Mirror-image organometallic osmium arene iminopyridine halido complexes exhibit similar potent anticancer activity.

Four chiral Os(II) arene anticancer complexes have been isolated by fractional crystallization. The two iodido complexes, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 2, (S)-ImpyMe: N-(2-pyridylmethylene)-(S)-1-phenylethylamine) and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 4, (R)-ImpyMe: N-(2-pyridylmethylene)-(R)-1-phenylethylamine), showed higher anticancer activity (lower IC50 values) towards A2780 human ovarian cancer cells than cisplatin and were more active than the two chlorido derivatives, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 1, and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 3. The two iodido complexes were evaluated in the National Cancer Institute 60-cell-line screen, by using the COMPARE algorithm. This showed that the two potent iodido complexes, 2 (NSC: D-758116/1) and 4 (NSC: D-758118/1), share surprisingly similar cancer cell selectivity patterns with the anti-microtubule drug, vinblastine sulfate. However, no direct effect on tubulin polymerization was found for 2 and 4, an observation that appears to indicate a novel mechanism of action. In addition, complexes 2 and 4 demonstrated potential as transfer-hydrogenation catalysts for imine reduction.

Nanofocused synchrotron X-ray absorption studies of the intracellular redox state of an organometallic complex in cancer cells.

Synchrotron nanoprobe X-ray absorption (XAS) studies of a potent organo-osmium arene anticancer complex in ovarian cancer cells at subcellular resolution allow detection and quantification of both OsII and OsIII species, which are distributed heterogeneously in different areas of the cells.

Osmium: an appraisal of environmental exposure.

In the U.S., the chief source of new osmium is copper refining, where this metal is produced as a byproduct. Probably less than 10% of the osmium in the original copper ore is recovered, and 1000-3000 oz troy of osmium is lost each year to the environment as the toxic, volatile tetroxide from copper smelters. In 1971, about 2000 oz troy of osmium was domestically refined, most of which was from secondary sources. An additional 4169 oz troy of osmium was toll-refined. Major uses for osmium tetroxide identified are for catalysis, especially in steroid synthesis, and for tissue staining. Minor uses of osmium metal are for electrical contacts and for imparting hardness to alloys for mechanical pivots, etc. Unreclaimed osmium tetroxide that reaches wastewater streams is probably rapidly reduced by organic matter to nontoxic osmium dioxide or osmium metal, which would settle out in the sediment of the water course. Waste osmium metal, itself innocuous and chemically resistant, would be oxidized to the toxic tetroxide if incinerated. Because of the small amounts used and their wide dispersal, the amounts of osmium tetroxide in wastewater and air should pose no hazard to man or the environment. The chief acute toxic effects of osmium tetroxide are well known and include eye and respiratory-tract damage. Few data are available that provide information on possible effects of nonacute exposure resulting from environmental contamination by osmium. However, workers continually exposed to osmium tetroxide vapors (refiners and histologists) and rheumatoid arthritis patients who have received intra-articular injections of osmic acid solutions have shown no apparent damage from exposure to low levels of osmium.

[Radiological opacities after intra-articular injection of osmic acid. Relationship with the injection site (author's transl)]. / Opacités radiologiques après synoviorthèse du genou à l'acide osmique. Relation avec le site d'injection.

Abnormal radiological opacities are sometimes observed after intra-articular injection of osmic acid. These opacities are radio-opaque because osmium is a heavy metal (atomic number = 76). They are usually found near the suprapatellar pouch which is the usual injection site. A parasynovial injection (or back flow from the joint cavity) of some of the osmic solution, followed by concentration and fixation of the osmic deposits at this level, seems to be the cause of these radiological opacities. This could be the reason for the poor clinical results encountered in some cases of osmic acid therapy followed by such deposits.

Specimen preparation for "block face" scanning electron microscopy (BFSEM). An energy-dispersive X-ray spectroscopy study

In this paper we describe a SEM block-face technique in which block faces of large dimensions can be examined in a high-resolution SEM under high vacuum. The results of different tissue contrast methods have been studied and, in addition to osmium, potassium permanganate has been used as a staining medium for the first time in BFSEM. The study also examined the effects of uranyl acetate and phosphotungstic acid. The following organs of adult albino rats were examined: colonic mucosa, spinal ganglion, anterior pituitary gland and exocrine pancreas.Six preparation protocols, referred to here as treatments, were applied and evaluated according to three criteria: 1st the visual quality of the digital images, 2nd the measurements of the signal-noise ratio (SNR) of the digital images with and without beam deceleration (BD), and 3rd the X-ray microanalysis of samples, treated according to the 6 proposed protocols, demonstrating the presence and relative quantity of the elements used to stain the cellular structures, enabling visualisation with the electron microscope. In conclusion, it can be said that treatments with osmium produced better results than those containing potassium permanganate. Treatments with the addition of thiocarbohydrazide (TCH) considerably increased the osmium deposits (ligand effect) and proved highly effective. Finally, it should be noted that the method proposed, called here 2D BFSEM, can be very useful not only in histology but also in histo-pathology, for example in the study of biopsies and - last but not least - in embryology: all these are situations in which it is important to avoid a loss of material due to preparation exigencies

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In vivo tumour and metastasis reduction and in vitro effects on invasion assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model.

We have compared the organometallic arene complexes [(eta(6)-biphenyl)M(ethylenediamine)Cl](+) RM175 (M=Ru(II)) and its isostructural osmium(II) analogue AFAP51 (M=Os(II)) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6x more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231 cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo.

[Local treatment of chronic arthritis with radionuclides]. / Die lokale Behandlung chronischer Arthritiden mit Radionukliden

Radiosynoviorthesis plays an important role in local treatment of rheumatoid arthritis. Depending on the size of the joint, radionuclides are used at different depths of penetration. Data from the literature and our own results with 396 treated joints indicate that in 2/3 of cases good therapeutic effects are achieved, e.g. the effect on the local inflammatory process is comparable with surgical synovectomy. This is in agreement with the results of our longterm follow-up of 141 joints after radiosynoviorthesis. As with surgical synovectomy, early synoviorthesis was most successful; however, longterm observations revealed a slight increase in local recurrences. These and primary non-responder cases show a good response to secondary injection of radionuclides. The effect of intraarticular injection of isotopes is possibly due to irradiative action on the inflamed cells, with subsequent fibrosis of the synovium. Side effects of radiosynoviorthesis are rare and generally avoidable. Since late complications cannot be excluded, careful consideration should be given to the indication for radiosynoviorthesis. Radiosynoviorthesis represents an alternative treatment to surgical synovectomy in patients over 40 years of age.

A study of the variable heavy chain (VH) regions in human polyclonal IgM rheumatoid factors.

Ten IgM polyclonal rheumatoid factor (RF) preparations isolated from sera from various patients with rheumatoid arthritis (RA) were investigated with respect to their variable heavy chain (VH) subgroups. They were tested in a haemagglutination inhibition system using red cells sensitized with myeloma proteins with known chemical VH subgroups and anti-VH subgroup specific antisera. Most of the preparations showed a considerable degree of restriction to one VH subgroup. Seven of the IgM-RF preparations were restricted to the VHIII subgroup, two to the VHI subgroup and one to the VHII subgroup. However, a weak reaction in other VH subgroup systems was seen in several instances. Two normal IgM fractions from healthy persons showed no VH subgroup restriction, and showed a rather similar degree of reaction in all the three subgroup systems.

Morphological findings in joint cartilage after osmic acid treatment.

Punch biopsy specimens from the cartilage of the lateral condyle of the femur in 29 patients suffering from rheumatoid arthritis were taken during surgical synovectomy of knee joints and investigated by light or electron microscopy. Eleven patients had never received osmic acid injections in this particular joint, whereas 18 had had such injections 1-24 months prior to surgery. By light microscopy only minor differences could be seen between controls and cartilage treated with osmic acid, whereas with electron microscopy, increased amounts of dark-staining cell debris were visible in samples taken after osmic acid treatment. The perilacunar matrix appeared normal. There was no irregularity of collagen fibres at the surface of the cartilage. It is concluded that osmic acid causes limited superficial damage to the cartilage. The question whether this is of any clinical consequence in the form of subsequent degenerative joint disease, must be solved by clinical follow-up studies.

[Synoviorthesis of the knee using osmic acid: apropos of 61 injections]. / Synoviorthèses du genou par l'acide osmique. A propos de 61 injections.

The authors report their experience of 61 injections of osmic acid into the knee during the course of rheumatoid polyarthritis. The results stated to be very good and good, are classified by the disappearance of pain, swelling and stiffness, or a improvement in any one of these criteria. As observed in 67% of cases at the third month the result following changed with time. While these favourable results persisted into the fifth month, there was a remarkable maintenance of them to the 30th month in those patients who it was able to follow so long. The most distinct and lasting results were seen in those joints which showed the least radiological change. Tolerance of the injection of osmic acid was satisfactory apart from several painful reactions which improved in the 24 hours following injection. Two cases of thrombo-phlebitis were seen and one case of rupture of the synovium. If the results obtained with osmic acid appear less impressive than those obtained with isotopes, the simplicity of the method attracts attention as it needs no complicated equipment and is applicable to young invalids.

Intra-articular triamcinolone hexacetonide and osmic acid in persistent synovitis of the knee.

43 rheumatoid knees with persistent effusion were treated by intra-articular injections of triamcinolone hexacetonide (40 mg) or combined triamcinolone - osmic acid. Both treatments produced long-lasting improvements in the treated knees. Osmic acid seemed to potentiate the effect of the steroid. This demonstrated by measurement of joint circumference and local 99mTc uptake. In the general clinical evaluation the difference between the treatments was not noticeable. The percentage of 'excellent' and 'good' improvements was 36 at 12 months in the steroid-group and 44 in the steroid-osmic acid group.

Osmic acid in rheumatoid synovitis. A controlled study.

Ninety-nine adult RA patients with knee joint synovitis were randomized into two groups. The knee joints of the first group (52 patients) were treated with osmic acid and those of the second group (47 patients) with a placebo. After 6 months, the incidence of hydrops and pain was statistically less significant in joints treated with osmic acid. the result was better in joints without advanced radiological destruction. It is concluded that osmic acid is still of benefit in the local treatment of rheumatoid knee joint synovitis at an early stage.