Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic gene therapy involves the transfer into the body of a gene whose protein product reaches the blood and has a beneficial effect on a patient. Both retroviral and adenovirus-associated viral vectors have resulted in stable but only moderate systemic levels of blood proteins. Adenoviral vectors have resulted in very high levels of expression that diminishes over days or weeks. Hepatic gene therapy has achieved levels of the anticoagulant protein C in blood that would protect against spontaneous thromboses in homozygous protein-C deficiency, and levels of tissue plasminogen activator that can lyse pulmonary emboli. Hypercholesterolemia has been ameliorated transiently by transfer of the low-density lipoprotein receptor gene into the livers of animals with familial hypercholesterolemia or by promoting lipid transfer via a variety of alternative mechanisms. Hypertension has been reduced by the transfer of genes for kallikrein or atrial natriuretic peptide into the liver, or by expressing antisense for the angiotensin II type I receptor after intravenous injection in neonates. Finally, fasting but not fed hyperglycemia has been ameliorated in animal models of diabetes by transfer of an insulin gene into the liver or by expression of insulin from implanted fibroblasts. Gene therapy has the potential to treat these cardiovascular diseases. However, improvements in levels of long-term expression and the ability to regulate expression in response to physiologic changes will be required before this approach will be implemented for most of these disorders in humans.
Trends Cardiovasc Med 1999 Aug
PMID:Systemic gene therapy for cardiovascular disease. 1063 21

Vitamin-K-dependent proteins are found in both the pro- and anti-coagulation cascades, and their use in coagulation therapies is expanding rapidly. The vitamin-K-dependent, gamma-carboxyglutamic acid (Gla)-containing regions of proteins in this family are homologous and are responsible for membrane association. Site-directed mutations that enhance the membrane affinity of protein C, an anticoagulant, and of factor VII, a procoagulant, have been identified. These protein C and Factor VII mutants show enhanced activity in many assays, offering opportunities to study the role of membrane in blood clotting reactions and proteins that may have greater therapeutic value.
Trends Cardiovasc Med 1999 Aug
PMID:Enhancement of vitamin-K-dependent protein function by modification of the gamma-carboxyglutamic acid domain: studies of protein C and factor VII. 1063 22

An important mechanism of regulation of blood coagulation is the anticoagulant protein C pathway. In this pathway, the anticoagulant activity of activated protein C is increased by its cofactor protein S. The cofactor activity of protein S can be regulated by binding to complement regulatory C4b-binding protein (C4BP). The sites of interaction of protein S and C4BP are discussed.
Trends Cardiovasc Med 2000 Feb
PMID:The interaction between anticoagulant protein S and complement regulatory C4b-binding protein (C4BP). 1115 Jul 33

Thrombin is an allosteric enzyme that interacts with multiple procoagulant substrates such as specific clotting factors and cell surface thrombin receptors, as well as the anticoagulant substrate protein C. Functional mapping of thrombin's interactions with its various substrates has been carried out using a collection of thrombin mutants generated by systematic alanine scanning mutagenesis. A thrombin mutant, E229K, has been identified that has essentially lost all of its procoagulant properties while retaining its ability to activate protein C, thus functioning as an anticoagulant in vitro and in vivo. It is also found that specific and distinct domains are involved in thrombin's interaction with thrombomodulin (TM) and the subsequent activation by the thrombin/TM complex of protein C and the thrombin-activatable fibrinolysis inhibitor (TAFI).
Trends Cardiovasc Med 2000 Feb
PMID:Dissociation of thrombin's substrate interactions using site-directed mutagenesis. 1115 Jul 36

Cranial sinovenous disorders comprise a disparate group of illnesses affecting one or more intracranial venous sinuses and cerebral veins, alone or in combination, due to a variety of causes. As medical knowledge advances, fewer and fewer patients have an "idiopathic" diagnosis, with causes clarified in an ever-increasing number of patients. These not only include the long-known puerperal, marantic, infective, and traumatic causes, but in recent years, also a variety of congenital and acquired coagulation disorders, such as protein S, protein C, and antithrombin III deficiency. Certain sinuses are preferentially involved with certain causative entities; for example, cavernous and lateral sinuses are more frequently occluded in relation to infectious processes, either directly or as a parameningeal focus, whereas the superior sagittal sinus is most often occluded by trauma, tumor, or coagulopathy. The optimal treatment of sinovenous occlusion depends on establishing the cause with alacrity, because delays in diagnosis may lead to life-threatening hyperpyrexia, elevations in intracranial pressure, venous infarctions, seizures, coma, and death. However, because up to a third of patients with nonseptic occlusions may survive untreated, with few residua, controversy persists regarding optimal management. There has been a dearth of randomized, prospective treatment trials in this group of disorders. The little data that exist suggest that rapid control of infection, seizure prophylaxis, and anticoagulation must be achieved early so as to prevent progression of thrombosis and intracranial venous hypertension. In recent years, direct retrograde venous thrombolysis has become increasingly available, and has produced such remarkable results that it is likely soon to become the primary treatment of choice for the nontraumatic or nontumoral occlusions.
Curr Treat Options Cardiovasc Med 2001 Oct
PMID:Cerebral Sinovenous Thrombosis. 1152 23

This article provides a description of the clinical disorders associated with the development of acute noncardiogenic pulmonary edema, better known as clinical acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). Much has been learned about the mechanisms by which the lung is injured in patients with sepsis, pneumonia, aspiration of gastric contents, and following major trauma. In the last 5 years, major progress has been made in the treatment of patients with ALI/ARDS. A lung protective ventilatory strategy with a low tidal volume (6 mL/kg/predicted body weight) in conjunction with a plateau pressure limit of 30 cm H(2)0 attenuated the severity of clinical lung injury and reduced mortality by 22%. Ironically, after years of searching for anti-inflammatory treatments for ALI/ARDS, it turns out that a lung protective ventilatory strategy has proven to be the most efficacious anti-inflammatory treatment ever discovered for ALI/ARDS. However, it is still possible that pharmacologic treatments also may enhance survival. For example, a recent report that activated protein C reduces mortality in patients with sepsis raises hope that the incidence and severity of sepsis-induced ALI/ARDS may be reduced by treatment with this agent that has both anti-inflammatory and anticoagulant properties. Also, therapy directed at hastening the resolution of lung injury by increasing the functional recovery of the alveolar epithelium may be of value, both in diminishing the fibroproliferative phase of ALI/ARDS as well as accelerating the resolution of alveolar edema.
Curr Treat Options Cardiovasc Med 2002 Apr
PMID:Clinical Acute Lung Injury and Acute Respiratory Distress Syndrome. 1185 76

A 28-year-old man with heterozygous protein C deficiency presented with Budd-Chiari syndrome resulting from hepatic vein obstruction. Over the next 40 months, standard oral anticoagulant therapy and multiple percutaneous interventions aimed at relieving hepatic vein obstruction could not prevent progression of the disease ultimately to cirrhosis and death. Serial angiography provided unique documentation of the relentless progression of hepatic venous obstruction, which was related to the disease and to iatrogenic factors. Operative findings obtained during unsuccessful mesocaval shunt surgery revealed that venous disease in protein C deficiency can be far more extensive than is clinically anticipated. The ineffectiveness of therapy in this patient may be related to standard oral anticoagulant therapy being insufficient to offset the risk of recurrent thrombosis and progression to an advanced stage of vascular damage.
Cardiovasc Intervent Radiol
PMID:Relentless progression of venous obstruction in a case of Budd-Chiari syndrome related to heterozygous protein C deficiency. 1190 52

This study investigated whether activated protein C (APC) improves the cerebral vasospasm in an experimental subarachnoid hemorrhage that was produced by the intracisternal injection of autologous blood. Male rabbits were divided into the following four groups: APC 0.1-and 0.5-mg groups, in which 0.1 and 0.5 mg APC were injected into the cisterna magna, respectively; a placebo group, in which saline was injected instead of APC; and a sham operation group that did not get injections of autologous blood, APC, and saline. On day 2, amount of clot in the basal cistern was significantly (p < 0.01) decreased in the APC 0.5-mg group. Percent diameter of the basilar artery on day 2 to that before injecting the blood was angiographically determined as 97.1 +/- 3.8% in the APC 0.5-mg group, which was significantly (p < 0.001) greater than the corresponding value in the placebo group (74.8 +/- 3.4%). The impaired endothelium-dependent relaxation following subarachnoid hemorrhage was normalized in the APC 0.5-mg group (p < 0.0001). These results suggest that APC would improve cerebral vasospasm following subarachnoid hemorrhage, possibly by decreasing the amount of subarachnoid clot and normalizing the impaired nitric oxide production/release.
J Cardiovasc Pharmacol 2002 May
PMID:Inhibitory effect of activated protein C on cerebral vasospasm after subarachnoid hemorrhage in the rabbit. 1197 17

A 51-year-old female underwent redo mitral valve replacement with a pericardial bioprosthesis because of acute thrombotic obstruction of a mechanical valve, in spite of adequate anticoagulation with warfarin. Her protein C level was 24% of the normal value and protein S was reduced to 54% of normal.
Asian Cardiovasc Thorac Ann 2002 Jun
PMID:Acute thrombotic obstruction of mitral valve prosthesis: low protein C level. 1207 45

DPC423, 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, is a synthetic, orally bioavailable, competitive, and selective inhibitor of human coagulation factor Xa (K(i) [nM]: factor Xa, 0.15; trypsin, 60; thrombin, 6000; plasma kallikrein, 61; activated protein C, 1800; factor IXa, 2200; factor VIIa, >15,000; chymotrypsin, >17,000; urokinase, >19,000; plasmin, >35,000; tissue plasminogen activator, >45,000; complement factor I, 44,000 [IC(50)]). In vitro, DPC423 produced anticoagulant effects in human plasma in which it doubled prothrombin time, activated partial thromboplastin time, and Heptest clotting time at 3.1 +/- 0.4, 3.1 +/- 0.4, and 1.1 +/- 0.5 microM, respectively. In dogs, DPC423 had a good pharmacokinetic profile with an oral bioavailability of 57%, a plasma clearance of 0.24 L/kg/h, and a plasma half-life of 7.5 h. In rabbit and rat models of arteriovenous shunt thrombosis, DPC423 was an effective antithrombotic agent with an IC(50) of 150 and 470 nM, respectively. The antithrombotic effect of DPC423 is likely to be related to the inhibition of factor Xa but not to the inhibition of thrombin or due to direct inhibition of platelet aggregation. Therefore, based on potency, selectivity, efficacy, and oral bioavailability, DPC423 was selected for clinical development as an oral anticoagulant for the potential treatment of thrombotic disorders. Preliminary human data suggest that DPC423 is orally bioavailable in humans and has a long plasma half-life.
Cardiovasc Drug Rev 2002
PMID:Nonpeptide factor Xa inhibitors: DPC423, a highly potent and orally bioavailable pyrazole antithrombotic agent. 1217 91


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