Эндоваскулярные методики профилактики и лечения сосудистого спазма вследствие разрыва церебральных аневризм: за и против

This review highlights current approaches to endovascular therapy of cerebral angiospasm in non-traumatic subarachnoid hemorrhage due to a ruptured cerebral aneurysm (CA). The main clinical guidelines for the management of patients with CA rupture are highlighted, clinical studies on the use of balloon angioplasty, intra-arterial administration of various vasodilators are presented, the advantages and complications of using various techniques are described. В данном обзоре освещены современные подходы к эндоваскулярной терапии церебрального ангиоспазма при нетравматическом субарахноидальном кровоизлиянии вследствие разрыва церебральной аневризмы (ЦА). Освещены основные клинические рекомендательные протоколы по ведению пациентов с разрывом ЦА, представлены клинические исследования, посвященные применению баллонной ангиопластики, интраартериальному введению различных вазодилататоров, описаны преимущества и осложнения использования различных методик.

Forskolin: A Successful Therapeutic Phytomolecule

Forskolin, a labdane diterpene is the main active ingredient in the ayurvedic herb Coleus forskohlii (Labatiae) that has been used in India since ancient times. The root portion of the plant has been traditionally used for medicinal purposes and contains the active constituent, forskolin. Historically, it has been used to treat hypertension, congestive heart failure, eczema, colic, respiratory disorders, painful urination, insomnia, and convulsions. Clinical studies have justified these traditional uses and indicate its therapeutic potential in asthma, angina, psoriasis, and prevention of cancer metastases. The present review summarizes these reports along with the advancements in research on forskolin as a therapeutic molecule.Keywords: Forskolin, Coleus forskohli, labdane diterpeneEast and Central African Journal of Pharmaceutical Sciences Vol. 13 (2010) 25- 3

colforsinの強心作用に対するアシドーシスの影響:用量反応試験

筑波大学博士(医学)博士論文・平成24年3月25日授与(甲第6598号

Endovascular treatment versus standard management for cerebral vasospasm in aneurysmal subarachnoid haemorrhage

Review question: in this review we assessed the effectiveness and safety of endovascular therapy (i.e. intra-arterial vasodilator infusion, balloon angioplasty, stent or combined therapy) compared to standard management for treatment of cerebral vasospasm in adults with aneurysmal subarachnoid hemorrhage. Background: although 30% of patients with cerebral vasospasm develop delayed cerebral ischemia, currently there is no way to know whether a patient would have this complication. There are a wide range of treatment options and the choice is based on the experience of the clinicians, patient preferences and adverse effects. Studies characteristics: we searched the available literature up to 2 May 2020 and included 26 controlled studies with 1783 patients. The studies included both men and women aged over 18 years with clinical and radiological diagnosis of aneurysmal subarachnoid haemorrhage and cerebral vasospasm. Ten studies (799 patients) included people that had been treated with endovascular treatment and compared with medical therapy. In most studies, people received intra-arterial vasodilatory infusion (i.e. papaverine, nimodipine, nicardipine, colforsin). Fifteen studies compared endovascular therapy against each other technique (912 participants). One study (72 patients) included three arms (medical therapy, intra-arterial vasodilator infusion and balloon angioplasty). Key results: long-term functional status and angiographic improvement suggest superiority with intra-arterial vasodilator compared to medical treatment (moderate / serous risk of bias). We found no difference on adverse events rate between endovascular therapy and medical treatment (moderate / serous risk of bias). Quality of evidence: results should be interpreted with caution because the risk of bias, imprecision, inconsistency and heterogeneity.Pregunta de investigación: en este trabajo se evaluó la efectividad y la seguridad del tratamiento endovascular (i.e. infusión intraarterial de vasodilatador, angioplastia con balón, stent recuperable o terapia combinada) en comparación con el tratamiento estándar para el manejo del vasoespasmo cerebral en adultos con hemorragia subaracnoidea aneurismática. Antecedentes: aunque el 30% de los pacientes con vasoespasmo cerebral desarrollan isquemia cerebral tardía, actualmente no hay forma de saber que pacientes desarrollarán esta complicación. Existe una amplia gama de opciones terapéuticas y la elección se basa en la experiencia clínica, las preferencias del paciente y los eventos adversos. Características de los estudios: se realizó búsqueda sistemática de estudios controlados hasta el 2 de mayo de 2020. Se incluyó 26 estudios con 1783 pacientes. Los estudios incluyeron hombres y mujeres mayores de 18 años con diagnóstico clínico y radiológico de hemorragia subaracnoidea aneurismática y de vasoespasmo cerebral. Diez estudios (799 pacientes) incluyeron pacientes que recibieron terapia endovascular versus tratamiento médico. La mayoría de los estudios utilizó infusión intraarterial de vasodilatador (i.e. papaverina, nimodipino, nicardipino, colforsina, etc.). Quince estudios (912 pacientes) compararon diferentes modalidades de terapia endovascular entre sí. Un estudio (72 pacientes) incluyó tres brazos de comparación (terapia médica, vasodilatardor intraarterial y angioplastia con balón). Resultados clave: el estado funcional a largo plazo y la mejoría angiográfica sugiere ser superior con vasodilatador intraarterial comparado con tratamiento médico (riesgo de sesgo moderado / serio). No se observó diferencias significativas en los eventos adversos entre la terapia endovascular versus el tratamiento médico (riesgo de sesgo moderado / serio). Calidad de la evidencia: los resultados deben interpretarse con cautela: riesgo de sesgo, imprecisión, inconsistencia y heterogeneidad.Línea de investigación: Neuroimágenes.Especialidades Médica

A melanocyte lineage program confers resistance to MAP kinase pathway inhibition

BRAFV600E-mutant malignant melanomas depend on RAF/MEK/ERK (MAPK) signaling for tumor cell growth1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAFV600E melanoma2, 3; however, resistance to these agents remains a formidable challenge2, 4. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here, we performed systematic gain-of-function resistance studies by expressing >15,500 genes individually in a BRAFV600E melanoma cell line treated with RAF, MEK, ERK, or combined RAF/MEK inhibitors. These studies revealed a cyclic AMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAFV600E melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF/MEK-inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAP kinase pathway and histone deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF/MEK/ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics

Continuous Selective Intra-Arterial Application of Nimodipine in Refractory Cerebral Vasospasm due to Aneurysmal Subarachnoid Hemorrhage

Background. Cerebral vasospasm is one of the leading courses for disability in aneurysmal subarachnoid hemorrhage. Effective treatment of vasospasm is therefore one of the main priorities for these patients. We report about a case series of continuous intra-arterial infusion of the calcium channel antagonist nimodipine for 1-5 days on the intensive care unit. Methods. In thirty patients with aneurysmal subarachnoid hemorrhage and refractory vasospasm continuous infusion of nimodipine was started on the neurosurgical intensive care unit. The effect of nimodipine on brain perfusion, cerebral blood flow, brain tissue oxygenation, and blood flow velocity in cerebral arteries was monitored. Results. Based on Hunt & Hess grades on admission, 83% survived in a good clinical condition and 23% recovered without an apparent neurological deficit. Persistent ischemic areas were seen in 100% of patients with GOS 1-3 and in 69% of GOS 4-5 patients. Regional cerebral blood flow and computed tomography perfusion scanning showed adequate correlation with nimodipine application and angiographic vasospasm. Transcranial Doppler turned out to be unreliable with interexaminer variance and failure of detecting vasospasm or missing the improvement. Conclusion. Local continuous intra-arterial nimodipine treatment for refractory cerebral vasospasm after aSAH can be recommended as a low-risk treatment in addition to established endovascular therapies

Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant

Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican-gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican-b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design