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Analytical product study of germanium-containing medicine by different ICP-MS applications.

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.

Chromatography, High Pressure Liquid↗

Mutagenicity, carcinogenicity and teratogenicity of germanium compounds.

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.

Animals↗

An evaluation of germanium detectors employed for the measurement of radionuclides deposited in lungs using an experimental and Monte Carlo approach.

A study was undertaken to evaluate the performance of an advanced design broad energy germanium detector for the in vivo measurement of radionuclides in lungs. Relative counting efficiency, background, and sensitivity for lung counting arrays consisting of four, three, and two 80-mm-diameter by 20-mm-thick (80 x 20 mm) broad energy germanium detectors were simulated by collecting spectra with the single 80 x 20 mm broad energy germanium at each of four locations over a humanoid torso phantom. Regions of interest were evaluated for photon energies ranging from 17 to 1,500 keV. The 80 x 20 mm detector arrays were then benchmarked against a standard array of four 70-mm-diameter by 20-mm-thick (70 x 20 mm) broad energy germanium detectors. Since testing new equipment can be an expensive and time consuming process, an alternative approach, using Monte Carlo simulations instead of physical measurements, was also evaluated and compared to experimental data. With this approach, counting efficiency and minimum detectable amount were simulated for two sizes of germanium detectors (70 mm and 80 mm diameter) at four different crystal thicknesses (15, 20, 25, and 30 mm). For the experimental measurements, arrays consisting of three and four 80 x 20 mm broad energy germanium detectors resulted in an increase in counting efficiencies, relative to the standard array, at all photon energies. The greatest relative increase was observed for the four-detector array (24-35%). In contrast, counting efficiency decreased, relative to the standard array, by 24-28% with a two-detector array. Arrays consisting of two and three 80 x 20 mm broad energy germanium detectors resulted in decreased relative background at all photon energies, with the exception of the 946 keV photon for the three-detector array. The most significant decrease in background occurred with the two-detector array (28 to 40%), while background was increased by 18-43% for the four-detector array. Arrays consisting of three and four 80 x 20 mm broad energy germanium detectors resulted in increased relative sensitivity at all photon energies. The three-detector array provided the greatest sensitivity at photon energies below 344 keV. The four-detector array provided slightly better measurement sensitivity at photon energies greater than 344 keV. The two 80 x 20 mm detector array provided sensitivity unexpectedly comparable to the standard array. Monte Carlo predictions on how size affects counting efficiency and minimum detectable amount agreed well with the experimental results. From the Monte Carlo predictions, the effect of detector thickness on counting efficiency was unimportant at photon energies up to 60 keV and independent of detector diameter. At higher photon energies for both detector diameters, the counting efficiency decreased as the thickness decreased. The values of minimum detectable amount for the 70-mm and 80-mm diameter detectors did not differ by more than 15% at 17 keV or 20% at 60 keV when compared to detectors of equivalent thickness. Minimum detectable amount increased slightly at 17 keV and rose by approximately 52% at 660 keV, with decreases in thickness from 30 mm to 15 mm.

Equipment Design↗

Germanium intoxication with sensory ataxia.

Sensory ataxia in inorganic germanium intoxication is rare. A 63-year-old housewife had taken inorganic germanium preparations at a dosage of 36 mg a day for about 6 years (total dose about 80 g). She subsequently developed difficulty in writing and gait disturbance with peripheral neuropathy and renal involvement. Germanium, which is not usually detected in the non-germanium user, was accumulated in her hair and nails, permitting a diagnosis of inorganic germanium intoxication. The peripheral neuropathy and renal injury were not reversible after discontinuing the preparation. Pneumonia and sepsis then supervened and the patient died. Autopsy findings showed degeneration and loss of the dorsal root ganglion cells and degeneration of the dorsal column of the spinal cord. Two previously reported cases presented with ataxia. These patients took germanium for long periods and/or large quantities like our case. It was supposed that sensory ataxia was induced by chronic and dose dependent toxicity of inorganic germanium.

Aged↗

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.

1 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.

Administration, Oral↗

[Studies on photosensitive dyes binding to monocrystalline germanium surface].

In this paper, two simple cyanine dyes were synthesized through allyl alcohol monomer, and were bound to the polished monocrystalline germanium surface using a new chemical method. Raman spectra and X-ray photoelectron spectra (XPS) were used to analyze the dye-binding germanium wafers. In comparison with the contrast germanium wafer, the dye-binding germanium wafers showed that the intensity of the first grade Raman peak of the germanium substrate was reduced and some new Raman peaks corresponding to the dyes appeared from 600 to 3,200 cm-1. And from XPS, C-N, S-C, C-O bonds were proved to have been bound to the germanium surface. In conclusion, the two dyes were bound covalently to germanium wafers through Ge-O bond.

Carbocyanines↗

Renal failure caused by long-term use of a germanium preparation as an elixir.

Two Japanese women and one Japanese man, who had been taking the same germanium preparation, mainly containing inorganic germanium, as an elixir for health almost every day at 90 mg of germanium per day for 6 to 20 months, suffered from chronic renal failure. Histological examination of the kidney in one patient showed marked interstitial changes with vacuolar degeneration of the renal tubules. High germanium concentrations were found in hair and nails of the three patients, but no germanium was detected in hair or nails of normal persons. These results suggest that long-term use of a germanium preparation at high dosage can cause serious renal tubular damage and renal failure due to germanium toxicity.

Adult↗

[Experimental studies on effects of zinc and germanium on immune function and anti-oxidation in mice].

Zinc and germanium concentrations in serum, liver and muscle of mice, T-lymphocyte subgroup proportion, serum superoxide dismutase (SOD) activity and malonodialdehyde (MDA) were determined to study whether there exist synergism or antagonism between zinc and germanium. Results showed there existed, to certain extent, competitive effects of serum zinc and germanium in mice. When concentration of serum zinc increased, that of germanium decreased, or vise versa. There existed certain relationship between zinc and germanium concentrations in serum and those in muscle and liver of mice, and between those and CD3 count and SOD activity. Immune function in mice was influenced and their T-lymphocyte subgroup proportion changed with changes in serum zinc and germanium concentrations. With increased germanium and decreased zinc serum concentrations, CD3 and CD1 counts decreased, CD8 count unchanged, and the ratio of CD1 to CD3 decreased, which showed certain antagonist effects of them as they operated together. But, no antagonism was observed in their anti-oxidant effects, SOD activity increased to varied extent, and the level of MDA decreased.

Adjuvants, Immunologic↗

Comparison of germanium oxide fibers with silica and sapphire fiber tips for transmission of erbium: YAG laser radiation.

BACKGROUND AND OBJECTIVES: Endoscopic applications of the Erbium:YAG laser have been limited due to the lack of a suitable optical fiber delivery system. The purpose of this study was to compare the transmission of Er:YAG laser radiation through germanium oxide trunk fibers with silica and sapphire fiber tips for potential use in contact tissue ablation during endoscopy. STUDY DESIGN/MATERIALS AND METHODS: Er:YAG laser radiation with a wavelength of 2.94 microm, pulse length of 300 microseconds, pulse energies from 5 to 1,360 mJ, coupled into pulse repetition rates of 3-10 Hz, was through 1-m-long germanium oxide fibers with either 1-cm-long, 550-microm-diameter silica or sapphire tips. RESULTS: Transmission through the germanium oxide/sapphire fibers measured 65+/-5% compared with 55+/-4% for the germanium oxide/silica fibers (P<0.05). The damage threshold for the hybrid fibers averaged 309+/- 44 mJ and 126+/-43 mJ, respectively (n = 7 fibers each) (P<0.05). The highest pulse energies transmitted through the fibers were 700 mJ and 220 mJ, respectively. CONCLUSIONS: Improved index-matching of the trunk fiber and fiber tip at 2.94 microm resulted in higher transmission and damage thresholds for the germanium oxide/sapphire fibers. The germanium oxide/sapphire fiber may represent a promising mid-infrared optical fiber delivery system for use in endoscopic applications of the Er:YAG laser requiring a flexible, biocompatible, and robust fiber delivery system for contact tissue ablation.

Aluminum Oxide↗

Transmission of Q-switched erbium:YSGG (lambda=2.79 microm) and erbium:YAG (lambda=2.94 microm) laser radiation through germanium oxide and sapphire optical fibres at high pulse energies.

The erbium:YSGG and erbium:YAG lasers are used for tissue ablation in dermatology, dentistry and ophthalmology. The purpose of this study was to compare germanium oxide and sapphire optical fibres for transmission of sufficient Q-switched erbium laser pulse energies for potential use in both soft and hard tissue ablation applications. Fibre transmission studies were conducted with Q-switched (500 ns) Er:YSGG (lambda=2.79 microm) and Er:YAG (lambda=2.94 microm) laser pulses delivered at 3 Hz through 1-m-long, 450-mum germanium oxide and 425-mum sapphire optical fibres. Transmission of free-running (300 micros) Er:YSGG and Er:YAG laser pulses was also conducted for comparison. Each set of measurements was carried out on seven different sapphire or germanium fibres, and the data were then averaged. Fibre attenuation of Q-switched Er:YSGG laser energy measured 1.3+/-0.1 dB/m and 1.0+/-0.2 dB/m for the germanium and sapphire fibres, respectively. Attenuation of Q-switched Er:YAG laser energy measured 0.9+/-0.3 dB/m and 0.6+/-0.2 dB/m, respectively. A maximum Q-switched Er:YSGG pulse energy of 42 mJ (26-30 J/cm(2)) was transmitted through the fibres. However, fibre tip damage was observed at energies exceeding 25 mJ (n=2). Both germanium oxide and sapphire optical fibres transmitted sufficient Q-switched Er:YSGG and Er:YAG laser radiation for use in both soft and hard tissue ablation. This is the first report of germanium and sapphire fibre optic transmission of Q-switched erbium laser energies of 25-42 mJ per pulse.

Aluminum Oxide↗

Abuse of germanium associated with fatal lactic acidosis.

Germanium compounds are marketed as nonprescription drugs in Europe and are recommended by the suppliers for AIDS and metastatic cancer disease. We observed a patient with nonmetastatic 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 predominantly in straight proximal tubule cells with normal appearance of renal interstitium and glomeruli. The liver showed panlobular steatosis. Urine, 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.

Acidosis↗

[Evaluation of germanium dioxide neurotoxicity in rats and monkeys].

Toxic side effects of germanium dioxide contained in drugs that promote health, include nephropathy, anemia and peripheral neuropathy. Although the neuropathy, which we are interested in, is believed to occur in the patients taking excessive amounts of germanium dioxide, the pathogenesis of such neuropathy is not well understood. Therefore, we studied whether germanium dioxide causes the degeneration of the peripheral nerve in rats and monkeys. Our results showed that in rats, germanium dioxide administered orally and intraperitoneally, 100 mg/kg per day, 3 days a week for 8 weeks and 400 mg/kg per day, once a week for 8 weeks, respectively, did not produce a degeneration of myelinated fibers in teased fiber preparations and Epon-embedded sections of the peripheral nerve. In two monkeys also, germanium dioxide, administered orally, 30 to 40 mg/kg per day, 5 days a week for 8 months, did not produce a degeneration of myelinated fibers of the sural nerve on biopsy, although our results revealed proteinuria and elevated blood urea nitrogen. Further studies are warranted to elucidate the pathogenesis of germanium dioxide induced neuropathy.

Animals↗

Bioaccumulation of Germanium by Pseudomonas putida in the Presence of Two Selected Substrates.

The uptake of germanium by Pseudomonas putida ATCC 33015 was studied in the presence of catechol or acetate or both as representative substrates differing in their ability to form complexes with this element. The bacteria were taken from a batch culture grown on acetate as the sole carbon source. Cells introduced into a medium containing germanium and either catechol or a mixture of catechol and acetate accumulated germanium in a biphasic way. After a lower level of accumulation that corresponded to the value obtained in the presence of acetate was reached, a further increase in the germanium content up to a higher saturation level was observed. The appearance of the second step of accumulation, which corresponded to the linear degradation of catechol, proved that catechol facilitated the transport of germanium into the cells through the nonspecific uptake of the germanium-catechol complex by an inducible catechol transport system.

Journal Article↗

Acute and subacute inhalation toxicity of germanium dioxide in rats.

Two acute (4 hr) and one subacute (4 wk) inhalation toxicity studies on germanium dioxide (purity > or = 99%, mean particle size 1.7-2.6 microns) were conducted in young adult Wistar rats. In the acute studies, exposure of two groups of five rats of each sex to maximum attainable concentrations of either 3.10 g amorphous or 1.42 g hexagonal germanium dioxide/m3 for 4 hr was not lethal. In the subacute study, four groups of five rats of each sex were exposed to 0, 16, 72 and 309 mg hexagonal germanium dioxide/m3 for 6 hr/day, 5 days/wk during 4 wk. Two additional groups of 5 rats per sex, exposed either to 0 or to 309 mg/m3, were kept for a 33-day post-exposure period. At the end of the treatment period, changes were observed only in rats of the high concentration group: these changes were decreased body weight gain (both sexes), decreases in haematocrit (females) and thrombocyte count (both sexes), and increases in neutrophil count (both sexes) and white blood cell count (females). On clinical chemistry evaluation, decreased fasting blood glucose (females), decreased total protein concentration (both sexes), increased plasma alanine aminotransferase and aspartate aminotransferase activities (females), increased plasma urea nitrogen (males) and increased plasma bilirubin level (females) were observed. In addition, urinary volume was elevated, and urine density and pH were lowered in both sexes. Relative weights of kidneys, spleen, heart and lungs were higher than in controls. Microscopic examination revealed effects on renal tubular epithelium. Effects on growth, kidneys, and liver were still present at the end of the 33-day recovery period. It was concluded that the 4-hr LC50 value of amorphous germanium dioxide was greater than 3.10 g/m3 and that of the hexagonal form greater than 1.42 g/m3. The no-adverse-effect-level in the 4-wk study using hexagonal germanium dioxide was 72 mg/m3.

Administration, Inhalation↗

Tubulointerstitial nephropathy persisting 20 months after discontinuation of chronic intake of germanium lactate citrate.

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.

Adult↗

PET/CT: comparison of quantitative tracer uptake between germanium and CT transmission attenuation-corrected images.

UNLABELLED: In PET, transmission scanning for attenuation correction has most commonly been performed with an external positron-emitting radionuclide source, such as (68)Ge. More recently, combined PET/CT scanners have been developed in which the CT data can be used for both anatometabolic image formation and attenuation correction of the PET data. The purpose of this study was to assess the quantitative differences between CT-based and germanium-based attenuation-corrected PET images. METHODS: Twenty-eight patients with known or suspected cancer underwent whole-body (18)F-FDG PET/CT scanning for clinical diagnostic purposes. For each patient, attenuation maps were obtained from both the CT scan and the (68)Ge transmission data, and 2 different attenuation-corrected emission datasets were produced. Measured activity concentrations (both mean and maximum) from identical regions of interest in representative normal organs and in 36 pathologic foci of uptake were compared. RESULTS: CT-corrected emission images generally showed slightly higher radioactive concentration values than did germanium-corrected images (P < 0.01) for all lesions and all normal organs except the lung. Mean and maximum radioactivity concentrations were 4.3%-15.2% higher for CT-corrected images than for germanium-corrected images. Calculated radioactivity concentrations were significantly greater in osseous lesions than in nonosseous lesions (11.0% vs. 2.3%, P < 0.05, for mean value; 11.1% vs. 2.1%, P < 0.01, for maximum value). A weak positive correlation was observed between the CT Hounsfield units within the regions of interest and the percentage difference in apparent tracer activity in the CT-corrected images. CONCLUSION: Although quantitative radioactivity values are generally comparable between CT- and germanium-corrected emission PET images, CT-based attenuation correction produced radioactivity concentration values significantly higher than the germanium-based corrected values. These effects, especially in radiodense tissues, should be noted when using and comparing quantitative PET analyses from PET and PET/CT systems.

Algorithms↗

Inhibition of senile amyloidosis of mice by biscarboxyethyl germanium sesqui-oxide.

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.

Amyloidosis↗

[An autopsy case of chronic germanium intoxication presenting peripheral neuropathy, spinal ataxia, and chronic renal failure].

We report here an autopsy case of chronic germanium intoxication with major pathological changes in the central and peripheral sensory nervous systems. The patient was a 4-year-old girl who had suffered from gait disturbance and generalized muscle weakness for 22 months. She had been given orally germanium compounds (containing germanium dioxide, 225-450 mg/day) for the previous 28 months. In addition to the findings of chronic renal failure and anemia, she presented characteristic neurological symptoms exemplified by diffuse muscle atrophy, tongue fasciculation, sensory impairment and truncal ataxia as well as areflexia. Median and ulnar sensory nerve conduction velocities were also reduced. On the 17th hospital day, she died of renal failure. In addition to conspicuous degeneration of renal tubular cells, pathological studies revealed marked nerve fiber loss, degeneration and gliosis in the dorsal column of the spinal cord, which were most conspicuous in the thoracic and cervical cord. Axonal degenerative changes were also conspicuous in the sural and sciatic nerves. High concentration of germanium was detected in the brain, cerebellum, spinal cord, sciatic nerve, liver and kidney. It was suggested that the neural involvement in the current case was caused by chronic toxicity of germanium.

Ataxia↗