RESUMEN
PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Antagonistas de Receptores Adrenérgicos alfa 1 , Doxazosina , Paraganglioma , Feocromocitoma , alfa-Metiltirosina , Humanos , Doxazosina/uso terapéutico , Doxazosina/administración & dosificación , Femenino , Masculino , Feocromocitoma/cirugía , Feocromocitoma/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias de las Glándulas Suprarrenales/cirugía , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Estudios Retrospectivos , Paraganglioma/tratamiento farmacológico , Paraganglioma/cirugía , Adulto , Anciano , alfa-Metiltirosina/uso terapéutico , alfa-Metiltirosina/administración & dosificación , alfa-Metiltirosina/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Quimioterapia Combinada , Cuidados Preoperatorios/métodos , Resultado del TratamientoRESUMEN
Hypertension in children with neuroblastoma is uncommon and can be difficult to control due to the potential for multiple underlying causes. We present the case of a pediatric patient with high-grade neuroblastoma which was complicated by hypertensive emergency. The patient had imaging suggestive of renal artery compression, as well as significantly elevated normetaphrine levels. Multiple anti-hypertensive agents, including an angiotensin converting enzyme inhibitor, α- and ß-adrenergic receptor blockers, and a tyrosine hydroxylase inhibitor, were initiated prior to tumor excision. While her blood pressure improved during the post-operative period, she continued to require multiple antihypertensive medications due to residual tumor burden. In this report, we highlight the importance of careful, multidisciplinary management to avoid peri-operative complications in patients with catecholamine-producing tumors.
Asunto(s)
Hipertensión , Neuroblastoma , Femenino , Niño , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Antihipertensivos/efectos adversos , Catecolaminas , Presión Sanguínea , Neuroblastoma/complicaciones , Neuroblastoma/terapiaRESUMEN
CONTEXT: Treatment of pheochromocytoma and paraganglioma (PPGL) requires preintervention titration of alpha- and beta-adrenergic blockade, but patients may still be at risk for complications from catecholamine excess. Metyrosine decreases catecholamine production, making it an attractive therapeutic adjunct for select patients. EVIDENCE ACQUISITION: A systematic literature review was performed (Ovid Medline and Scopus databases) on December 17, 2019, including studies with humans and original data. Studies with 10 or more patients on metyrosine for PPGL were included. Studies were screened for overlapping populations, and the most comprehensive study was included. The references of included studies were reviewed for additional data. Patient data from our institution between 2000 and 2015 were also reviewed. EVIDENCE SYNTHESIS: Metyrosine is well tolerated when used for a short course and can improve intraoperative outcomes in PPGL. Metyrosine should be considered when a difficult PPGL resection is expected (eg, pericardiac paraganglioma, abdominal paraganglioma with great vessel involvement), a large release of catecholamines is anticipated (eg, ablative therapy, chemotherapy), or when standard alpha- and beta-adrenergic blockade are not tolerated or cannot adequately control hypertension. Side effects are generally mild and self-limited, with sedation in a majority of patients. Extrapyramidal side effects are rare but can limit use of metyrosine. Because of its expense and limited availability, metyrosine use should be carefully planned and timed in relation to surgery. CONCLUSIONS: Metyrosine is a safe addition to traditional alpha- and beta-adrenergic blockade and should be considered in those patients with PPGL at high risk for acute release of catecholamines.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Paraganglioma/tratamiento farmacológico , Feocromocitoma/tratamiento farmacológico , alfa-Metiltirosina/uso terapéutico , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Combinada , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/etiología , Paraganglioma/complicaciones , Paraganglioma/epidemiología , Paraganglioma/patología , Feocromocitoma/complicaciones , Feocromocitoma/epidemiología , Feocromocitoma/patología , alfa-Metiltirosina/efectos adversosRESUMEN
We recently conducted an open-label phase I/II study to evaluate the efficacy and safety of preoperative and chronic treatment with metyrosine (an inhibitor of catecholamine synthesis) in pheochromocytoma/paraganglioma (PPGL) in Japan. We compared creatinine-corrected metanephrine fractions in spot urine and 24-hour urine samples (the current standard for the screening and diagnosis of PPGLs) from 16 patients to assess the therapeutic effect of metyrosine. Percent changes from baseline in urinary metanephrine (uMN) or normetanephrine (uNMN) were compared between spot and 24-hour urine samples. Mean percent changes in uMN or uNMN in spot and 24-hour urine were -26.36% and -29.27%, respectively. The difference in the percent change from baseline between uMN or uNMN in spot and 24-hour urine was small (-2.90%). The correlation coefficient was 0.87 for percent changes from baseline between uMN or uNMN measured in spot and 24-hour urine. The area under the receiver operator characteristic (ROC) curve of uMN or uNMN measured in spot urine vs. 24-hour urine (reference standard) to assess the efficacy of metyrosine treatment was 0.93. Correlations and ROCs between 24-hour urinary vanillylmandelic acid, adrenaline, and noradrenaline and 24-hour uMN or uNMN were similar to those between spot uMN or uNMN and 24-hour uMN or uNMN. No large difference was observed between spot and 24-hour urine for the assessment of metyrosine treatment by quantifying uMN or uNMN in Japanese patients with PPGLs. These results suggest that spot urine samples may be useful in assessing the therapeutic effect of metyrosine.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/orina , Metanefrina/orina , Paraganglioma/orina , Feocromocitoma/orina , alfa-Metiltirosina/uso terapéutico , Adolescente , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Normetanefrina/orina , Paraganglioma/tratamiento farmacológico , Paraganglioma/cirugía , Feocromocitoma/tratamiento farmacológico , Feocromocitoma/cirugía , Cuidados Preoperatorios/métodos , Curva ROC , Sensibilidad y Especificidad , alfa-Metiltirosina/administración & dosificación , alfa-Metiltirosina/efectos adversosRESUMEN
To assess the efficacy, safety, and pharmacokinetics of metyrosine (an inhibitor of catecholamine synthesis) in patients with pheochromocytoma/paraganglioma (PPGL), we conducted a prospective, multi-center, open-label study at 11 sites in Japan. We recruited PPGL patients aged ≥12 years requiring preoperative or chronic treatment, receiving α-blocker treatment, having baseline urinary metanephrine (uMN) or normetanephrine (uNMN) levels ≥3 times the upper limit of normal values, and having symptoms associated with excess catecholamine. Metyrosine treatment was started at 500 mg/day and modified according to dose-adjustment criteria up to 4,000 mg/day. The main outcome measure was the proportion of patients who achieved at least 50% reduction in uMN or uNMN levels from baseline. Sixteen patients (11 males/5 females) aged 12-86 years participated. After 12 weeks of treatment and at the last evaluation of efficacy, the primary endpoint was achieved in 31.3% of all patients, including 66.7% of those under preoperative treatment and 23.1% of those under chronic treatment. Sedation, anemia, and death were reported in 1 patient each as serious adverse drug reactions during the 24-week treatment. Metyrosine was shown to be tolerated and to relieve symptoms by reducing excess catecholamine in PPGL patients under both preoperative and chronic treatment.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Paraganglioma/tratamiento farmacológico , Feocromocitoma/tratamiento farmacológico , alfa-Metiltirosina/uso terapéutico , Adolescente , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Niño , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Paraganglioma/patología , Feocromocitoma/patología , Resultado del Tratamiento , Adulto Joven , alfa-Metiltirosina/efectos adversosRESUMEN
INTRODUCTION: To describe outcomes of patients with metyrosine (MET) pretreatment for abdominal surgical resection of pheochromocytoma or paraganglioma (PCC/PGL) compared with patients who had phenoxybenzamine (PBZ) pretreatment. METHODS: Retrospective review of perioperative outcomes for PCC/PGL patients treated with MET and propensity-matched comparison of MET and PBZ (MET + PBZ) with PBZ alone. RESULTS: MET preparation was given in 63 cases (26 laparoscopic and 37 open, of which 55 also received PBZ). All patients had wide perioperative hemodynamic oscillations. Patients with open procedures required more intravenous fluids and blood transfusions; 35% required postoperative vasopressor infusions for hypotension and 38% developed acute kidney injury. One laparoscopic procedure required postoperative vasopressor infusion, and 12% of patients developed acute kidney injury. Forty-five MET + PBZ patients were propensity-matched with PBZ-only patients. Intraoperatively, MET + PBZ patients had lower minimum systolic and diastolic blood pressures than PBZ-only patients (median systolic, 74 vs 80 mm Hg, P = 0.01; median diastolic, 42 vs 46 mm Hg, P = 0.005) and larger intraoperative blood pressure oscillations (median systolic range, 112 vs 93 mm Hg, P = 0.06; median diastolic range, 58 vs 51 mm Hg, P = 0.02). Postoperative vasopressor infusion use was similar between MET + PBZ and PBZ only (16% vs 11%, P = 0.76). Major outcomes were not different between regimens. CONCLUSION: Large hemodynamic oscillations were present in our PCC/PGL patients treated with MET + PBZ. These patients had a wider range of intraoperative blood pressure variations than PBZ-only patients. No differences in postoperative comorbid outcomes were found between MET + PBZ and PBZ-only groups.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Hemodinámica/efectos de los fármacos , Paraganglioma/cirugía , Feocromocitoma/cirugía , Vasoconstrictores/administración & dosificación , alfa-Metiltirosina/administración & dosificación , Neoplasias de las Glándulas Suprarrenales/cirugía , Adulto , Quimioterapia Combinada , Femenino , Humanos , Periodo Intraoperatorio , Laparoscopía , Masculino , Persona de Mediana Edad , Fenoxibenzamina/administración & dosificación , Periodo Posoperatorio , Puntaje de Propensión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare chromaffin cell tumors which secrete catecholamines and form part of the family of neuroendocrine tumors. Although a rare cause of secondary hypertension in pediatrics, the presentation of hypertension in these patients is characteristic, and treatment is definitive. The gold standard for diagnosis is via measurement of plasma free metanephrines, with imaging studies performed for localization, identification of metastatic lesions and for surgical resection. Preoperative therapy with alpha-blocking agents, beta blockers, and potentially tyrosine hydroxylase inhibitors aid in a safe pre-, intra- and postoperative course. PCC and PGL are inherited in as much as 80% of pediatric cases, and all patients with mutations should be followed closely given the risk of recurrence and malignancy. While the presentation of chromaffin cell tumors has been well described with multiple endocrine neoplasia, NF1, and Von Hippel-Lindau syndromes, the identification of new gene mutations leading to chromaffin cell tumors at a young age is changing the landscape of how clinicians approach such cases. The paraganglioma-pheochromocytoma syndromes (SDHx) comprise familial gene mutations, of which the SDHB gene mutation carries a high rate of malignancy. Since the inheritance rate of such tumors is higher than previously described, genetic screening is recommended in all patients, and lifelong follow-up for recurrent tumors is a must. A multidisciplinary team approach allows for optimal health-care delivery in such children. This review serves to provide an overview of pediatric PCC and PGL, including updates on the preferred methods of imaging, guidelines on gene testing as well as management of hypertension in such patients.
RESUMEN
This study investigated the effect of metyrosine against ketamine-induced cardiotoxicity in rats and compared the results with the effect of metoprolol. In this study, rats were divided into groups A, B and C. In group A, we investigated the effects of a single dose of metyrosine (150 mg/kg) and metoprolol (20 mg/kg) on single dose ketamine (60 mg/kg)-induced cardiotoxicity. In group B, we investigated the effect of metyrosine and metoprolol, which were given together with ketamine for 30 days. In group C, we investigated the effect of metyrosine and metoprolol given 15 days before ketamine and 30 days together with ketamine on ketamine cardiotoxicity. By the end of this process, we evaluated the effects of the levels of oxidant-antioxidant parameters such as MDA, MPO, 8-OHGua, tGSH, and SOD in addition to CK-MB and TP I on cardiotoxicity in rat heart tissue. The experimental results show that metyrosine prevented ketamine cardiotoxicity in groups A, B and C and metoprolol prevented it in only group C.
Asunto(s)
Antioxidantes/farmacología , Cardiopatías/prevención & control , Ketamina , Metoprolol/farmacología , Miocitos Cardíacos/efectos de los fármacos , alfa-Metiltirosina/farmacología , Animales , Biomarcadores/metabolismo , Citoprotección , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Cardiopatías/inducido químicamente , Cardiopatías/metabolismo , Masculino , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Factores de TiempoRESUMEN
BACKGROUND: Osteoporosis is a chronic disease characterized by a decrease in bone mineral density (BMD) and corruption of the microarchitectural structure of bone tissue. OBJECTIVE: It was investigated whether methylprednisolone had a favorable effect on osteoporotic bone tissue in Oophorectomy induced osteoporotic rats whose endogenous adrenaline levels are suppressed with metyrosine. MATERIALS AND METHODS: Bone Mineral Density, number of osteoblast-osteoclast, bone osteocalcin levels and alkaline phosphatase (ALP) measurements were performed. Obtained results were compared with that of alendronate. RESULTS: Oophorectomy induced osteoporosis was exacerbated by methylprednisolone. Alentronate prevented ovariectomised induced osteoporosis, but it couldn't prevent methylprednisolone +ovariectomised induced osteoporosis in rats. CONCLUSION: Combined treatment with methylprednisolon and metyrosine was the best treatment for preventing osteoporosis but metyrosine alone couldn't prevent osteoporosis in ovariectomised rats.