RESUMEN

Snakebite is a neglected tropical disease with a massive global burden of injury and death. The best current treatments, antivenoms, are plagued by a number of logistical issues that limit supply and access in remote or poor regions. We explore the anticoagulant properties of venoms from the genus Micrurus (coral snakes), which have been largely unstudied, as well as the effectiveness of antivenom and a small-molecule phospholipase inhibitor-varespladib-at counteracting these effects. Our in vitro results suggest that these venoms likely interfere with the formation or function of the prothrombinase complex. We find that the anticoagulant potency varies widely across the genus and is especially pronounced in M. laticollaris. This variation does not appear to correspond to previously described patterns regarding the relative expression of the three-finger toxin and phospholipase A2 (PLA2) toxin families within the venoms of this genus. The coral snake antivenom Coralmyn, is largely unable to ameliorate these effects except for M. ibiboboca. Varespladib on the other hand completely abolished the anticoagulant activity of every venom. This is consistent with the growing body of results showing that varespladib may be an effective treatment for a wide range of toxicity caused by PLA2 toxins from many different snake species. Varespladib is a particularly attractive candidate to help alleviate the burden of snakebite because it is an approved drug that possesses several logistical advantages over antivenom including temperature stability and oral availability.

Asunto(s)

Anticoagulantes/toxicidad , Serpientes de Coral , Venenos Elapídicos/toxicidad , Acetatos/farmacología , Acetatos/uso terapéutico , Animales , Coagulación Sanguínea/efectos de los fármacos , Venenos Elapídicos/antagonistas & inhibidores , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Cetoácidos , Ratones , Inhibidores de Fosfolipasa A2/farmacología , Inhibidores de Fosfolipasa A2/uso terapéutico , Receptores de Fosfolipasa A2/efectos de los fármacos , Mordeduras de Serpientes/tratamiento farmacológico , Especificidad de la Especie , Tromboplastina/metabolismo , Tiempo de Coagulación de la Sangre Total

RESUMEN

BACKGROUND AND OBJECTIVES: Rituximab (RTX) is considered to be a promising drug for curing membranous nephropathy. However, the efficacy and safety of RTX in treating membranous nephropathy remain uncertain. This meta-analysis aimed to investigate the efficacy and safety of RTX in patients with membranous nephropathy. METHODS: A literature search was performed using Pubmed, Embase, OVID, and Cochrane Library and randomized controlled trials (RCTs) case-controls and cohort studies published till 30 July 2019 were assessed. The studies assessing the efficacy and safety of RTX in patients with membranous nephropathy were included. RESULTS: Eight relevant trials involving 542 patients were included in the meta-analysis. It was found that RTX did not significantly improve serum albumin levels and e-GFR when compared with the control group (including cyclosporine and cyclophosphamide, chlorambucil, prednisone, non-immunosuppressive anti-proteinuria treatment), serum albumin levels (OR = 0.31, 95%CI-0.12-0.74, P = .15), e-GFR (OR = -1.49, 95%CI-17.14-14.17, P = .85). However, RTX did reduce the serum creatinine (OR = -0.01, 95%CI-0.36-0.34, P = .95) and urinary protein (OR = -2.39, 95%CI -7.30 -2.53, P = .34) levels. Also, in comparison to the control group, RTX did improve the total remission rate (OR = 1.63, 95%CI 0.48-5.54, P = .43), achieve a higher rate of complete remission (OR = 2.54, 95%CI 1.65-3.90, P < .01) and also reduced the amount of M-type phospholipase A2 receptor-Antibody depletion in patients (OR = 5.59, 95%CI 1.81-17.2, P = .003). RTX-related adverse events were mostly mild (most infusion-related reactions) in nature and serious adverse events were rare. CONCLUSION: RTX proved to be efficient, well-tolerated and a safe drug in the treatment of membranous nephropathy. Most patients reach complete remission during the follow-up period, and relapse is rare. RTX may turn out to be promising in membranous nephropathy patients.

Asunto(s)

Antineoplásicos Inmunológicos/uso terapéutico , Glomerulonefritis Membranosa/tratamiento farmacológico , Rituximab/uso terapéutico , Adulto , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Estudios de Casos y Controles , Clorambucilo/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclosporina/uso terapéutico , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Glomerulonefritis Membranosa/fisiopatología , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Proteinuria/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Fosfolipasa A2/efectos de los fármacos , Receptores de Fosfolipasa A2/inmunología , Inducción de Remisión , Rituximab/efectos adversos , Seguridad , Albúmina Sérica/efectos de los fármacos , Resultado del Tratamiento

RESUMEN

Acute d-amphetamine (d-Amph) administration to rats leads to the release of arachidonic acid (AA, 20:4n-6) as a second messenger following indirect agonism at dopamine D2-like receptors in the brain. We hypothesized that chronically administered d-Amph in rats also would alter brain AA metabolism and signalling. To test this, adult male rats were injected i.p. daily for 2 wk with saline or 2.5 mg/kg d-Amph. After a 1-d washout, the unanaesthetized rats were injected acutely with i.v. saline, 1 mg/kg quinpirole (a D2-like receptor agonist) or 5.0 mg/kg SKF-38393 (a D1-like receptor agonist), followed by i.v. [1-14C]AA. The AA incorporation coefficient k* (brain radioactivity/integrated plasma radioactivity), a marker of AA signalling and metabolism, was quantified using autoradiography in each of 62 brain regions. Compared with chronic saline, chronic d-Amph widely decreased baseline values of k* in brain regions having D2-like receptors. On the other hand, chronic amphetamine did not alter the k* responses to quinpirole seen in chronic saline-treated rats. SKF-38393 had minimal effects on k* in both chronic saline-treated and amphetamine-treated rats, consistent with D1-like receptors not being coupled to AA signalling. The ability of chronic d-Amph after 1-d washout to down-regulate baseline values of k* probably reflects neuroplastic changes in brain AA signalling, and may correspond to depressive behaviours noted following withdrawal from chronic amphetamine in humans and in rats.

Asunto(s)

Ácido Araquidónico/metabolismo , Química Encefálica/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Ácido Araquidónico/farmacocinética , Autorradiografía , Biomarcadores/análisis , Biomarcadores/metabolismo , Estimulantes del Sistema Nervioso Central/administración & dosificación , Depresión Química , Dextroanfetamina/administración & dosificación , Agonistas de Dopamina/farmacología , Ácidos Grasos no Esterificados/sangre , Semivida , Procesamiento de Imagen Asistido por Computador , Inyecciones Intraperitoneales , Masculino , Quinpirol/farmacología , Ratas , Ratas Endogámicas F344 , Receptores de Dopamina D2/agonistas , Receptores de Fosfolipasa A2/efectos de los fármacos , Transducción de Señal/efectos de los fármacos