A phase II prospective open-label escalating dose trial of recombinant interleukin-11 in mild von Willebrand disease

von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1-8 deamino-d-arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin-11 (rhIL-11), a gp-130 signalling cytokine with haematopoietic and anti-inflammatory activity, increases VWF antigen and its activity in heterozygous VWF+/− mice and dogs. To determine the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD, we conducted a phase II prospective open-label trial of rhIL-11 at 10, 25 and 50 μg kg−1 subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL-11, which was sustained through 7 days of dosing to 1.5- to 3-fold over baseline. Following intravenous DDAVP, 0.3 μg kg−1, on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL-11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two- to eightfold over baseline, suggesting that the mechanism of rhIL-11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL-11 was well tolerated with less than grade-1 hypertension, hypokalaemia and fluid retention. Recombinant IL-11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population

Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders

Status report on solid control in leachates

Sludge pretreatment will involve some combination of washing and leaching with sodium hydroxide solutions to remove soluble salts and amphoteric material such as alumina. It is of paramount importance to prevent gelation and uncontrolled solid formation in tanks, transfer lines, and process equipment. An evaluation of results of washing and caustic leaching indicates that washing is more effective in dissolving sludge solids than subsequent sodium hydroxide treatment. Only aluminum and chromium were removed more effectively by caustic leaching than by water washing

Conventional and Dense Gas Techniques for the Production of Liposomes: A Review

The aim of this review paper is to compare the potential of various techniques developed for production of homogenous, stable liposomes. Traditional techniques, such as Bangham, detergent depletion, ether/ethanol injection, reverse-phase evaporation and emulsion methods, were compared with the recent advanced techniques developed for liposome formation. The major hurdles for scaling up the traditional methods are the consumption of large quantities of volatile organic solvent, the stability and homogeneity of the liposomal product, as well as the lengthy multiple steps involved. The new methods have been designed to alleviate the current issues for liposome formulation. Dense gas liposome techniques are still in their infancy, however they have remarkable advantages in reducing the use of organic solvents, providing fast, single-stage production and producing stable, uniform liposomes. Techniques such as the membrane contactor and heating methods are also promising as they eliminate the use of organic solvent, however high temperature is still required for processing

OrphanAnesthesia - A common project of the Scientific Working Group of Paediatric Anaesthesia of the German Society of Anaesthesiology and Intensive Care Medicine

The target of OrphanAnesthesia is the publication of anaesthesia recommendations for patients suffering from rare diseases in order to improve patients' safety. When it comes to the management of patients with rare diseases, there are only sparse evidencebased facts and even far less knowledge in the anaesthetic outcome. OrphanAnesthesia would like to merge this knowledge based on scientific publications and proven experience of specialists making it available for physicians worldwide free of charge. All OrphanAnesthesia recommendations are standardized and need to pass a peer review process. They are being reviewed by at least one anaesthesiologist and another disease expert (e.g. paediatrician or neurologist) involved in the treatment of this group of patients. The project OrphanAnesthesia is internationally oriented. Thus all recommendations will be published in English. Starting with issue 5/2014, we'll publish the OrphanAnesthesia recommenations as a monthly supplement of A&I (Anästhesiologie & Intensivmedizin). Thus they can be accessed and downloaded via www.aionline.info. As being part of the journal, the recommendations will be quotable. Reprints can be ordered for payment

Low-level liquid waste decontamination by ion exchange

Improved processes are being developed to treat contaminated liquid wastes that have been and continue to be generated at Oak Ridge National Laboratory. Both inorganic and organic ion-exchange methods have given promising results. Nickel and cobalt hexacyanoferrate(2) compounds are extremely selective for cesium removal, with distribution coefficients in excess of 10{sup 6} and remarkable insensitivity to competition from sodium and potassium. They tend to lose effectiveness at pH > {approximately}11, but some formulations are useful for limited periods of time up to pH {approximately}13. Sodium titanate is selective for strontium removal at high pH. The separations are so efficient that simple batch processes can yield large decontamination factors while generating small volumes of solid waste. A resorcinol-based resin developed at the Savannah River Site gave superior cesium removal, compared with other organic ion exchangers; the distribution coefficient was limited primarily by competition from potassium and was nearly independent of sodium. The optimum pH was {approximately}12.5. It was much less effective for strontium removal, which was limited by competition from sodium. 8 refs., 6 figs., 9 tabs

Sludge treatment studies

Solid formation in filtered leachates and wash solutions was seen in five of the six sludges treated by Enhanced Sludge Washing. Solid formation in process solutions takes a variety of forms: very fine particles, larger particulate solids, solids floating in solution like egg whites, gels, crystals, and coatings on sample containers. A gel-like material that formed in a filtered leachate from Enhanced Sludge Washing of Hanford T-104 sludge was identified as natrophosphate, Na{sub 7}(PO{sub 4}){sub 2}F{center_dot}19H{sub 2}O. A particulate material that formed in a filtered caustic leachate from Hanford SX-113 sludge contained sodium and silicon. This could be any of a host of sodium silicates in the NaOH-SiO{sub 2}-H{sub 2}O system. Acidic treatment of Hanford B-202 sludge with 1 M, 3 M, and 6 M HNO{sub 3} sequential leaching resulted in complete dissolution at 75 C, but not at ambient temperature. This treatment resulted in the formation of solids in filtered leachates. Analyses of the solids revealed that a gel material contained silica with some potassium, calcium, iron, and manganese. Two phases were embedded in the gel. One was barium sulfate. The other could not be identified, but it was determined that the only metal it contained was bismuth

A low-temperature process for the denitration of Hanford single-shell tank, nitrate-based waste utilizing the nitrate to ammonia and ceramic (NAC) or nitrate to ammonia and glass (NAG) process: Phase 2 report

Continuing benchtop studies using Hanford single-shell tank (SST) simulants and actual Oak Ridge National Laboratory (ORNL) low-level waste (LLW), employing a new denitration process for converting nitrate to ammonia and ceramic (NAC), have conclusively shown that between 85 and 99% of the nitrate can be readily converted to gaseous ammonia. In this process, aluminum powders can be used to convert alkaline, nitrate-based supernate to ammonia and an aluminum oxide-sodium aluminate-based solid. The process may be able to use contaminated aluminum scrap metal from DOE sites to effect the conversion. The final, nitrate-free ceramic product can be pressed and sintered like other ceramics or silica and/or fluxing agents can be added to form a glassy ceramic or a flowable glass product. Based upon the starting volumes of 6.2 and 3.1 M sodium nitrate solution, volume reductions of 50 to 70% were obtained for the waste form produced. Sintered pellets produced from supernate from Melton Valley Storage Tanks (MVSTs) have been leached in accordance with the 16.1 leach test for the radioelements {sup 85}Sr and {sup 137}Cs. Despite lengthy counting times, {sup 85}Sr could not be detected in the leachates. {sup 137}Cs was only slightly above background and corresponded to a leach index of 12.2 to 13.7 after 8 months of leaching. Leach testing of unsintered and sintered reactor product spiked with hazardous metals proved that both sintered and unsintered product passed the Toxicity Characteristic Leaching Procedure (TCLP) test. Design of the equipment and flowsheet for a pilot demonstration-scale system to prove the nitrate destruction portion of the NAC process and product formation is under way