cardiovascular-agents and Intracranial-Hemorrhages

Topics: Cardiovascular Agents; Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intracranial Hemorrhages; Severity of Illness Index

Treatments for spontaneous intracerebral, thrombolytic-induced and intraventricular hemorrhages (IVH) are still at the preclinical or early clinical investigational stages. There has been some renewed interest in the use of surgical evacuation surgery or thrombolytics to remove hematomas, but these techniques can be used only for specific types of brain bleeding. The STICH (Surgical Trial in Intracerebral Haemorrhage) clinical trials should provide some insight into the potential for such techniques to counteract hematoma-induced damage and subsequently, morbidity and mortality. More recently, clinical trials (ATACH [Antihypertensive Treatment in Acute Cerebral Hemorrhage] and INTERACT [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]) have begun testing whether or not regulating blood pressure affects the well-being of hemorrhage patients, but the findings thus far have not conclusively demonstrated a positive result. More promising trials, such as the early stage CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) and the late stage FAST (Factor VIIa for Acute Hemorrhagic Stroke Treatment), have addressed whether or not manipulating oxidative stress and components of the blood coagulation cascade can achieve an improved prognosis following spontaneous hemorrhages. However, CHANT was halted prematurely because although it showed that the spin trap agent NXY-059 was safe, it also demonstrated that the drug was ineffective in treating acute ischemic stroke. In addition, the recombinant activated factor VII FAST trial recently concluded with only modestly positive results. Despite a beneficial effect on the primary end point of reducing hemorrhage volume, controlling the coagulation cascade with recombinant factor VIIa did not decrease the mortality rate. Consequently, Novo Nordisk has abandoned further development of the drug for the treatment of intracerebral hemorrhaging. Even though progress in hemorrhage therapy that successfully reduces the escalating morbidity and mortality rate associated with brain bleeding is slow, perseverance and applied translational drug development will eventually be productive. The urgent need for such therapy becomes more evident in light of concerns related to uncontrolled high blood pressure in the general population, increased use of blood thinners by the elderly (e.g., warfarin) and thrombolytics by acute ischemic stroke patients, respectively. The future of drug development for hemorrhage may requi

Topics: Animals; Antihypertensive Agents; Antioxidants; Benzenesulfonates; Blood Pressure; Cardiovascular Agents; Coagulants; Disease Models, Animal; Drug Design; Enzyme Inhibitors; Erythropoietin; Excitatory Amino Acid Antagonists; Factor VIIa; Hemostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracranial Hemorrhages; Oxidative Stress; Signal Transduction; Stroke; Treatment Outcome

A patient's prognosis, including mortality, after intracranial hemorrhage (ICH) is strongly related to the disruption of the blood-brain barrier caused by damage to vascular endothelial cells (ECs). We reported previously that cilostazol, a phosphodiesterase III inhibitor, ameliorated collagenase-induced ICH in a mouse model. We also reported that cilostazol protected cultured ECs in a blood-brain barrier model. However, the influence of cilostazol on vascular structure and cell morphology remains unclear. Therefore, we investigated whether cilostazol exerts protective effects on vascular structures, such as the extracellular matrix (ECM). A mouse model of collagenase-induced ICH was used to observe structures of the brain vasculature in a peri-hemorrhagic lesion using transmission electron microscopy. We then evaluated the morphology of the ECM and cytoskeleton in human brain microvasculature ECs by immunostaining. The brain vasculature was changed 24 h after induction of ICH. Cilostazol (30 mg/kg, orally) suppressed the thinning of the basement membrane, which is formed by the ECM components collagen IV and laminin. Moreover, this drug also suppressed the enlargement of ECs caused by ICH. Collagenase treatment (30 U/ml) of human brain microvasculature ECs caused a decrease in collagen IV expression and an increase in the number and size of the intercellular spaces, as indicated by β-actin immunostaining. Pretreatment of with 10 µM cilostazol suppressed these increases in the number and size of the intercellular spaces. These findings suggest that cilostazol protects the ECM of the brain microvasculature against ICH both in vivo and in vitro.

Topics: Administration, Oral; Animals; Brain; Cardiovascular Agents; Cells, Cultured; Cilostazol; Collagen Type IV; Collagenases; Cytoskeleton; Disease Models, Animal; Extracellular Matrix; Humans; Intracranial Hemorrhages; Male; Mice; Microscopy, Electron, Transmission; Microvessels; Neuroprotective Agents; Phosphodiesterase 3 Inhibitors; Random Allocation; Tetrazoles

Decision Aids (DA) are well established in various fields of medicine. It can improve the quality of decision-making and reduce decisional conflict. In neonatal care, and due to scientific equipoise, neonatologists caring for extreme low birth weight (ELBW) infants are in need to elicit parents' preferences with regard to the use of indomethacin therapy in ELBW infants. We aimed to develop a DA that elicits parents' preferences with regard to indomethacin therapy in ELBW infants.. We developed a DA for the use of the indomethacin therapy in ELBW infants according to the Ottawa Decision Support Framework. The development process involved parents, neonatologists, DA developers and decision making experts. A pilot testing with healthy volunteers was conducted through an evaluation questionnaire, a knowledge scale, and a validated decisional conflict scale.. The DA is a computer-based interactive tool. In the first part, the DA provides information about patent ductus arteriosus (PDA) as a disease, the different treatment options, and the benefits and downsides of using indomethacin therapy in preterm infants. In the second part, it coaches the parent in the decision making process through clarifying values and preferences. Volunteers rated 10 out of 13 items of the DA positively and showed significant improvement on both the knowledge scale (p = 0.008) and the decisional conflict scale (p = 0.008).. We have developed a computer based DA to assess parental preferences with regard to indomethacin therapy in preterm infants. Future research will involve measurement of parental preferences to guide and augment the clinical decisions in current neonatal practice.

Topics: Adult; Bronchopulmonary Dysplasia; Cardiovascular Agents; Decision Support Techniques; Ductus Arteriosus, Patent; Female; Hemorrhage; Humans; Indomethacin; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Intracranial Hemorrhages; Lung Diseases; Parents; Pilot Projects; Severity of Illness Index

To determine the relative risk of severe intraventricular hemorrhage (IVH) between two very early indomethacin treatment strategies.. Retrospective chart review of infants <29 weeks gestation and <1350 g who received either indomethacin prophylaxis or very early echocardiography with indomethacin treatment only if the ductus arteriosus was patent.. A total of one hundred and two infants received prophylactic indomethacin (pINDO). Echochardiography was performed on 158 infants, of whom 117 received indomethacin. Infants receiving pINDO had lower gestational age, but similar birth weight, gender, race, antenatal steroid exposure, delivery mode, Apgar scores, and need for resuscitation as infants evaluated by echocardiography. Grades III to IV IVH was observed less frequently in infants who received pINDO (OR 0.27, 95% CI 0.10 to 0.77, p=0.014). Frequency of side effects and recurrent patent ductus arteriosus did not differ between treatment groups.. pINDO reduces severe IVH when compared to an early echocardiography strategy.

Topics: Cardiovascular Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Ductus Arteriosus, Patent; Echocardiography; Female; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Intracranial Hemorrhages; Male; Retrospective Studies; Severity of Illness Index; Time Factors