Therapeutic potential of an orally effective small molecule inhibitor of plasminogen activator inhibitor for asthma.

Asthma is one of the most common respiratory diseases. Although progress has been made in our understanding of airway pathology and many drugs are available to relieve asthma symptoms, there is no cure for chronic asthma. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators, has pleiotropic functions besides suppression of fibrinolysis. In this study, we show that administration of TM5275, an orally effective small-molecule PAI-1 inhibitor, 25 days after ovalbumin (OVA) sensitization-challenge, significantly ameliorated airway hyperresponsiveness in an OVA-induced chronic asthma model. Furthermore, we show that TM5275 administration significantly attenuated OVA-induced infiltration of inflammatory cells (neutrophils, eosinophils, and monocytes), the increase in the levels of OVA-specific IgE and Th2 cytokines (IL-4 and IL-5), the production of mucin in the airways, and airway subepithelial fibrosis. Together, the results suggest that the PAI-1 inhibitor TM5275 may have therapeutic potential for asthma through suppressing eosinophilic allergic response and ameliorating airway remodeling.

Anti-tissue plasminogen activator (tPA) as an effective therapy of neonatal hypoxia-ischemia with and without inflammation.

Hypoxic-ischemic brain injury is an important cause of neurodevelopmental deficits in neonates. Intrauterine infection and the ensuing fetal inflammatory responses augment hypoxic-ischemic brain injury and attenuate the efficacy of therapeutic hypothermia. Here, we review evidences from preclinical studies suggesting that the induction of brain parenchymal tissue-type plasminogen activator (tPA) plays an important pathogenic role in these conditions. Moreover, administration of a stable-mutant form of plasminogen activator inhibitor-1 called CPAI confers potent protection against hypoxic-ischemic injury with and without inflammation via different mechanisms. Besides intracerebroventricular injection, CPAI can also be administered into the brain using a noninvasive intranasal delivery strategy, adding to its applicability in clinical use. In sum, the therapeutic potential of CPAI in neonatal care merits further investigation with large-animal models of hypoxia-ischemia and cerebral palsy.

Taming neonatal hypoxic-ischemic brain injury by intranasal delivery of plasminogen activator inhibitor-1.

BACKGROUND AND PURPOSE: Plasminogen activator inhibitor-I (PAI-1), a ≈50-kDa serine protease inhibitor, markedly reduces the extravascular toxicity of tissue-type plasminogen activator in experimental hypoxic-ischemic (HI) brain injury of newborns. However, the current treatment with PAI-1 requires intracerebroventricle injection to cross the blood-brain barrier, which is an invasive procedure of limited clinical potential. Thus, we tested whether intranasal administration of PAI-1 can bypass blood-brain barrier and mitigate neonatal HI brain injury. METHODS: Rat pups were subjected to HI, with or without lipopolysaccharide pre-exposure, followed by intranasal delivery of a stable-mutant form of PAI-1 (CPAI). RESULTS: Immunoblotting showed that CPAI sequentially entered the olfactory bulbs and cerebral cortex after intranasal delivery and reduced ≈75% of brain atrophy in HI or lipopolysaccharide-sensitized HI injury. Mechanistically, CPAI attenuated HI-induced plasminogen activators and lipopolysaccharide/HI-induced nuclear factor-κB signaling, neuroinflammation, and blood-brain barrier permeability. CONCLUSIONS: Intranasal delivery of CPAI is an effective treatment of experimental HI brain injury of newborns. Clinical application of this experimental therapy merits further investigation.

Aerosolized tissue plasminogen inhibitor improves pulmonary function in sheep with burn and smoke inhalation.

Acute respiratory distress syndrome is a major complication in patients with thermal injury. The obstruction of the airway by cast material, composed in part of fibrin, contributes to deterioration of pulmonary gas exchange. We tested the effect of aerosol administration of tissue plasminogen activator, which lyses fibrin clots, on acute lung injury in sheep that had undergone combined burn/smoke inhalation injury. Anesthetized sheep were given a 40% total body surface, third degree burn and were insufflated with cotton smoke. Tissue plasminogen activator (TPA) was nebulized every 4 h at 1 or 2 mg for each nebulization, beginning 4 h after injury. Injured but untreated control sheep developed multiple symptoms of acute respiratory distress syndrome: decreased pulmonary gas exchange, increased pulmonary edema, and extensive airway obstruction. These control animals also showed increased pulmonary transvascular fluid flux and increased airway pressures. These variables were all stable in sham animals. Nebulization of saline or 1 mg of TPA only slightly improved measures of pulmonary function. Treatment of injured sheep with 2 mg of TPA attenuated all the pulmonary abnormalities noted above. The results provide evidence that clearance of airway obstructive cast material is crucial in managing acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

Evaluación retrospectiva del uso de activador tisular del plasminógeno (rt-PA) en el manejo del infarto agudo de miocardio en el servicio de urgencias de la Clínica Shaio

Objetivo: Evaluar el uso de activador tisular del plasminógeno recombinante (rt-PA) en los pacientes con IAM que ingresaron por el servicio de urgencias. Materiales y métodos: Estudio descriptivo retrospectivo de corte transversal en donde se tomaron todos los pacientes con diagnóstico de IAM al ingreso en urgencias durante el período comprendido entre enero de 1996 hasta julio de 1997 en los cuales se utilizó la terapia trombolítica con rt-PA. Se administró el esquema acelerado de rt-PA seguido por infusión de heparina para mantener PTT entre 50 y 70 segundos por 24 a 48 horas. Las indicaciones para administrar rt-PA fueron: edad menor de 75 años, infarto de localización anterior y tiempo de evolución menor de 6 horas. La recolección de la información se realizó a partir de la historia clínica. Las variables estudiadas fueron edad, sexo, tipo de infarto, localización, clasificación de killip, tiempo de evolución al momento de la consulta, uso, tipo y causa de exclusión de trombosis con rt-AP. permeabilidad de la arteria relacionada con el infarto, realización de angioplastia, requerimiento de cirugía (electiva o de urgencia), complicaciones y mortalidad antes de la intervención con angioplastia electiva o cirugía. Resultados: De un total de 458 pacientes con diagnóstico de IAM se realizó terapia de recanalización en 206 pacientes (44.5 por ciento), 12 con angioplastia primaria (6 por ciento), 146 (70.5 por ciento) con STK y 48 (23.5 por ciento) con rt-PA. De estos pacientes 42 (87.5 por ciento) fueron hombres y 6 (12.5 por ciento) mujeres. Las edades estuvieron entre 42 años el más joven y 75 años el de mayor edad, con un promedio de 60-17 años. El tiempo promedio de consulta a urgencias después del inicio de los síntomas fue de 4.9 horas. Ningún paciente entró con Killip IV, 3 (6.5 por ciento) Killip I, 14 (29 por ciento) en Killip II yb 31 (64.5 por ciento) en Killip III. La principal causa de exclusión de trombólisis con rt-PA fue la consulta fuera de tiempo > 6 horas. Se presentó un caso de hemorragia de vías digestivas clasificada como menor ya que no requirió transfusión. De las complicaciones secundarias al IAM se presentó choque en 4 (8.3 por ciento), arritmia ventricular en 3 (6.2 por ciento); pericarditis en 2 (4.15 por ciento); angina post IAM en 1 (2.5 por ciento); insuficiencia mitral en 1 (2.5 por ciento); trombo intracavitario 1 (2.5 por ciento). La mortalidad entre los pacientes trombolizados...

Studies of recombinant plasminogen activator inhibitor-1 in rabbits. Pharmacokinetics and evidence for reactivation of latent plasminogen activator inhibitor-1 in vivo.

The pharmacokinetics of human recombinant plasminogen activator inhibitor-1 (rPAI-1) was studied in rabbits. Latent rPAI-1 (0-2 units of tissue-type plasminogen activator neutralizing activity per microgram protein); reactivated rPAI-1 (approximately 150 units/micrograms); and chloramine T-oxidized, nonreactivatable rPAI-1 (approximately 0.7 units/microgram) were studied. The pharmacokinetic parameters for the disposition of rPAI-1 antigen after an intravenous bolus injection of 1.0 or 2.5 mg/kg rPAI-1 were very similar for all three forms: the initial volume of distribution was approximately 60 ml/kg, the initial half-life in plasma was 6 minutes, and the plasma clearance was approximately 4 ml/kg/min. The disposition of PAI activity after injection of reactivated rPAI-1 was similar to that of rPAI-1 antigen. Injection of latent rPAI-1 was associated with a nearly threefold increase in the specific activity of circulating PAI-1 from 2 units/micrograms to 5.0 +/- 1.1 units/micrograms (p less than 0.01) within 1 minute, followed by a cumulative 25-fold increase in specific activity over 1 hour (p = 0.01). In contrast, the specific activity of oxidized or reactivated preparations of rPAI-1 did not increase in the first several minutes after injection. These findings support the existence of a fast-acting but low-capacity mechanism for the reactivation of rPAI-1 in vivo.