Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Involvement of AVP in several pathological states is now established and specific modulation of the different AVP receptor subtypes (V1a, V1b and V2) offers new clinical perspectives for treating major diseases. Recent years have marked a turning point with the design and the use of the first nonpeptide vasopressin receptor antagonists expressing various selectively profile. In that field, we report here the characterization of SR 121463A a highly selective, orally-active antagonist of vasopressin V2 receptors in several models in vitro and in vivo. This compound displayed competitive nanomolar affinity for V2 receptors in various species including man and exhibited a highly selective AVP V2 profile. In vitro, SR 121463A potently antagonized AVP-stimulated adenylyl cyclase activity in human kidney preparations (Ki = 0.26 +/- 0.04 nM) without any intrinsic agonistic effect. In normally-hydrated rats, SR 121463A induced dose-dependent powerful and long-lasting aquaresis after intravenous (0.003 to 0.3 mg/kg) or oral (0.03 to 10 mg/kg) administration. The action of SR 121463A is purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In vasopressin-deficient Brattleboro rats, SR 121463A is devoid of any V2 antidiuretic agonist properties. In addition, this compound potently antagonized DDAVP extrarenal V2 effects on hemostasis factor release (FVIII, vW and t-PA) in dogs (ID50 approximately 10 micrograms/kg i.v.). Thus, SR 121463A is the most potent and selective, orally-active V2 antagonist yet described. It is a useful ligand for exploring V2 receptors and the therapeutical usefulness of pure V2 aquaretic agents in several water-retaining diseases and congestive heart failure.
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PMID:Nonpeptide antagonists for vasopressin receptors. Pharmacology of SR 121463A, a new potent and highly selective V2 receptor antagonist. 1002 34

In von Willebrand disease, the main goals of treatment are to correct the dual defect of haemostasis caused by a reduced or abnormal von Willebrand factor (vWF), i.e. the prolonged bleeding time (BT) and the deficiency of factor VIII coagulant activity (FVIII:C). The synthetic vasopressin analogue, desmopressin (DDAVP), has reduced the need for transfusions in most of the mild forms of von Willebrand disease but DDAVP is ineffective in type 3 and in other severe cases of types 1 and 2 von Willebrand disease. For many years cryoprecipitate has been the mainstay of replacement therapy but, after the introduction of virucidal methods, concentrates containing FVIII/vWF have been considered much safer than cryoprecipitate and proposed in von Willebrand disease management. FVIII/vWF concentrates have been produced and tested by many authors but there is only one report describing four virus-inactivated FVIII/vWF concentrates evaluated in a cross-over randomized trial. According to these in vitro and pharmacokinetic data, the following information can be derived: (a) no FVIII/vWF concentrate had an intact multimeric structure similar to that of normal plasma or of cryoprecipitate; (b) all FVIII/vWF concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed in the concentrate devoid of FVIII:C; (c) no FVIII/vWF concentrate consistently normalized the BT in a sustained fashion. On the other hand, clinical haemostasis can be achieved in the management of bleeding episodes and of surgery for most of von Willebrand disease cases regardless of whether the BT is corrected; in the few rare cases with mucosal bleeding not controlled by FVIII/vWF concentrates, infusion of DDAVP or platelet concentrates can be administered in addition.
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PMID:Optimizing therapy with factor VIII/von Willebrand factor concentrates in von Willebrand disease. 1002 12

Replacement therapy with blood products has long been the only available therapeutic option for patients with bleeding disorders. Plasma-derived cryoprecipitate and factor (F) VIII concentrates, which have been used for hemophilia A patients, involve the risk of transmitting blood-borne diseases. Both plasma-derived and recombinant FVIII concentrates are expensive, and there is a global shortage. The synthetic vasopressin analogue desmopressin acetate (1-deamino-[8-D-arginine]-vasopressin, DDAVP) increases plasma concentrations of coagulation FVIII and von Willebrand factor (vWF) two fold to six fold through endogenous release. The drug is an attractive therapeutic alternative because it carries no risk of transmission of infectious diseases. Desmopressin is today a widely used hemostatic agent not only in patients with mild hemophilia A or von Willebrand disease (vWD) but also in those with congenital or acquired platelet dysfunction. There is a long clinical experience with the drug because it has been used for prevention of bleedings in connection with invasive procedures and for treatment of bleedings since the mid-1970s. Not all hemophilia A patients can be treated. The clinical usefulness depends on the postdesmopressin plasma concentration of FVIII, which in turn depends on the patient's basal FVIII level. Therefore, a test dose is recommended in candidate patients. In general, only the mildest hemophilia A patients respond sufficiently. Optimal hemostatic effect is achieved with a dosage of 0.3 microg/kg given intravenously. An intranasal desmopressin spray is suitable for the home treatment.
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PMID:Desmopressin in mild hemophilia A: indications, limitations, efficacy, and safety. 1264 May 72

The mechanism of the transient beneficial effect of 1-deamino(8-D-arginine) vasopressin (dDAVP) infusion in the hemostasis of some BSS patients is not fully understood. We have studied the effect of dDAVP infusion in a BSS patient using an ex vivo perfusion system. Additional coagulation and flow cytometry studies were also performed. Prolonged bleeding time (> 30 min) was not affected by dDAVP infusion. However, perfusion experiments performed with low molecular weight heparin anticoagulated blood (which permits the study of fibrin deposition on perfused subendothelium) showed a significant increase in platelet deposition (6.2% before dDAVP infusion; 20.3% after) and fibrin formation. dDAVP infusion also caused an increase in prothrombin consumption compared with base line values (33 vs 46%). Flow cytometry studies of the patients platelets showed no changes in binding of monoclonal antibodies against CD41, CD36, CD62P or CD63. The increase in thrombus formation observed in perfusions may be dependent on FVIII since it could be reproduced by adding purified free or von Willebrand factor (vWf)-associated FVIII to the patient's blood in vitro. The shortening effect of dDAVP on bleeding time observed in some Bernard-Soulier syndrome patients might be related to an increase in factor FVIII levels induced by dDAVP infusion.
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PMID:1-Deamino (8-D-arginine) vasopressin infusion partially corrects platelet deposition on subendothelium in Bernard-Soulier syndrome: the role of factor VIII. 1680 Oct 84

The synthetic vasopressin analogue (1-deamino-8-D-arginine-vasopressin) increases plasma concentration of factor VIII and von Willebrand factor in normal subjects and patients with mild haemophilia A and von Willebrand disease. Since its first clinical use in 1977, desmopressin has become the treatment of choice for patients with haemophilia A and factor VIII coagulant activity (FVIII:C) > 5% and has spared several patients the risk of acquiring blood-borne viral infections due to the use of non-virally inactivated plasma-derived FVIII concentrates. An average two to sixfolds FVIII:C increase is typically observed in most patients and return to baseline occurs usually within 8 hours. Several clinical studies have demonstrated the clinical efficacy and safety of desmopressin and the availability of concentrated formulation for subcutaneous injection and of a nasal spray has paved the way to home-treatment. However, overall it appears that haemophilic children may have a lower rate of biologic response compared to adults and a minority of adult patients are not able to attain clinically useful FVIII:C levels post-desmopressin administration. Thus, in every patient with haemophilia A likely to be treated or candidate to an elective invasive procedure, a test-infusion/injection should be carried out to assess the future usefulness of the compound.
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PMID:Desmopressin for the treatment of haemophilia. 1817 90

Utilization of the synthetic vasopressin analogue (1-deamino-8-D-arginine-vasopressin, DDAVP) in treatment of mild haemophilia A (MHA, specific clotting factor VIII activity level 0.05-0.4 IU mL(-1) ) is convenient and effective for many but not all patients. Genetic testing for patients with MHA is increasingly recognized as providing valuable information for patient care beyond informing reproductive decisions, and as more patients are genotyped, mutation data can be utilized to individualize treatment decisions. To determine if genetic information informs response to DDAVP, a retrospective chart review was performed under Institutional Review Board approval to extract patient data with MHA, genetic mutation results, and response to DDAVP challenge. 62 patients met inclusion criteria. Complete responses (C) presented in mean value IU mL(-1) (range), were recorded for 32 of 62(52%) subjects: pre 0.19(0.04-0.45) and post 0.78(0.5-1.95); partial responses (P) were recorded for 15 of 62(24%) subjects: pre 0.1(0.06-0.15) and post 0.4(0.3-0.47); responses that were not clinically significant (N) were recorded for 15 of 62(24%) subjects: pre 0.17(0.02-0.34) and post 0.25(0.03-0.44). Subjects (related and unrelated) with the same mutation showed a trend towards a similar response to DDAVP. Eight genotypes were common to two or more subjects (n = 26). Two genotypes were concordant in all subjects [p.Ser2192Ile n = 3(C), p.Ala2220Pro n = 2(P)]. Of mutations in the C1 or C2 domains, 13 of 15(87%) subjects responded to DDAVP [C = 9(60%); P = 4(27%); n = 2(13%)]. Baseline FVIII:C did not predict magnitude of response to DDAVP. Genetic mutation results can assist with predicting DDAVP responsiveness, but baseline FVIII:C may not.
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PMID:Factor VIII mutation and desmopressin-responsiveness in 62 patients with mild haemophilia A. 2371 Dec 94

The last decade of acute heart failure (HF) research is characterized by disappointments in large phase 2 and 3 pharmacologic studies of therapeutics including calcium-sensitizing agents and antagonists of endothelin, vasopressin, and adenosine. As a result, pharmacologic management for acute HF has changed little in recent years, and adverse event rates remain higher than in chronic HF. Despite neutral results in many acute HF trials, recent studies including RELAX-AHF, ASTRONAUT, and PRONTO have highlighted the role of appropriate timing of patient enrollment, targeting the "right" patients, and selecting appropriate end points and sites. We describe lessons learned from recent trials in acute HF and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from November 30 to December 1, 2012.
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PMID:Learning from recent trials and shaping the future of acute heart failure trials. 2409 41

The management of von Willebrand disease (VWD) is based upon the dual correction of the primary hemostasis defect, due to the inherited deficiency of von Willebrand factor (VWF), and of the secondary defect of factor VIII coagulant activity (FVIII:C), due to the loss of binding and stabilization by VWF of this intrinsic coagulation factor in flowing blood. The traditional therapeutic weapons (the synthetic derivative of the antidiuretic hormone desmopressin and plasma-derived VWF/FVIII concentrates) are able to transiently correct both the defects. With the goal of tackling the primary deficiency in the disease, that is, VWF, but at the same time exploiting the normal capacity of patients to produce FVIII, the novel approach of replacing only VWF was implemented in the last 10 years. Following the manufacturing of a concentrate fractionated from human plasma and of one obtained by recombinant DNA technology, clinical studies have shown that VWF-only products correct not only the primary VWF deficiency but also the secondary FVIII:C deficiency. The demonstrated efficacy of these products in various clinical situations and, ultimately, in such a hemostasis-challenging context as surgery testifies to the effectiveness and safety of this approach. It remains to be seen whether VWF-only products are efficacious and safe in still-unexplored situations, such as use in children; the long-term use for prophylaxis; and in recurrent gastrointestinal (GI) bleeding due to angiodysplasia, a major therapeutic problem in VWD.
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PMID:New therapies for von Willebrand disease. 3171 63

The management of von Willebrand disease (VWD) is based upon the dual correction of the primary hemostasis defect, due to the inherited deficiency of von Willebrand factor (VWF), and of the secondary defect of factor VIII coagulant activity (FVIII:C), due to the loss of binding and stabilization by VWF of this intrinsic coagulation factor in flowing blood. The traditional therapeutic weapons (the synthetic derivative of the antidiuretic hormone desmopressin and plasma-derived VWF/FVIII concentrates) are able to transiently correct both the defects. With the goal of tackling the primary deficiency in the disease, that is, VWF, but at the same time exploiting the normal capacity of patients to produce FVIII, the novel approach of replacing only VWF was implemented in the last 10 years. Following the manufacturing of a concentrate fractionated from human plasma and of one obtained by recombinant DNA technology, clinical studies have shown that VWF-only products correct not only the primary VWF deficiency but also the secondary FVIII:C deficiency. The demonstrated efficacy of these products in various clinical situations and, ultimately, in such a hemostasis-challenging context as surgery testifies to the effectiveness and safety of this approach. It remains to be seen whether VWF-only products are efficacious and safe in still-unexplored situations, such as use in children; the long-term use for prophylaxis; and in recurrent gastrointestinal (GI) bleeding due to angiodysplasia, a major therapeutic problem in VWD.
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PMID:New therapies for von Willebrand disease. 3180 84


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