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1.
BMC Pulm Med ; 24(1): 198, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38649880

RESUMEN

BACKGROUND: Iopamidol is a non-ionic, water-soluble iodine contrast agent that is considered safe for intravenous or intra-arterial administration and is widely used both in the general population and in patients undergoing oncological treatment. While adverse reactions to iopamidol have been documented, to date, no pulmonary and gastric hemorrhages induced by iopamidol have been reported in oncology patients. We report the first case of this complication. CASE PRESENTATION: We report the case of a 60-year-old woman with marginal zone lymphoma who was receiving antineoplastic therapy. As part of the investigation for the condition, she underwent chest enhancement CT with iopamidol. Shortly thereafter(within five minutes), she experienced hemoptysis and hematemesis. She was intubated and admitted to the intensive care unit. Pre- and post-contrast images demonstrated the course of the hemorrhage. Flexible bronchoscopy and gastroscopy on the following day showed no active bleeding, and the patient recovered completely after antiallergy treatment. We speculate that contrast-induced hypersensitivity was the most likely cause of the transient pulmonary and gastric bleeding. CONCLUSION: Although rare, the complications of iopamidol, which may cause allergic reactions in the lungs and stomach, should be considered.


Asunto(s)
Medios de Contraste , Hemoptisis , Yopamidol , Linfoma de Células B de la Zona Marginal , Tomografía Computarizada por Rayos X , Humanos , Femenino , Persona de Mediana Edad , Medios de Contraste/efectos adversos , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/complicaciones , Yopamidol/efectos adversos , Yopamidol/administración & dosificación , Hemoptisis/inducido químicamente , Hemorragia Gastrointestinal/inducido químicamente , Enfermedades Pulmonares/inducido químicamente , Broncoscopía , Hematemesis/inducido químicamente
2.
Gan To Kagaku Ryoho ; 50(11): 1203-1205, 2023 Nov.
Artículo en Japonés | MEDLINE | ID: mdl-38056875

RESUMEN

The case is of a 66-year-old woman who visited a general practitioner with a chief complaint of cough. She was referred to the Internal Medicine Department of our hospital because an abnormal shadow was found in her chest X-ray examination. A CT scan suspected her to have a metastatic lung tumor, and gastric cancer was diagnosed on primary site search. The patient was started on G-SOX therapy. After 2 courses, she experienced massive hematemesis and was referred to the hospital. A CT scan revealed arterial bleeding into the stomach. She went into cardiac arrest shortly afterward, and cardiopulmonary resuscitation was started. Hemostasis was obtained by interventional radiology(IVR). Upper gastrointestinal endoscopy performed after hemostasis showed the tumor to be necrotic and shrunk. Bleeding from advanced gastric cancer is common; however, bleeding due to the effects of chemotherapy have been reported. We report a case of massive bleeding and cardiopulmonary arrest during chemotherapy.


Asunto(s)
Paro Cardíaco , Neoplasias Gástricas , Humanos , Femenino , Anciano , Neoplasias Gástricas/patología , Hematemesis/inducido químicamente , Hemorragia , Paro Cardíaco/inducido químicamente , Paro Cardíaco/terapia
3.
Curr Opin Gastroenterol ; 38(5): 443-449, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35916320

RESUMEN

PURPOSE OF REVIEW: Upper gastrointestinal bleeding (UGIB) has significant morbidity and UGIB cases have been described in coronavirus disease 2019 (COVID-19) patients. Management of this condition can be challenging considering both the possible severe COVID-19-related pneumonia as well as the risk of the virus spreading from patients to health operators. The aim of this paper is to review the most recent studies available in the literature in order to evaluate the actual incidence of UGIB, its clinical and endoscopic manifestations and its optimal management. RECENT FINDINGS: UGIB has an incidence between 0.5% and 1.9% among COVID-19 patients, and it typically presents with melena or hematemesis. Peptic ulcers are the most common endoscopic findings. High Charlson Comorbidity Index (CCI), dialysis, acute kidney injury and advanced oncological disease increase the risk for UGIB. Although anticoagulants are commonly used in COVID-19 patients they are not associated with an increased incidence of UGIB. Conservative management is a common approach that results in similar outcomes compared to upper GI endoscopic treatment. Apparently, UGIB in COVID-19 seems not have a detrimental effect and only one study showed an increased mortality in those who developed UGIB during hospitalization. SUMMARY: Incidence of UGIB in COVID-19 patients is similar to that of the general population. Despite the widespread use of anticoagulants in these patients, they are not associated with an increased risk of UGIB. Conservative management could be an effective option, especially for patients that are at risk of intubation.


Asunto(s)
COVID-19 , Anticoagulantes/uso terapéutico , COVID-19/complicaciones , Hemorragia Gastrointestinal/epidemiología , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Hematemesis/inducido químicamente , Hematemesis/epidemiología , Humanos , Melena/inducido químicamente , Melena/complicaciones , Melena/epidemiología , Estudios Retrospectivos
5.
Vasc Endovascular Surg ; 55(5): 510-514, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33550927

RESUMEN

Intramural hematoma of the esophagus (IHE) represents a rare condition on the spectrum of esophageal injuries. The most common symptoms are hematemesis, epigastric pain or retrosternal chest pains, odynophagia, and dysphagia. Early recognition of IHE is important as it may mimic other diseases such as myocardial infarction, pulmonary embolism, Mallory-Weiss tears, Boerhaave's syndrome, ruptured aortic aneurysms, and aortic dissection. Computed tomography is the preferred investigation method, and treatment is usually conservative. We herein present 2 cases of IHE associated with catheter-directed thrombolysis in the setting of pulmonary embolism.


Asunto(s)
Cateterismo/efectos adversos , Hemorragia Gastrointestinal/inducido químicamente , Hematoma/inducido químicamente , Embolia Pulmonar/tratamiento farmacológico , Terapia Trombolítica/efectos adversos , Anciano , Hemorragia Gastrointestinal/diagnóstico por imagen , Hematemesis/inducido químicamente , Hematoma/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico por imagen , Resultado del Tratamiento
6.
WMJ ; 119(2): 129-131, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32659068

RESUMEN

INTRODUCTION: Recent outbreaks of brodifacoum-induced coagulopathy resulting from the use of synthetic cannabinoids represents a growing public health concern. Brodifacoum is a commonly used and commercially available rodenticide that has anticoagulant properties. As new, unregulated synthetic cannabinoids enter the market, the potential for further outbreaks continues to rise. CASE PRESENTATION: We report a case of severe bleeding secondary to inhalation of synthetic cannabinoids contaminated with brodifacoum. The patient had been evaluated for several months of ongoing, unexplained vaginal bleeding and developed hematemesis and rectal bleeding 2 weeks after her last reported use. DISCUSSION: There have been previous reports of hemorrhage after exposure to synthetic marijuana in rare cases, including an outbreak of severe bleeding and reported synthetic marijuana use in the Midwestern region of the United States in 2018. CONCLUSION: While hemorrhaging after exposure to synthetic cannabinoids has been reported previously, we use this case to increase awareness of the potentially deadly exposures to brodifacoum from synthetic cannabinoids use in Wisconsin. By increasing awareness, emergency department physicians and state agencies can collaborate more effectively when responding in these cases.


Asunto(s)
4-Hidroxicumarinas/envenenamiento , Cannabinoides/envenenamiento , Hemorragia Gastrointestinal/inducido químicamente , Hematemesis/inducido químicamente , Rodenticidas/envenenamiento , Hemorragia Uterina/inducido químicamente , Administración por Inhalación , Adulto , Femenino , Humanos , Wisconsin
7.
Rev Esp Enferm Dig ; 111(12): 971-972, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31718201

RESUMEN

Polypharmacy is a frequent phenomenon. For that reason, drugs side effects are increasing, including lesions in the gastrointestinal (GI) tract. Multiple drugs can induce damage to the GI mucosa. NSAIDs are the most characteristic, however there are other drugs, that can cause a harmful effect in the digestive tract, such as iron. We present the case of a 91-year-old man with hematemesis due to iron intake.


Asunto(s)
Compuestos Ferrosos/efectos adversos , Gastritis/inducido químicamente , Hematemesis/inducido químicamente , Anciano de 80 o más Años , Anemia/tratamiento farmacológico , Gastritis/patología , Gastroscopía , Humanos , Isquemia/inducido químicamente , Isquemia/complicaciones , Masculino , Membrana Mucosa/patología , Estómago/irrigación sanguínea
8.
BMJ Case Rep ; 12(9)2019 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-31511269

RESUMEN

A 2.5-year-old boy with a history of (transient) congenital hyperinsulinism was admitted to the paediatric ward with recurrent hypoglycaemia. Diazoxide 5 mg/kg/day and hydrochlorothiazide 2 mg/kg/day were initiated. After increasing the dose of diazoxide to 10 mg/kg/day, the child developed mild rectal bleeding, petechiae, epistaxis and haematemesis. Blood screening showed severe thrombocytopaenia. Diazoxide and hydrochlorothiazide were stopped, and his platelet count normalised. Drug rechallenge was positive. Drug-induced immune thrombocytopaenia was diagnosed.


Asunto(s)
Antihipertensivos/efectos adversos , Diazóxido/efectos adversos , Hidroclorotiazida/efectos adversos , Trombocitopenia/inducido químicamente , Preescolar , Quimioterapia Combinada/efectos adversos , Epistaxis/inducido químicamente , Hematemesis/inducido químicamente , Humanos , Hiperinsulinismo/congénito , Hiperinsulinismo/tratamiento farmacológico , Masculino , Enfermedades del Recto/inducido químicamente
9.
Clin J Gastroenterol ; 12(6): 552-555, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30955165

RESUMEN

Everolimus is an mTOR (the mammalian target of rapamycin) inhibitor, which is used for the treatment of advanced renal cell carcinoma. Life-threatening hemorrhages are extremely rare adverse effect of everolimus. We herein report a successfully treated case of severe everolimus-related gastrointestinal hemorrhage by emergency surgical resection for patient with advanced renal cell carcinoma. A 72-year-old male was diagnosed with renal cell carcinoma, for which everolimus was administered after unsuccessful treatment with sunitinib and sorafenib. The patient suddenly developed hematemesis 4 weeks after administration. Upper gastrointestinal endoscopy showed gastric antral vascular ectasia. Once the hemorrhage was successfully cauterized by argon plasma coagulation, everolimus was discontinued. However, the patient after re-administration of everolimus developed hematemesis again and exhibited hemorrhage shock. Since therapeutic endoscopy could not achieve hemostasis, the patient underwent emergency distal gastrectomy with Billroth I reconstruction. The patient's vital signs and hemoglobin level stabilized after the surgery. Thereafter, the patient made a satisfactory recovery, and was discharged on postoperative day 10.


Asunto(s)
Antineoplásicos/efectos adversos , Everolimus/efectos adversos , Hematemesis/inducido químicamente , Gastropatías/inducido químicamente , Anciano , Coagulación con Plasma de Argón , Carcinoma de Células Renales/tratamiento farmacológico , Cauterización/métodos , Sustitución de Medicamentos , Hematemesis/prevención & control , Humanos , Neoplasias Renales/tratamiento farmacológico , Masculino , Gastropatías/prevención & control
12.
Clin J Gastroenterol ; 12(2): 193-195, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30251013

RESUMEN

Fundic gland polyps (FGPs) are generally considered benign. Proton-pump inhibitors (PPIs) are used worldwide as first-line therapy for gastroesophageal reflux disease and nonsteroidal anti-inflammatory drug-induced ulcer treatment. Long-term use of PPIs increases the risk of FGP development. We report an extremely rare case of PPI-induced FGPs with hematemesis. A 37-year-old woman taking daily rabeprazole presented to the hospital with a complaint of hematemesis and tarry stools. Esophagogastroduodenoscopy (EGD) revealed > 20 pedunculated polyps in the gastric body and fundus. Histological examination showed multiple fragments of fundic gland mucosa with dilated glands. Based on these findings and the clinical history, FGPs were diagnosed. Rabeprazole use was discontinued. Repeat EGD performed 9 months later showed a significant decrease in the number and size of the polyps. FGPs are small polyps typically located in the gastric corpus and fundus. They are commonly reported in patients in their 60s and predominantly in females. We conclude that PPI use is a risk factor for the development of FGPs and hematemesis.


Asunto(s)
Reflujo Gastroesofágico/tratamiento farmacológico , Hematemesis/inducido químicamente , Pólipos/inducido químicamente , Inhibidores de la Bomba de Protones/efectos adversos , Neoplasias Gástricas/inducido químicamente , Adulto , Endoscopía del Sistema Digestivo , Femenino , Fundus Gástrico/patología , Humanos , Pólipos/diagnóstico , Pólipos/patología , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología
13.
Intern Med ; 58(8): 1093-1096, 2019 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-30568137

RESUMEN

The patient was diagnosed with ulcerative colitis and received remission induction therapy with prednisolone. While they developed muscle pain in the lower extremities after starting prednisolone, they ultimately achieved clinical remission. After discharge, hematemesis and gastric discomfort developed. Esophagogastroduodenoscopy showed mucosal edema, redness, and oozing bleeding in the gastric body. In addition, the patient had bloody stool and was considered to have a relapse of ulcerative colitis. They therefore received remission induction therapy with tacrolimus. The patient achieved clinical remission again; however, gastric discomfort and muscle pain remained. A drug lymphocyte stimulation test revealed positivity for prednisolone; therefore, the patient was diagnosed with an allergy to prednisolone.


Asunto(s)
Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Hematemesis/inducido químicamente , Prednisolona/efectos adversos , Prednisolona/uso terapéutico , Administración Oral , Adulto , Hipersensibilidad a las Drogas/fisiopatología , Humanos , Masculino , Mesalamina/uso terapéutico , Inducción de Remisión , Tacrolimus/uso terapéutico , Resultado del Tratamiento
14.
Dis Esophagus ; 30(6): 1-6, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-29207003

RESUMEN

Esophageal stricture is a major secondary complication of ingesting caustic agents. We examined our experiences with caustic injuries with a view to finding clinical and biological risk factors of esophageal strictures secondary to caustic ingestion. Records were retrieved for 58 adults admitted consecutively to our intensive care unit for caustic ingestion. Fifty cases were managed conservatively and therefore retained for analyses. Patients were grouped according to whether they developed strictures or not during the follow-up period. Mucosal damage was assessed by emergency endoscopy. Eleven patients (22%) developed a stricture. At referral, dysphagia, epigastric pain, and hematemesis were associated with secondary stricture (respectively P = 0.047, P = 0.008, P = 0.02). A high Zargar endoscopic grade (above IIa; P = 0.02), the ingestion of strong acids or alkalis (P = 0.006), hyperleukocytosis (P = 0.02), and a low prothrombin ratio (P = 0.002) were associated with a higher risk of developing a stricture. The median delay of stricture diagnosis was 12 (8;16) days after ingestion, with extreme values from 4 to 26 days. Initial symptoms such as dysphagia or hematemesis, early endoscopy showing >IIa grade esophagitis, and certain laboratory results should draw the physician's attention to a high risk of esophageal stricture.


Asunto(s)
Quemaduras Químicas/complicaciones , Mucosa Esofágica/lesiones , Estenosis Esofágica/inducido químicamente , Dolor Abdominal/inducido químicamente , Adulto , Quemaduras Químicas/diagnóstico por imagen , Quemaduras Químicas/terapia , Trastornos de Deglución/inducido químicamente , Endoscopía Gastrointestinal , Mucosa Esofágica/diagnóstico por imagen , Femenino , Hematemesis/inducido químicamente , Humanos , Concentración de Iones de Hidrógeno , Puntaje de Gravedad del Traumatismo , Leucocitosis/inducido químicamente , Masculino , Persona de Mediana Edad , Protrombina/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven
15.
J Dig Dis ; 18(9): 504-510, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28749602

RESUMEN

OBJECTIVE: Evaluations of upper gastrointestinal toxicity from ketamine abuse are uncommon. This study investigated the clinical pattern of upper gastrointestinal symptoms in patients inhaling ketamine. METHODS: In a cross-sectional study of 611 consecutive patients who were seeking treatment for ketamine uropathy in a tertiary hospital setting between August 2008 and June 2016, their clinical pattern of upper gastrointestinal symptoms was evaluated and compared with a control population of 804 non-users. RESULTS: A total of 168 (27.5%) patients abusing ketamine (mean age 26.3 years, 58.9% female) reported the presence of upper gastrointestinal symptoms. These symptoms were significantly more prevalent in patients inhaling ketamine than in those who were not (27.5% vs 5.2%, P < 0.001). Their mean duration of ketamine abuse before symptom presentation was 5.0 ± 3.1 years. The presenting symptoms included epigastric pain (n = 155, 25.4%), recurrent vomiting (n = 48, 7.9%), anemia (n = 36, 5.9%) and gastrointestinal bleeding (n = 20, 3.3%). Uropathy symptoms were preceded by upper gastrointestinal symptoms for 4.4 ± 3.0 years in 141 (83.9%) patients. Logistic regression showed that elder age (odds ratio [OR] 1.06, P = 0.04), active abuser status (OR 1.60, P = 0.04) and longer duration of ketamine abuse (OR 1.00, P = 0.04) were independent factors associated with upper gastrointestinal toxicity. CONCLUSIONS: Although epigastric symptoms are unusual in the young population, upper gastrointestinal toxicity was highly prevalent in those inhaling ketamine. Enquiries about ketamine abuse are recommended when assessing young patients with epigastric symptoms.


Asunto(s)
Analgésicos/efectos adversos , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/epidemiología , Ketamina/efectos adversos , Trastornos Relacionados con Sustancias/complicaciones , Dolor Abdominal/inducido químicamente , Dolor Abdominal/epidemiología , Administración por Inhalación , Adolescente , Adulto , Analgésicos/administración & dosificación , Anemia/inducido químicamente , Anemia/epidemiología , Estudios de Casos y Controles , Enfermedad Crónica , Estudios Transversales , Úlcera Duodenal/inducido químicamente , Úlcera Duodenal/epidemiología , Endoscopía Gastrointestinal , Esofagitis/inducido químicamente , Esofagitis/epidemiología , Femenino , Gastritis/inducido químicamente , Gastritis/epidemiología , Hematemesis/inducido químicamente , Hematemesis/epidemiología , Humanos , Intestino Delgado/patología , Ketamina/administración & dosificación , Masculino , Melena/inducido químicamente , Melena/epidemiología , Metaplasia/inducido químicamente , Metaplasia/epidemiología , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/epidemiología , Enfermedades Urológicas/inducido químicamente , Enfermedades Urológicas/epidemiología , Vómitos/inducido químicamente , Vómitos/epidemiología , Adulto Joven
18.
Medicine (Baltimore) ; 96(51): e9391, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29390545

RESUMEN

RATIONALE: cetuximab, an epidermal growth factor receptor inhibitor, is a targeted therapeutic regimen of colorectal cancers. Several common adverse effects have been found, such as cutaneous or gastrointestinal toxicity. However, according to the articles had been published, upper gastrointestinal bleeding (UGIB) is considered to be rare and its mechanism remains unclear. PATIENT CONCERNS: In this report, we presented a 42-year-old male patient with advanced recto-sigmoid cancer. After palliative operation, the patient suffered from complete upper gastrointestinal (GI) obstruction, which was induced by extensive abdominal metastasis of the tumor. Considering his poor condition, we chose the targeted drug, cetuximab, as his further treatment. But after the application of cetuximab, the UGIB immediately happened twice in this patient. DIAGNOSIS: UGIB, as a rare complication of cetuximab, occured to the patient. INTERVENTIONS: We stopped the bleeding with thrombin, hemocoagulase and somatostatin and suspended the subsequent treatment plan of cetuximab. At the same time, anti-shock treatment was given immediately. OUTCOMES: He was died of respiratory and circulatory failure caused by UGIB and advanced tumor eventually. LESSONS: UGIB should be considered as a rare but severe complication of cetuximab. When cetuximab is applied for patients with advanced colon tumors, more cautions should be required if the patients are accompanied by upper gastrointestinal obstruction. In addition, for those patients who suffered from UGIB recently, cetuximab should be prohibited if the Rockall score ranged > 5 points.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Inmunológicos/efectos adversos , Cetuximab/efectos adversos , Hemorragia Gastrointestinal/inducido químicamente , Hematemesis/inducido químicamente , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Colon Sigmoide/tratamiento farmacológico , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/uso terapéutico , Resultado Fatal , Hemorragia Gastrointestinal/diagnóstico , Hematemesis/diagnóstico , Humanos , Masculino
19.
Rozhl Chir ; 95(8): 329-32, 2016.
Artículo en Checo | MEDLINE | ID: mdl-27650566

RESUMEN

UNLABELLED: Warfarin overdose with unmeasurable values of the prothrombin time (PT-INR) is a significant problem in the preoperative preparation of the patient for acute invasive surgery. In contrast to conventional blood clotting assays, rotational thromboelastometry (ROTEM) evaluates the coagulation profile of the whole blood and provides a more complex view of the coagulation status of the patient. Thromboelastometry results are available within about 10 minutes and help us to provide targeted "bedside" therapy of coagulopathy in a bleeding patient. In our case report we describe a case of a patient with warfarin overdose and unmeasurable PT-INR values. The patient was indicated for urgent gastroscopy because of haematemesis and abdominal surgery because of ileus. Haematemesis was stopped by ROTEM targeted treatment of coagulopathy and the operation was performed without bleeding complications with normal ROTEM despite the prolongation of PT-INR to 1.8. Finally, we would like to say that ROTEM method can be used for rapid management of warfarin-induced coagulopathy and that surgery may be performed safely without any correction of PT-INR in case of normal ROTEM. KEY WORDS: prothrombin time - bleeding - surgery thromboelastometry (ROTEM) warfarin.


Asunto(s)
Anticoagulantes/efectos adversos , Hematemesis/terapia , Cuidados Preoperatorios , Tromboelastografía , Warfarina/efectos adversos , Gastroscopía , Hematemesis/inducido químicamente , Humanos , Ileus/cirugía
20.
Toxicol Sci ; 151(2): 245-60, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26917699

RESUMEN

PRO304186, a humanized monoclonal antibody targeting soluble interleukin-17 A and F, was developed for autoimmune and inflammatory disease indications. When administered to cynomolgus monkeys PRO304186 induced unexpected adverse effects characterized by clinical signs of hematemesis, hematochezia, and moribundity. Pathology findings included hemorrhage throughout the gastrointestinal tract without any evidence of vascular wall damage or inflammatory cellular infiltration. Mechanistic investigation of these effects revealed mild elevations of serum MCP-1 and IL-12/23 but without a classical proinflammatory profile in PRO304186-treated animals. In vitro studies demonstrated off-target effects on vascular endothelial cells including activation of nitric oxide synthase leading to production of nitric oxide (NO) accompanied by increased mitochondrial membrane depolarization, glutathione depletion, and increased paracellular permeability. Additionally, endothelial cell-PRO304186-conditioned medium reduced myosin light chain phosphorylation in vascular smooth muscle cells. Furthermore, an ex vivo study utilizing segments from cynomolgus aorta and femoral artery confirmed PRO304186-induced endothelium-dependent smooth muscle relaxation and vasodilation mediated via NO. Finally, a single dose of PRO304186 in cynomolgus monkeys induced a rapid and pronounced increase in NO in the portal circulation that preceded a milder elevation of NO in the systemic circulation and corresponded temporally with systemic hypotension; findings consistent with NO-mediated vasodilation leading to hypotension. These changes were associated with non-inflammatory, localized hemorrhage in the gastrointestinal tract consistent with hemodynamic vascular injury associated with intense local vasodilation. Together, these data demonstrate that PRO304186-associated toxicity in monkeys was due to an off-target effect on endothelium that involved regional NO release resulting in severe systemic vasodilation, hypotension, and hemorrhage.


Asunto(s)
Anticuerpos Monoclonales Humanizados/toxicidad , Arterias/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Hemorragia Gastrointestinal/inducido químicamente , Hipotensión/inducido químicamente , Óxido Nítrico/metabolismo , Vasodilatación/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados/metabolismo , Arterias/metabolismo , Arterias/fisiopatología , Células Cultivadas , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Hemorragia Gastrointestinal/metabolismo , Hemorragia Gastrointestinal/fisiopatología , Hematemesis/inducido químicamente , Hematemesis/metabolismo , Hematemesis/fisiopatología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hipotensión/metabolismo , Hipotensión/fisiopatología , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Interleucina-17/metabolismo , Macaca fascicularis , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Cadenas Ligeras de Miosina/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Factores de Tiempo
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