128 research outputs found
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
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
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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
Nucleophilic Displacements in Supercritical Carbon Dioxide Under Phase-Transfer Catalysis Conditions. II. Effect of Pressure and Kinetics
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
Romantic Reconciliation as Influenced by Implicit Theories of Relationships and Information Seeking Style
This investigation examined the associations among implicit theories about the nature of relationships, information-seeking style, and the desire to reconcile. Participants included 217 individuals who were asked to recall a romantic relationship breakup that had occurred within 4 months of their participation in the study, and then complete a survey assessing implicit theories, information-seeking style, and desire for reconciliation
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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
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