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Marder V.J.,University of California at Los Angeles | Novokhatny V.,Talecris Biotherapeutics
Journal of Thrombosis and Haemostasis | Year: 2010

Direct fibrinolytics are proteolytic enzymes that degrade fibrin without requiring an intermediate step of plasminogen activation. This review summarizes the current information available for five such agents, namely, plasmin (the prototypical form), three derivatives of plasmin (mini-plasmin, micro-plasmin, and delta-plasmin), and alfimeprase, a recombinant variant of a snake venom α-fibrinogenase, fibrolase. Biochemical attributes of molecular size, fibrin binding and inhibitor neutralization are compared. Preclinical investigations that assess the potential for thrombolytic efficacy in vitro and in animal models of vascular occlusion and for hemostatic safety in animal models of bleeding are detailed. Clinical potential has been assessed in patients with peripheral arterial and graft occlusion, acute ischemic stroke, and access catheter and hemodialysis shunt occlusions. The direct fibrinolytic agents have impressive biochemical and preclinical foundations for ultimate clinical application. However, clinical trial results for micro-plasmin and alfimeprase have not measured up to their anticipated benefit. Plasmin has thus far shown encouraging hemostatic safety, but efficacy data await completion of clinical trials. Whether direct fibrinolytics will provide clinical superiority in major thrombotic disorders over currently utilized indirect fibrinolytics such as tissue plasminogen activator remains to be determined. © 2009 International Society on Thrombosis and Haemostasis.

Sundy J.S.,Duke University | Baraf H.S.B.,Center for Rheumatology and Bone Research | Yood R.A.,Fallon Clinic | Edwards N.L.,University of Florida | And 12 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context: Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control Disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need. Objective: To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout. Design, Setting, and Patients: Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406. Intervention: Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group). Main Outcome Measure: Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6. Results: In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebotreated patients reached the primary end point (0/23; 95% CI, 0%-15%; P=.001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008). Conclusion: Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo. Trial Registration clinicaltrials.gov Identifier: NCT00325195. ©2011 American Medical Association. All rights reserved.

Marder V.J.,University of California at Los Angeles | Jahan R.,University of California at Los Angeles | Gruber T.,University of California at Los Angeles | Goyal A.,University of California at Los Angeles | Arora V.,Talecris Biotherapeutics
Stroke | Year: 2010

Plasmin is a direct-acting thrombolytic agent with a striking hemostatic safety advantage over plasminogen activators in animal models of thrombolysis and bleeding. In contradistinction to plasminogen activators, which risk bleeding at any effective thrombolytic dose, plasmin is tolerated without bleeding at several-fold higher amounts than those needed for thrombolysis. Plasmin has been safe in a current trial in patients with peripheral arterial or graft occlusion, and efforts are now directed toward therapy of stroke caused by cerebral artery occlusion. A rabbit (4 kg body weight) model of 2-hour, thrombin-induced middle cerebral artery occlusion using angiographic documentation of vascular patency and recanalization was used to perform a dose-ranging study of plasmin, delivered by catheter over a median duration of 10 minutes. Plasmin induced early recanalization in all animals (3 per group) within 10 minutes after discontinuation of 3, 2, or 1 mg of agent infusion. Control saline infusion failed to induce recanalization in 3 of 3 subjects. Plasmin rapidly induces middle cerebral artery recanalization, as determined in an angiogram-based animal model of arterial occlusion. Based on these data and other information, a phase I/IIa clinical trial of plasmin in human middle cerebral artery ischemic stroke has been initiated. © 2010 American Heart Association, Inc.

Loladze V.V.,Rensselaer Polytechnic Institute | Loladze V.V.,Talecris Biotherapeutics | Makhatadze G.I.,Rensselaer Polytechnic Institute
Proteins: Structure, Function and Bioinformatics | Year: 2011

Statistical analysis of the residue separation between a pair of ionizable side chains within 4 Å of each other was performed on a set of 1560 non-homologous PDB structures. We found that the frequency of pairs of like charges (i.e., pairs consisting of acidic residues Asp and Glu or pairs consisting of basic residues Arg and Lys) is two orders of magnitude lower than the pairs of oppositely charged residues (salt-bridges). We also found that for pairs of like charges the distribution is skewed dramatically towards short residue separation (<3). On the basis of these observations, we hypothesize that at short residue separation the repulsion between charges does not contribute much to the protein stability and the effects are largely dominated by the long range charge-charge interactions with other ionizable groups in the protein molecule. To test this hypothesis, we incorporated various pairs of charged residues at position 63 and 64 of ubiquitin and compared the stabilities of these variants. We also performed calculations of the expected changes in the charge-charge interactions. A very good correlation between experimental changes in the stability of ubiquitin variants, and changes in the energy of charge-charge interactions provides support for the hypothesis that a pair of ionizable residues next to each other in sequence modulates protein stability via long range charge-charge interactions with the rest of the protein. © 2011 Wiley-Liss, Inc.

Kaplan A.,17 Bedford Park Ave | Kaplan A.,Family Physician Airways Group of Canada | Cosentino L.,Talecris Biotherapeutics
Canadian Family Physician | Year: 2010

OBJECTIVE: To provide a review of α 1-antitrypsin deficiency (AATD), α 1-antitrypsin (AAT) augmentation, and the recommendations for timely recognition and treatment. SOURCES OF INFORMATION: Published guidelines and the medical literature about AATD and AAT augmentation were reviewed. The information presented is based on available published literature obtained by searching PubMed, the Cochrane Library databases, and the reference lists of relevant articles. Searches were limited to English-language articles published between 1990 and 2009. MAIN MESSAGE: α 1- Antitrypsin deficiency, a genetic disorder characterized by low serum levels of AAT, predisposes affected patients to development of early-onset pulmonary disease (most commonly emphysema and chronic obstructive pulmonary disease) and occasionally even life-threatening liver disease. Despite being one of the most common inherited conditions (affecting about 1 in 2000 to 5000 people), AATD is underrecognized. This is unfortunate; although there is no cure for AATD, prompt diagnosis can help impede loss of lung function. Specific treatment of this deficiency with augmentation therapy is effective. CONCLUSION: α 1-Antitrypsin deficiency is a common genetic condition that can be involved in premature lung and liver disease. Consider the diagnosis to allow earlier institution of AAT augmentation therapy to slow the progression of premature lung disease in affected patients.

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