Transport of platinum-based pharmaceuticals in water-saturated sand and natural soil: Carboplatin and cisplatin species.

This study reports the transport characteristics of the pharmaceutical compounds carboplatin and cisplatin, and their respective derivatives, in saturated sand and soil columns. Pharmaceuticals are recognized as emerging pollutants of soil and water resources, but studies of the transport characteristics of organometallic pharmaceuticals in soil-water environments are rare. A recent study of oxaliplatin transport in natural soil raises the question of whether or not its behavior is representative of all Pt-based pharmaceuticals behavior in soil-water systems. To address this question, transport behaviors of carboplatin and cisplatin species were studied individually in packed sand columns under unamended conditions, and in packed soil columns under unamended and acetate-amended conditions. In contrast to oxaliplatin, carboplatin species exhibited very low affinity to both sand and soil surfaces: the retention of injected carboplatin was 3% and <6% for sand and soil, respectively. The affinity to soil was practically the same under the different redox conditions. The affinity of carboplatin to sand and soil surfaces was much smaller than the reported oxaliplatin affinity and the values reported in the literature. Cisplatin exhibited transport behavior similar to that of oxaliplatin in soil, including mild sensitivity to redox conditions (e.g., higher retention under acetate-amended conditions), overall exhibiting retention of 64-70% of the injected species. However, cisplatin also exhibited a similar retention in sand (retention of 45-53%), unlike the cases of carboplatin and oxaliplatin. The results indicate that similarly structured pharmaceuticals can exhibit very different transport characteristic in natural soil-water environments, and should therefore be studied and assessed individually.

Biological Recovery of Platinum Complexes from Diluted Aqueous Streams by Axenic Cultures.

The widespread use of platinum in high-tech and catalytic applications has led to the production of diverse Pt loaded wastewaters. Effective recovery strategies are needed for the treatment of low concentrated waste streams to prevent pollution and to stimulate recovery of this precious resource. The biological recovery of five common environmental Pt-complexes was studied under acidic conditions; the chloro-complexes PtCl42- and PtCl62-, the amine-complex Pt(NH3)4Cl2 and the pharmaceutical complexes cisplatin and carboplatin. Five bacterial species were screened on their platinum recovery potential; the Gram-negative species Shewanella oneidensis MR-1, Cupriavidus metallidurans CH34, Geobacter metallireducens, and Pseudomonas stutzeri, and the Gram-positive species Bacillus toyonensis. Overall, PtCl42- and PtCl62- were completely recovered by all bacterial species while only S. oneidensis and C. metallidurans were able to recover cisplatin quantitatively (99%), all in the presence of H2 as electron donor at pH 2. Carboplatin was only partly recovered (max. 25% at pH 7), whereas no recovery was observed in the case of the Pt-tetraamine complex. Transmission electron microscopy (TEM) revealed the presence of both intra- and extracellular platinum particles. Flow cytometry based microbial viability assessment demonstrated the decrease in number of intact bacterial cells during platinum reduction and indicated C. metallidurans to be the most resistant species. This study showed the effective and complete biological recovery of three common Pt-complexes, and estimated the fate and transport of the Pt-complexes in wastewater treatment plants and the natural environment.

Quantitative bioimaging of platinum group elements in tumor spheroids.

Limited drug penetration into tumor tissue is a significant factor to the effectiveness of cancer therapy. Tumor spheroids, a 3D cell culture model system, can be used to study drug penetration for pharmaceutical development. In this study, a method for quantitative bioimaging of platinum group elements by laser ablation (LA) coupled to inductively coupled plasma mass spectrometry (ICP-MS) is presented. Different matrix-matched standards were used to develop a quantitative LA-ICP-MS method with high spatial resolution. To investigate drug penetration, tumor spheroids were incubated with platinum complexes (Pt(II)acetylacetonate, cisplatin) and the palladium tagged photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP). Distribution and accumulation of the pharmaceuticals were determined with the developed method.

Flow injection analysis with electrochemical detection for rapid identification of platinum-based cytostatics and platinum chlorides in water.

Platinum-based cytostatics, such as cisplatin, carboplatin or oxaliplatin are widely used agents in the treatment of various types of tumors. Large amounts of these drugs are excreted through the urine of patients into wastewaters in unmetabolised forms. This phenomenon leads to increased amounts of platinum ions in the water environment. The impacts of these pollutants on the water ecosystem are not sufficiently investigated as well as their content in water sources. In order to facilitate the detection of various types of platinum, we have developed a new, rapid, screening flow injection analysis method with electrochemical detection (FIA-ED). Our method, based on monitoring of the changes in electrochemical behavior of analytes, maintained by various pH buffers (Britton-Robinson and phosphate buffer) and potential changes (1,000, 1,100 and 1,200 mV) offers rapid and cheap selective determination of platinum-based cytostatics and platinum chlorides, which can also be present as contaminants in water environments.

Determination of platinum traces contamination by graphite furnace atomic absorption spectrometry after preconcentration by cloud point extraction.

A simple and sensitive method is described for the determination of platinum surface contamination originating from cisplatin, carboplatin and oxaliplatin. Following extraction from swabs and preconcentration with the cloud point extraction (CPE) method, detection was by graphite furnace atomic absorption spectrometry (GFAAS). After desorption of platinum compounds from the swab, CPE involved on preconcentration of platinum in aqueous solution with diethyldithiocarbamate (DDTC) as chelating agent and Triton X-114 as extraction medium. DDTC is not only a chelating agent, but may also be a good candidate for the inactivation of platinum compounds. DDTC is recommended by the Word Health Organization (WHO) for the destruction of platinum-based anticancer drugs. The main factors affecting CPE efficiency, pH of the sample solution, concentrations of DDTC and Triton X-114, equilibration temperature and incubation time, were evaluated in order to enhance sensitivity of the method. The desorption of platinum compounds from the swab was investigated in parallel. Since platinum is bound to DDTC, it must exchange with copper in order to enhance platinum atomizing by GFAAS. A preconcentration factor of 29 was obtained for 10 mL of a platinum solution at 10 microg mL(-1). In optimal conditions, the limit of detection was 0.2 ng mL(-1), corresponding to 2.0 ng of platinum metal on the swab. Absorbance was linear between 0.7 and 15 ng mL(-1). The proposed method was applied for the determination of surface contamination by platinum compounds with correct results.

Platinum-group elements in sewage sludge and incinerator ash in the United Kingdom: assessment of PGE sources and mobility in cities.

Platinum-group element (PGE) concentrations in sewage sludge and incinerator ash compared with average PGE concentrations in road dust show a common pattern, characterized by a negative Rh anomaly. This similarity, found at 9 UK incinerators, suggests that there is a universal characteristic PGE pattern produced by common processes of dispersal of Pt, Pd and Rh derived from automobile catalytic converters. Ninety-one sewage sludge and incinerator ash samples from the sewage treatment facilities in Sheffield, Birmingham and 7 other UK cities were analyzed for PGE. The highest concentrations are 602ppb Pt and 710ppb Pd with lower maximum concentrations of 65ppb Rh, 100ppb Ru, 33ppb Ir and 12ppb Os. Ash from incinerated sewage was found to have higher PGE concentrations compared to the original sludge and the PGE ratios are preserved during incineration. Rh is more mobilized and dispersed than the other PGE as it is transported from roads into the drainage system and into sewage. Pt/Pd ratios of 1.0 in road dust and 0.9 in sewage and incinerator ash suggest that Pd is more mobile than Pt during dispersal. PGE abundances in stored incinerator ash of varying ages appear to have been affected by the variation in use of Pt, Pd and Rh in catalytic converters due to variation in their market prices. Concentrations of Os, Ir and Ru in ashes are greater in Sheffield and London than all the other city sites and may be derived from point industrial sources.

1H, 13C, 15N and 195Pt NMR studies of Au(III) and Pt(II) chloride organometallics with 2-phenylpyridine.

(1)H, (13)C, (15)N and (195)Pt NMR studies of gold(III) and platinum(II) chloride organometallics with N(1),C(2')-chelated, deprotonated 2-phenylpyridine (2ppy*) of the formulae [Au(2ppy*)Cl(2)], trans(N,N)-[Pt(2ppy*)(2ppy)Cl] and trans(S,N)-[Pt(2ppy*)(DMSO-d(6))Cl] (formed in situ upon dissolving [Pt(2ppy*)(micro-Cl)](2) in DMSO-d(6)) were performed. All signals were unambiguously assigned by HMBC/HSQC methods and the respective (1)H, (13)C and (15)N coordination shifts (i.e. differences between chemical shifts of the same atom in the complex and ligand molecules: Delta(1H)(coord) = delta(1H)(complex) - delta(1H)(ligand), Delta(13C)(coord) = delta(13C)(complex) - delta(13C)(ligand), Delta(15N)(coord) = delta(15N)(complex) - delta(15N)(ligand)), as well as (195)Pt chemical shifts and (1)H-(195)Pt coupling constants discussed in relation to the known molecular structures. Characteristic deshielding of nitrogen-adjacent H(6) protons and metallated C(2') atoms as well as significant shielding of coordinated N(1) nitrogens is discussed in respect to a large set of literature NMR data available for related cyclometallated compounds.

Guidance values for surface monitoring of antineoplastic drugs in German pharmacies.

OBJECTIVES: Antineoplastic drugs are widely used in anticancer therapy due to their cytotoxic activity but many of them are classified as carcinogenic, mutagenic, or teratogenic to humans. In order to evaluate personal exposure, surface monitoring has been successfully applied for several years. In this study, we present a statistical description of our data set from 102 German pharmacies and propose 'threshold guidance values (TGVs)' to facilitate interpretation of monitoring results. METHODS: Our database included 1008 results for platinum (PT) and 1237 for 5-fluorouracil (FU) collected in 102 pharmacies in Germany. Wipe sampling on site was performed with one validated procedure. PT concentrations were measured by voltammetry and FU by gas chromatography/mass spectrometry. Data were stratified into 10 locations and statistically evaluated. RESULTS: Contamination was detected on all surfaces in the pharmacies with high levels on storage shelves and floors. The median values for the different locations ranged from 0.20 to 1.70 pg cm(-2) (mean: 0.57 pg cm(-2)) for PT and from 2.50 to 10.00 pg cm(-2) (mean: 5.34 pg cm(-2)) for FU. The mean 75th percentiles were 3.92 pg cm(-2) (PT) and 28.90 pg cm(-2) (FU). The TGV 1 value was set at the median value and results below demonstrate good working practices. Contaminations above the TGV 2, which was assigned at the 75th percentile, show a clear need for optimizing the handling procedures. CONCLUSIONS: The introduction of TGVs helps to reduce occupational exposure and allows pharmacy personnel to benchmark their own contamination levels. This provides a basis for improvement in occupational safety precautions and for regular contamination controls.

Application of flavonoids - quercetin and rutin - as new matrices for matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis of Pt(II) and Pd(II) complexes.

Attempts are being made to overcome the resistance of tumour cells to platinum (Pt) drugs by the synthesis of new generations of Pt complexes, and it is important to find appropriate and simple methods for the characterization of those novel complexes. The additional applicability of such a method for the analysis of the interactions of metal complexes with biomolecules would be advantageous. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) seems to possess the capability to become this method of choice, since it could be applied to low-mass complexes as well as for the analysis of large biomolecules. In this work the applicability of flavonoids - quercetin and rutin - as matrices for MALDI-TOFMS analysis of dichlorido(ethylendiamine)platinum(II) ([PtCl(2)(en)]), dichlorido(diaminocyclohexane)platinum(II) ([PtCl(2)(dach)]) and chloride (diethylenetriamine) palladium(II) chloride ([PdCl(dien)]Cl) complexes is demonstrated. Spectra of Pt(II) and Pd(II) complexes recorded in the presence of quercetin and rutin are rather simple: Pt(II) complexes generate [M+Na](+) or [M+K](+)ions, whereas the investigated Pd(II) complex gives ions generated by the loss of one Cl(-) or HCl. Flavonoids give a relatively small number of well-defined ions in the low-mass region (at m/z 303.3 for quercetin and m/z 633.5 for rutin). Quercetin and rutin can be applied in much lower concentrations than other common MALDI matrices and require rather low laser intensity. We speculate that flavonoids stabilize the structures of the metal complexes and that they may be useful for the analysis of other biologically active metal complexes, thus implying their broader applicability.

Fluorescent method for platinum detection in buffers and serums for cancer medicine and occupational hazards.

Herein we demonstrate fluorescence detection of total platinum species in buffers and serums by a Pt(0)-catalyzed Tsuji-Trost type reaction to yield a fluorescent compound.

Speciation of inorganic platinum-chloride complexes in spiked environmental samples by SPE and ICP-AES.

A method for the separation of tetrachloroplatinate PtCl(4)(2-), and hexachloroplatinate PtCl(6)(2-), by solid-phase extraction, using a Dowex 1x10 anion exchange resin is proposed. The sequential elution and separation of PtCl(4)(2-), and PtCl(6)(2-) is achieved using selective complexing agents. The eluates, containing Pt(II) and Pt(IV) were analyzed by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Recoveries of 102% for PtCl(4)(2-) and 94% for PtCl(6)(2-) and detection limit of 15 ng g(-1) were achieved. Using this method determination of Pt(II) and Pt(IV) in soil samples, spiked with different platinum species was performed. The comparison with GFAAS determination showed a very good agreement.

Fate of cancerostatic platinum compounds in biological wastewater treatment of hospital effluents.

The present work focuses on the fate of two cancerostatic platinum compounds (CPC), cisplatin and carboplatin, as well as of two inorganic platinum compounds, [PtCl(4)](2-) and [PtCl(6)](2-) in biological wastewater treatment. Laboratory experiments modelling adsorption of these compounds onto activated sludge showed promising specific adsorption coefficients K(D) and K(OC) and Freundlich adsorption isotherms. However, the adsorption properties of the investigated substances were differing significantly. Adsorption decreased following the order cisplatin>[PtCl(6)](2-)>[PtCl(4)](2-)>carboplatin. LogK(D)-values were ranging from 2.5 to 4.3 , logK(OC) from 3.0 to 4.7. A pilot membrane bioreactor system (MBR) was installed in a hospital in Vienna and fed with wastewater from the oncologic in-patient treatment ward to investigate CPC-adsorption in a sewage treatment plant. During three monitoring periods Pt-concentrations were measured in the influent (3-250 microg l(-1) Pt) and the effluent (2-150 microgl(-1) Pt) of the treatment plant using ICP-MS. The monitoring periods (duration 30d) revealed elimination efficiencies between 51% and 63% based on averaged weekly input-output budgets. The derived logK(D)-values and logK(OC)-values ranged from 2.4 to 4.8 and from 2.8 to 5.3, respectively. Species analysis using HPLC-ICP-MS proofed that mainly carboplatin was present as intact drug in the influent and--due to low logK(D)--in the effluent of the MBR.

Platinum-group element concentrations in BCR-723: a quantitative review of published analyses.

BCR-723 is the only environmental certified reference material for platinum-group elements (PGEs) Pt, Pd and Rh. It has been an integral component of quality control/quality assurance procedures in environmental laboratories measuring PGEs, since 2001. Here, we present an extensive quantitative review of the published PGEs measured in BCR-723, since its introduction. A statistical examination of concentrations, measurement precision and accuracy for 25 studies is presented. Measurement typically starts with an aqua regia digestion, followed by some form of pre-concentration or separation procedure, and quantitation by ICP-MS. Use of a sample mass below the recommended value of 100 mg has been shown to produce biased results for acid-based digestions or with laser ablation. Platinum is the most precisely and accurately measured PGE in BCR-723, followed by Rh, and finally by Pd. Literature precision data for all autocatalyst PGEs did not differ significantly (alpha=0.05) from those obtained by the original laboratories used to certify BCR-723. Measurement accuracies for the literature tabulated PGE data did not differ significantly from zero, indicating an overall lack of directional bias. These results should be encouraging to the analytical community, but further advancements, especially for Pd quantification are required.

The RP-HPLC measurement and QSPR analysis of logP(o/w) values of several Pt(II) complexes.

The n-octanol/water partition coefficient, logP(o/w), for a set of 24 Pt(II)-complexes was estimated by means of reversed-phase high performance liquid chromatography (RP-HPLC) technique using a C18 (ODS, octadecyl silane) column as a stationary phase and water/methanol mixtures as mobile phases. Based on the known logP(o/w) of several Pt(II)-complexes, we set a method to correlate the partition coefficient of this kind of complexes with the corresponding retention parameters. The best result was obtained from extrapolation to 0% of the organic modifier (MeOH) of the aqueous eluant. A quantitative structure-property relationship (QSPR) was constructed using molecular descriptors derived from density functional theory (DFT) calculations, which was found to correlate and predict these values with good accuracy. The use of DFT calculations is required because group-additive methods fail due to lack of values for appropriate fragments for many Pt(II)-complexes.

In vitro comparison of the charge-injection limits of activated iridium oxide (AIROF) and platinum-iridium microelectrodes.

The charge-injection limits of activated iridium oxide electrodes (AIROF) and PtIr microelectrodes with similar geometric area and shape have been compared in vitro using a stimulation waveform that delivers cathodal current pulses with current-limited control of the electrode bias potential in the interpulse period. Charge-injection limits were compared over a bias range of 0.1-0.7 V (versus Ag/AgCl) and pulse frequencies of 20, 50, and 100 Hz. The AIROF was capable of injecting between 4 and 10 times the charge of the PtIr electrode, with a maximum value of 3.9 mC/cm2 obtained at a 0.7 V bias and 20 Hz frequency.

Symmetry properties of tetraammine platinum(II) with C2v and C4v point groups.

Let G be a weighted graph with adjacency matrix A=[a(ij)]. An Euclidean graph associated with a molecule is defined by a weighted graph with adjacency matrix D=[d(ij)], where for i not = j, d(ij) is the Euclidean distance between the nuclei i and j. In this matrix d(ii) can be taken as zero if all the nuclei are equivalent. Otherwise, one may introduce different weights for different nuclei. Balasubramanian (1995) computed the Euclidean graphs and their automorphism groups for benzene, eclipsed and staggered forms of ethane and eclipsed and staggered forms of ferrocene. This paper describes a simple method, by means of which it is possible to calculate the automorphism group of weighted graphs. We apply this method to compute the symmetry of tetraammine platinum(II) with C2v and C4v point groups.

Development of the "Cell Chip": a new in vitro alternative technique for immunotoxicity testing.

Predictive testing of immunotoxicity associated with chemical compounds is complicated and cannot be accomplished with a single test. As most of the existing tests for immunotoxicity employ experimental animals, there is an increasing need for alternative tests in vitro. We have developed a new system for in vitro immunotoxicity testing, which employs changes in cytokine expression observed in vitro as an endpoint indicating potential for perturbation of the immune system in vivo. This system named "fluorescent cell chip" (FCC) is based on a number of genetically modified cell lines that regulate the expression of a transgene coding for fluorescent protein enhanced green fluorescent protein (EGFP) in a similar way as they regulate expression of IL-1beta, IL-2, IL-4, IFN-gamma, IL-10, TNF-alpha, and beta-actin. Morphological and functional features of selected cell lines expressing EGFP under the control of cytokine promotors were compared with maternal cell lines and this comparison showed that critical functional features of the maternal cell lines were preserved in EGFP expressing cells. Two chemicals with known immunotoxic activities, cyclosporine A and potassium tetrachloro-platinate(II), mediated compound-specific pattern of inhibition and activation of reporter gene expression. Thus, the "fluorescent cell chip" has demonstrated potential for application as a predictive screening test for immunomodulatory activities of chemicals. The major advantage of this approach is the possibility to apply this test in high throughput screening of high number of compounds for their well defined biological activity.

Spectrophotometric studies of the interaction of noble metals with quercetin and quercetin-5'-sulfonic acid.

Results of some studies on the interaction of noble metals with quercetin (Q) and quercetin-5'-sulfonic acid (QSA), the compounds of flavonoid group, are presented. The reactions of chloride complexes of the metals: RuOHCl5(2-), PdCl4(2-), OsCl6(2-), PtCl6(2-) and AuCl4- with both reagents were examined. The redox reactions of ruthenium and gold with Q and QSA have been identified. The reaction of the metals with both reagents results in the formation of the oxidized form of Q that exhibits maximum absorbance at 291 nm. Ruthenium and gold react with the examined reagents under similar conditions: 0.04 M HCl and 1 x 10(-4) M Q (or QSA). The CH3OH + H2O (1:1) (Q) and pure aqueous (QSA) media can be used. The reaction of gold with Q is slow at room temperature. It can be accelerated by heating the solution being examined. The reaction proceeds significantly faster when the water-soluble sulfonic derivative of quercetin, quercetin-5'-sulfonic acid, is used as a reagent. The new species formed can make the basis of spectrophotometric methods for the determination of ruthenium and gold. The molar absorptivities at 291 nm are equal to 5.0 x 10(3) and 2.2 x 10(4) L mol(-1) cm(-1) for Ru and Au, respectively, independently of the reagent used. Some methods for the determination of the content of gold (0.04%) in a cosmetic cream were developed.

Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280.

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2-8 degrees C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting.