- ican. 255 (Dee). 78-88. 1986. Ge-132 Outline. Asai Germanium Res. Inst. 1984. Gicldanowski J. The Influence of Sanumgerman on the induction of spontaneous leukemia and the activity of killer cells (NK). Manuscript. 1986. Grzybek J. Biological activity of Sanumgerman in Allium Test. In: 1st lnt. Conf. on Germanium. Hanover. Oct. 1984. Lekim & Samochowiec. eds. Semmelweis-Verlag. 198.5. Hachisu M. Takahashi H, Koeda T, Sekizawa Y. Anal- gesic effect of novel organogermanium compound. Ge- 132. J. Pharmacobiodyn. 6, 814-20. 1983. Harisch G. Glutathione and glutathione-dependent enzymes of the rat liver after different doses of Sanum- german. In: 1st lnt. Conf. on Germanium. Hanover. Oct. 1984. Lekim & Samochowiec. eds. Semmelweis- Verlag. 1985. Hill B T. Bellamy A S. Metcalfe S. Hepburn P J. Masters J R, Whelan R D. Identification of synergistic combinations of Spirogermanium with S-Ruorouracil or cisplatin using a range of human tumour cell lines in vitro. Invest New Drugs 2. 29-33. 1984. Hill B. Whatley S A, Bellamy A S, Jenkins L H and Whelan R D H. Cytotoxic effects and biological activities of NSC-192965; Spirogermanium in vitro. Cancer Res. 42, 2852-6. 1982. lngeborg S. Germanium - From the general practice - for the general practice. In: 1st lnt. Conf. on Germanium. Hanover. Oct. lY84. Lekim & Samo- chowiec. eds. Semmelweis-Verlag. 1985. Kavanagh J J. Saul P B. Copeland L J. Gershenson D M. Krakoff 1 H. Continuous infusion spirogermanium for the treatment of refractory carcinoma of the ovary: a phase 11 trial. Cancer Treat. Rep. 69. 139-40. 1985. Kidd P M. Internat. Clinical Nutrition. Review. 7(l). 1 l-20. 1987.

214 hfEDICAL HYPOTHESES

27. Kleinrok Z, Lekim D. Jagiello-Wojtowicz E. B Chod- chowiec, eds. Semmelweis-Verlag. 1985.

28.

44.

45.

29.

46.

30.

Mizushima Y, Shoji Y. and Kaneko K. Restoration of impaired immunoresponse by Germanium in mice. Int. Arch. Allergy Appl. Immunol. 63, 338-9. 1980. Mrema J E, Slavik M, & Davis J. Spirogermanium: a new drug with antimalarial activity against chloroquine- resistant Plasmodium fulciparum. Int. J. Clin. Phar- macol. Ther Tox 4. 167-71. 1983. Nagata N, Yoneyama T, Yanagida K, Ushio K, Yana- gihara S, Matsubara 0. Eishi Y. Accumulation of germanium in the tissues of a long-term user of germanium preparation died of acute renal failure. J. Toxicol. Sci. 10, 333-41. 1985.

47.

31. 48.

New Scientist. or can the body protect itself? 18 Dec., pg 7. 1986. Paetz G. Case study: adenocarcinoma with liver metas- tases. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samochowiec. eds. Semmelweis-Verlag. 1985.

32. 49.

33.

34.

kowska A. Central action of sanumgerman in mice. Pol. J. Pharmacol. Pharm. 38. 299-307. 1986. Kleinrock Z, Jagiello-Wojtowicz E, Chodkowska A. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samochowiec. eds. Semmelweis-Verlag. 1985. Kobayashi H, Komuro T. Furue H. Effect of combination immunochemotherapy with an organogermanium compound, Ge-132. and antitumour agents on C57BL/6 mice bearing Lewis lung carcinoma (3LL). Gan-To- Kagaku-Ryoho 13. 12588-93. 1986. Kohlmunzer S. The Allium Test as a tool in search for potential oncostatics. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samochowiec. eds. Semmelweis-Verlag. 1985. Kokoschinegg P, and Kokoschinegg M. Biophysical results with Germanium and Sanumgerman - prelimi- nary experiences. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samochowiec. 1985. Komuro T. Kakimoto N, Katayama T. Hazato T. Inhib- itory effects of Ge-132 (carboxyethyl germanium sesquioxide) derivatives on enkephalin-degrading enzymes. Biotechnol. Appl. Biochem. 8, 379-86. 1986. Kuebler J P. Tormey D C. Harper G R. Chang Y C, Khandekar J D & Falkson G. Phase II study of spirogermanium in advanced breast cancer. Cancer Treat. Rep. 68, 1515-6. 1984. Kumano N. lshikawa T. Koinumar S. Kikumoto T, Suzuki S. Nakai Y & Konno K. Antitumor effect of the organogermanium compound Ge-132 on the Lewis lung carcinoma (3LL) in C57BL/6 (B6) mice. Tohoku J. Exp. Med. 146. 97-104. 1985.

50.

51.

Pinnameneni K. Yap H Y, Legha S S. Blumenschein G R. Bodev G P. Phase II studv of spiroeermanium in the treatment of metastatic breat cancer. Cancer Treat. Rep. 68, 1197-8. 1984. Rice L, Wheeler J W. and Geschickter C F, et al. Synthesis of 4. 4-diakyl-4-4 germacyclohexanone and 8,8- diakyl-8germanspiro 8 (4.5) decanes. J. Heterocyclic Chem. II, 1041-7. 1984.

52. 35.

53. 36.

Samochowiec L. Experience with Sanumgerman in Poland and Germany. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samochowiec, eds. Semmelweis-Verlag. 1985. Samochowiec L and Wojcicki J. Basic pharmacological properties of Sanumgerman. In: 1st Int. Conf. on Germanium. Hanover. Oct. 1984. Lekim & Samo- chowiec, ieds. Semmelweis-Verlag. 1985. Sato I. Yuan B D. Nishimura T, Tanaka N. Inhibition of tumor growth and metastastis in association with modification of immune response by novel organic germanium compounds. J. Biol. Response Mod. 4. 159-68. 1985.

37.

Lekim D. & Kehlbeck H. 1985. The biological activity of germanium. In: 1st Int. Conf. on Germanium. Hanover. Oct. 1984. Lekim & Samochowiec. eds. Semmelweis-Verlag. Lekim D, Samochowiec L. & Gieldanowski J. Oncostatic properties of Sanumgerman. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samo- chowiec, eds. Semmelweis-Verlag. 1985. Lekim D, Samochowiec L, and Gieldanowski J. Results of studies on antineoplastic activity of Sanumgerman preparation. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samochowiec, eds. Semmelweis- Verlag. 198.5. Levan A. The effect of colchicine on root mitoses in Allium. Hereditas 24. 471. 1938.

54.

55. 38

39

40

Levine S A. Kidd P M. Oxygen-nutrition for super health. J. Orthomol. Medicine. l(3). 145-8. 1986. Liem S H. The influence of Sanumgerman on the oxygen partial pressure of the oxygen multi-step process. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. .Lekim & Samochowiec. eds. Semmelweis-Verlag. 1985. Melnik S I, Bakhmedova A A, Nedorezova T P, lart- seva I V, Zhukova 0 S. Synthesis of anomeric 5- trime- thylgermyl-2-ideoxyuridines and study of their antiviral and cvtotoxic properties. Bioorg Khim. II, 1248-52. 1985. ’ . . Mino Y, Ota N, Sakao S. Shimomura S. Determination of Germanium in medical plants bv atomnic absorption spectrometry with electrothermal -atomization. Chem. Phar. Bull. 28(9). 2687-91. 1980. Mizushima M.‘ Satoh H. and Miyao K. Some pharmacological and clinical aspects of a novel organic germanium compound Ge-132. In: 1st Int. Conf. on Germanium. Hanover. Oct. 1984. Lekim & Samo-

Schein P S. The clinical pharmacology of Spiroger- manium, a unique anti cancer agent. In: 1st Int. Conf. on Germanium. Hanover, Oct. 1984. Lekim & Samo- chowiec. eds. Semmelweis-Verlag. 1985. Schein P S, Slavik, Smythe T. Hoth D. Smith F, Macdonald J S and Woolley P V. Phase I clinical trial of Spirogermanium. Cancer Treat. Rep. 64, 1051-56. 1980.

56.

41

42.

43.

57.

58.

59.

60.

Schulman P. David R B, Rafla S. Green M. Henderson E. Phase II trial of spirogermanium in advanced renal cell carcinoma: a Cancer and Leukemia Group B study. Cancer Treat. Rep. 68, 1305-6. 1984. Schroeder H A and Balassa J J. Abnormal trace metals in man: Germanium. J. chron. Dis. 20, 211-24. 1967. Suzuki F. Antitumor activity of Ge-132. a new organogermanium compound, in mice is expressed through the functions of macrophages and T lymphocytes. Gan-To Kagaku Rhoho 12, 1445-52. 1985. Suzuki F. Suppression of tumor growth by peritoneal macrophages isolated from mice treated with carboxyethylgermanium sesquioxide (Ge-132). Gan To Kagaku Ryoho 12, 2122-8. 1985. Suzuki F. Ability of sera from mice treated with Ge-132. an organo-germanium compound, to inhibit experimental murine ascites tumors. Gan To Kagaku Ryoho. I2, 2314-21. lY85.

THERAPEUTIC EFFECTS OF ORGANIC GERMANIUM

61.

62.

63.

64.

65.

66

Suzuki G & Pollard R B. Prevention of suppressed interferon gamma production in thermally injured mice by administration of a novel organogermanium compound, Ge-132. J. Interferon Res. 4, 223-33. 1984. Suzuki F. Brutkiewicz R R. Pollard R B. Importance of T-ceils and macrophages in the antitumor activity of carboxyethylgermanium sesquioxide (Ge-132). Anti- cancer Res. 5. 47Y-83. 1985.

Suzuki F, Brutkiewicz R R. Pollard R B. Cooperation of lymphokine(s) and macrophages in expression of antitumor activity of carboxyethylgermanium scsquioxide (Ge-132). Anticancer Res. b, 177-82. 1986. Tanaka N. Ohida J. Ono M. Yoshiwara H. Beika T. Terasawa A, Yamada J, Morioka S. Mannami T. Orita K. Augmentation of NK activity in peripheral blood lymphocyte in cancer patients by intermittent Ge-132 administration. Can To Kagaku Rvoho. Ii, 1303-h. lY84. Trope C. Mattsson W. Gynning I, Johnson J E. Sigurdsson K and Orbert B. Phase II study of Spiroger- manium in advanced ovarian malignancy. Cancer Treat. Rep. 65. IlY-120. lY81. Vogelzang N J. Gesme D H. Kennedy B J. A phase II

67.

68.

60.

70.

71.

72.

215

study of Spirogermanium in advanced human malignancy. Am. J. Clin. Oncol. 8. 341-4. lY85. Walker C M. Moody D J. Stites D P and Levy J A. CD8

lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 2.34. 1563-6. 1986. Watschinger G. Germanium. an extraordinary trace element in biological systems. In: 1st lnt. Conf. on Germanium. Hanover. Oct. 1984. Lekim & Samo- chowiec, eds. Semmelsweis-Verlag. 1985. Wodinsky et al. Screening data summaries. Drug Research & Dev. Program. Division of Cancer Treat- ment. National Cancer Institute, Bethesda. Ma. IY77. Woolley P V, Ahlgren J D. Byrne P J, Priego V M. & Schein P S. A phase I trial of spirogermanium administered on a continuous infusion schedule. Invest New Drugs. 2. 305-Y. lYX4. Yang S J, & RaHa S. Effect of Spirogermanium on V7Y Chinese hamster cells. Am. J. Clin. Oncol. 6. 331-7. lY83. Zouhek E. The Sanumgerman Therapy in Biological Medicine. In: 1st Int. Conf. on Germanium. Hanover. Oct. 19X3. Lekim B Samochowiec. eds. Semmelweis- Verlag. 108.5.

therapeutic effects of organic germanium...free radical scavenging, analgesia and heavy metal...

Documents