The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

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.

The Role for Metyrosine in the Treatment of Patients With Pheochromocytoma and Paraganglioma.

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.

Cytokine storms caused by novel coronavirus 2019 and treatment for cardiac injury.

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.

Preoperative Management of Pheochromocytoma and Paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, characterized by excessive release of catecholamines (CAs), and manifested as the classic triad of headaches, palpitations, profuse sweating, and a variety of other signs and symptoms. The diagnosis of PPGL requires both evidence of excessive release of CAs and anatomical localization of CA-secreting tumor. Surgery is the mainstay of treatment for all patients with PPGL unless contraindicated. However, without proper preparation, the release of excessive CAs, especially during surgery, can result in lethal cardiovascular complications. Herein, we briefly reviewed the pathogenesis of this disease, discussed the current approaches and evidence available for preoperative management, summarizing the results of the latest studies which compared the efficacies of preoperative management with or without α adrenergic-receptor antagonists, aiming to facilitate better understanding of the preoperative management of PPGL for the physicians.

A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer.

Purpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-in-human study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer. Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed. Results The most common drug related adverse events were hyperpigmentation and rash. All drug related adverse events were mild to moderate in intensity. Following treatment with SMK Therapy, 4 subjects achieved complete response, 6 partial response, and 17 stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (total clinical benefit 90%). Responses were observed within 6 weeks, and continued to improve, with 3 complete and 3 partial responders achieving best response after at least 3.2 months. Durable stable disease was observed, lasting a median duration of 11 months (range 1-31 months). Median overall survival for all subjects was 29.8 months, and median PFS was 13 months. Following 6 weeks of treatment, most (83.3%) subjects showed an improvement in Eastern Cooperative Oncology Group (ECOG) score and an improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ 30) global health status (baseline 61.2 ± 25.0; end of Cycle 1 80.7 ± 14.7; n = 29; p < 0.001). Conclusions The results of this study support continued development of SM-88.

Correlation between urinary fractionated metanephrines in 24-hour and spot urine samples for evaluating the therapeutic effect of metyrosine: a subanalysis of a multicenter, open-label phase I/II study.

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.

Efficacy and safety of metyrosine in pheochromocytoma/paraganglioma: a multi-center trial in Japan.

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.

Preoperative Metyrosine Improves Cardiovascular Outcomes for Patients Undergoing Surgery for Pheochromocytoma and Paraganglioma.

BACKGROUND: The goal of preoperative pharmacotherapy for pheochromocytoma (PCC) and paraganglioma (PGL) resection is to minimize intraoperative hemodynamic instability and perioperative cardiovascular complications, but no standard preoperative regimen exists. Historically, treatment used metyrosine and phenoxybenzamine (MP). The recent metyrosine shortage required that phenoxybenzamine alone (PA) be used for treatment. The authors examined their experience to determine the impact of preoperative metyrosine treatment on patient outcomes. METHODS: A retrospective cohort study investigated patients who underwent initial PCC/PGL resection (2000-2014). The primary outcome was intraoperative hemodynamics, measured by heart rate (HR) and systolic blood pressure (SBP). The secondary outcomes included perioperative complications and cardiovascular-specific complications (CVC). Univariate analysis was performed, and adjusted risk differences were estimated after confounding was taken into account. RESULTS: Of 174 patients, 142 (81.6 %) were in the MP group. The MP and PA patients had comparable intraoperative use of antihypertensives (83.9 vs 78.1 %; p = 0.443), vasopressors (74.6 vs 87.5 %; p = 0.120), and fluid resuscitation (mean, 24.4 vs 24.8 ml/min; p = 0.761). Although the perioperative complication rate did not differ significantly between the MP and PA groups (respectively 23.4 vs 34.4 %; p = 0.198), the PA patients had a 15.8 % higher rate of CVC even after controlling for confounders (p = 0.034). Compared with the MP patients, the PA patients had significantly more hemodynamic instability intraoperatively, with a greater range in HR (7.4 bpm; p = 0.034) and SBP (14.8 mmHg; p = 0.020). CONCLUSIONS: In this study, preoperative metyrosine improved intraoperative hemodynamic stability and decreased CVC rates in patients undergoing PCC/PGLresection. These data suggest that the addition of preoperative metyrosine may improve operative outcomes.

Failure of metyrosine therapy for preoperative management of pheochromocytoma: a case report.

PURPOSE: Pheochromocytomas (PHEOS) are rare catecholamine-secreting adrenal tumours requiring surgical resection. Preoperative alpha-adrenergic receptor blockade to prevent intraoperative hypertension has traditionally been achieved with phenoxybenzamine. Due to changes in the availability of phenoxybenzamine in Canada, alternate therapies are needed for patients. We report our first experience using metyrosine, a tyrosine hydroxylase inhibitor, for preoperative management in a symptomatic patient with a unilateral PHEO. CLINICAL FEATURES: A 50-yr-old male was referred to our centre with a history of symptoms suggestive of a catecholamine-secreting PHEO, including tachycardia, diaphoresis, nervousness, and tremor. Computerized tomography revealed a right adrenal mass, and additional positive imaging and elevated urine epinephrine levels supported a diagnosis of PHEO. The patient was admitted to hospital five days prior to surgery, and metyrosine therapy was initiated and titrated to 4 g daily over four days. Despite adequate blood pressure (BP) control leading up to the resection, the initial BP reading in the operating room was 191/106 mmHg, but it subsequently declined and was well controlled during induction (100-110 mmHg systolic BP). Significant hypertension (up to 201/110 mmHg) developed upon tumour manipulation and resolved with phentolamine administration and surgical isolation of the tumour. The patient's BP remained stable throughout the residual part of the procedure and in the recovery room and step-down unit. CONCLUSION: In the case of this patient's PHEO, the use of metyrosine was unsatisfactory in achieving sufficient inhibition of catecholamine synthesis as evidenced by significant intraoperative hypertension. Metyrosine could have a role in preoperative management of these patients, but it may not be optimal as monotherapy for some patients with actively secreting tumours.

Perioperative management of a patient with a nonresectable pheochromocytoma.

OBJECTIVE: To describe the clinical course of a patient with a nonresectable pheochromocytoma during urgent hip surgery. METHODS: To describe the clinical management and postoperative outcome of the patient and review the relevant literature. RESULTS: An 85-year-old male with a nonresectable pheochromocytoma required urgent hip surgery following a traumatic hip fracture. He was perioperatively managed with phenoxybenzamine, metyrosine, and metoprolol to avoid potential pheochromocytoma-related complications. He remained hemodynamically stable and recovered from the surgery without complications. CONCLUSIONS: This case illustrates the successful management of a patient requiring urgent surgery in the setting of a nonresectable pheochromocytoma, which is rarely described in the literature.

Low dose alpha-methyl-para-tyrosine (AMPT) in the treatment of dystonia and dyskinesia.

AMPT (alpha-methyl-para-tyrosine) is an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis. In clinical settings, AMPT is approved to treat pheochromocytoma. Dystonias and dyskinesias seem to have their origin in inconsistent regulation of dopamine function in dopamine pathways. This paper presents case histories of the clinical efficacy of AMPT for treating certain individuals with neuroleptic-induced dystonia or dyskinesia. The authors propose that a special utility of AMPT in tardive disorders may be related to a downregulation of tyrosine hydroxylase activity that may be increased by neuroleptic-induced effects on tyrosine hydroxylase phosphorylation.

Diagnosis and management of pheochromocytoma during pregnancy: a case report.

Pheochromocytoma is known to increase morbidity and mortality. We describe a case of pheochromocytoma during pregnancy. A patient was transferred to our hospital during gestational week 15 with severe hypertension, acute pulmonary edema, and cardiomyopathy. One day after transfer, she had a spontaneous abortion of the fetus. One week after hospital transfer, she developed acute dyspnea, supraventricular tachycardia degenerating into ventricular tachycardia, and respiratory failure requiring mechanical ventilation. Pheochromocytoma caused by a right adrenal mass was diagnosed. The patient was treated with titrated doses of phenoxybenzamine, intravenous nicardipine, and metyrosine over a period of 3 weeks with resultant stabilization of her blood pressure. She underwent a successful right adrenalectomy 1 month after her initial presentation. Four months after surgery, all antihypertensive medications were discontinued and her blood pressure remained stable 1 year after the surgery. This case describes the maternal morbidity and fetal mortality that may be associated with pheochromocytoma during pregnancy.

Three cases of malignant pheochromocytoma treated with cyclophosphamide, vincristine, and dacarbazine combination chemotherapy and alpha-methyl-p-tyrosine to control hypercatecholaminemia.

We describe 3 cases of malignant pheochromocytoma with multiple metastases which were treated with cyclophosphamide, vincristine and dacarbazine (CVD) combination chemotherapy and alpha-methyl-p-tyrosine. Case 1 was operated on first but hypercatecholaminemia could not be completely controlled. Cases 2 and 3 received chemotherapy, CVD combination chemotherapy and/ or alpha-methyltyrosine and good control of hypercatecholaminemia was attained. In all cases it was possible to control hypercatecholaminemia during most of the time they were administered a-methyltyrosine despite the presence of tumors. None of the patients suffered hypertension crises. In our patients treatment with CVD plus a-methyl-p-tyrosine proved to be safe and ameliorated the clinical course.

Preoperative treatment and survival of patients with pheochromocytomas.

BACKGROUND: Operative treatment is the method of choice for pheochromocytomas. The best success of the operation requires both good operative technique and effective preoperative medication. Phenoxybenzamine hydrochloride, an alpha-receptor blocker, has been our traditional premedication. Since 1988 we have used it in a combination with alpha-methylthyrosine, a catecholamine-synthesis blocker. AIM: To evaluate different preoperative medications. MATERIAL AND METHODS: Between 1984 and 1994 22 patients were operated on for pheochromocytomas in Tampere University Hospital. Five patients received alpha-receptor blocker, three patients received catecholamine-synthesis blocker, and 14 patients received their combination for a median of 33 days prior to the operation. RESULTS: Three of the five patients receiving alpha-receptor blocker, two of the three patients receiving catecholamine-synthesis blocker, and four of the 14 patients receiving combination therapy demonstrated high systolic blood pressure during the operation. Three patients, one in the alpha-receptor blocker group and two in the combination therapy group, demonstrated a short hypotensive period during the operation. None of the patients experienced severe perioperative cardiac arrhythmias. Mild sedation occurred similarly in either premedications, but the treatment did not need to be discontinued due to adverse reactions. There was no hospital mortality. Two patients had postoperative complications. CONCLUSION: Our initial experience with the combination therapy with alpha-receptor blocker and catecholamine-synthesis blocker is encouraging.