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Pharmacology Research & Perspectives Aug 2020α1-adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and...
α1-adrenoceptor antagonists are widely used for hypertension (eg, doxazosin) and benign prostatic hypertrophy (BPH, eg, tamsulosin). Some antidepressants and antipsychotics have been reported to have α1 affinity. This study examined 101 clinical drugs and laboratory compounds to build a comprehensive understanding of α1-adrenoceptor subtype affinity and selectivity. [3H]prazosin whole-cell binding was conducted in CHO cells stably expressing either the full-length human α1A, α1B, or α1D-adrenoceptor. As expected, doxazosin was a high-affinity nonselective α1-antagonist although other compounds (eg, cyclazosin, 3-MPPI, and ARC239) had higher affinities. Several highly α1A-selective antagonists were confirmed (SNAP5089 had over 1700-fold α1A selectivity). Despite all compounds demonstrating α1 affinity, only BMY7378 had α1D selectivity and no α1B-selective compounds were identified. Phenoxybenzamine (used in pheochromocytoma) and dibenamine had two-component-binding inhibition curves at all three receptors. Incubation with sodium thiosulfate abolished the high-affinity component suggesting this part is receptor mediated. Drugs used for hypertension and BPH had very similar α1A/α1B/α1D-adrenoceptor pharmacological profiles. Selective serotonin reuptake inhibitors (antidepressants) had poor α1-adrenoceptor affinity. Several tricyclic antidepressants (eg, amitriptyline) and antipsychotics (eg, chlorpromazine and risperidone) had high α1-adrenoceptor affinities, similar to, or higher than, α blockers prescribed for hypertension and BPH, whereas others had poor α1 affinity (eg, protriptyline, sulpiride, amisulpiride, and olanzapine). The addition of α blockers for the management of hypertension or BPH in people already taking tricyclic antidepressants and certain antipsychotics may not be beneficial. Awareness of the α-blocking potential of different antipsychotics may affect the choice of drug for those with delirium where additional hypotension (eg, in sepsis) may be detrimental.
Topics: Adrenergic alpha-Antagonists; Animals; Antidepressive Agents; Antipsychotic Agents; CHO Cells; Cricetulus; Humans; Receptors, Adrenergic, alpha-1
PubMed: 32608144
DOI: 10.1002/prp2.602 -
Endocrinology, Diabetes & Metabolism... Mar 2020Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing's syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man...
SUMMARY
Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing's syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man presented following an episode of presumed gastroenteritis with vomiting and general malaise. Further episodes of diarrhoea, joint pains and palpitations followed. On examination, he was hypertensive with no clinical features to suggest hypercortisolaemia. He was subsequently found to have raised plasma normetanephrines of 3.98 nmol/L (NR <0.71) and metanephrines of 0.69 nmol/L (NR <0.36). An adrenal CT showed a 3.8 cm right adrenal nodule, which was not MIBG-avid but was clinically and biochemically consistent with a phaeochromocytoma. He was started on alpha blockade and referred for right adrenalectomy. Four weeks later, on the day of admission for adrenalectomy, profound hypokalaemia was noted (serum potassium 2.0 mmol/L) with non-specific ST-segment ECG changes. He was also diagnosed with new-onset diabetes mellitus (capillary blood glucose of 28 mmol/L). He reported to have gained weight and his skin had become darker over the course of the last 4 weeks. Given these findings, he underwent overnight dexamethasone suppression testing, which showed a non-suppressed serum cortisol of 1099 nmol/L. Baseline serum ACTH was 273 ng/L. A preliminary diagnosis of ectopic ACTH secretion from the known right-sided phaeochromocytoma was made and he was started on metyrapone and insulin. Surgery was postponed for 4 weeks. Following uncomplicated laparoscopic adrenalectomy, the patient recovered with full resolution of symptoms.
LEARNING POINTS
Phaeochromocytomas are a rare source of ectopic ACTH secretion. A high clinical index of suspicion is therefore required to make the diagnosis. Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing's syndrome, thus complicating tumour removal. Removal of the primary tumour often leads to full recovery. The limited literature suggests that the presence of ectopic Cushing's syndrome does not appear to have any long-term prognostic implications.
PubMed: 32168466
DOI: 10.1530/EDM-20-0011 -
Frontiers in Endocrinology 2020Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ)... (Review)
Review
Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ) showed great promise in some MMP patients, especially those with germline mutation. We reported a patient with MPP who did not have any known germline genetic change and responded remarkably well to TMZ monotherapy. The patient was a 41-year-old woman with local and distant recurrence (soft tissues and bone metastases) of retroperitoneal paraganglioma. She suffered from dizziness, palpitation, sweating, weight loss and constipation, with the blood pressure fluctuating substantially from 130/100 mmHg to 190/120 mmHg, although she was on phenoxybenzamine and metoprolol medication. The patient showed clinical and radiological response after 3-cycle TMZ therapy. Upon 15 cycles of TMZ therapy, her symptoms were dramatically alleviated, urinary norepinephrine excretion decreased from 1,840 μg/24 h to 206 μg/24 h, and CT showed that the lesions further shrank. Molecular profiling of the tumor tissue of the patient revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase () promoter and a negative immunostaining for MGMT. Globally, only 26 cases of MPP treated with TMZ have been described so far. TMZ is effective, especially in patients with mutation, which can be explained by the silencing of MGMT expression as a consequence of promoter hypermethylation in -mutated tumors. Although, in general, patients with mutation or MGMT promoter hypermethylation have better response to TMZ, there are also exceptions. Severe side effects are uncommon, with only 17.4% patients experiencing Grade 3 toxicities, including lymphopenia, and hypertension. TMZ is effective and safe in MPP patients, and, it may work better on patients with -related MPP. Measurement of MGMT expression might help assess the tumor sensitivity to TMZ but this needs further systematic investigation.
Topics: Adrenal Gland Neoplasms; Adult; Antineoplastic Agents, Alkylating; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Humans; Mutation; Paraganglioma; Pheochromocytoma; Prognosis; Promoter Regions, Genetic; Succinate Dehydrogenase; Temozolomide; Tumor Suppressor Proteins
PubMed: 32132978
DOI: 10.3389/fendo.2020.00061 -
Journal of the American Heart... Mar 2020Background We previously reported that pralidoxime facilitated restoration of spontaneous circulation by potentiating the pressor effect of epinephrine. We determined...
Background We previously reported that pralidoxime facilitated restoration of spontaneous circulation by potentiating the pressor effect of epinephrine. We determined the optimal dose of pralidoxime during cardiopulmonary resuscitation and evaluated the involvement of α-adrenoceptors in its pressor action. Methods and Results Forty-four pigs randomly received 1 of 3 doses of pralidoxime (40, 80, or 120 mg/kg) or saline placebo during cardiopulmonary resuscitation, including epinephrine administration. Pralidoxime at 40 mg/kg produced the highest coronary perfusion pressure, whereas 120 mg/kg of pralidoxime produced the lowest coronary perfusion pressure. Restoration of spontaneous circulation was attained in 4 (36.4%), 11 (100%), 9 (81.8%), and 3 (27.3%) animals in the saline, 40, 80, and 120 mg/kg groups, respectively (<0.001). In 49 rats, arterial pressure response to 40 mg/kg of pralidoxime was determined after saline, guanethidine, phenoxybenzamine, or phentolamine pretreatment, and the response to 200 mg/kg pf pralidoxime was determined after saline, propranolol, or phentolamine pretreatment. Pralidoxime at 40 mg/kg elicited a pressor response. Phenoxybenzamine completely inhibited the pressor response, but guanethidine and phentolamine did not. The pressor response of pralidoxime was even greater after guanethidine or phentolamine pretreatment. Pralidoxime at 200 mg/kg produced an initial vasodepressor response followed by a delayed pressor response. Unlike propranolol, phentolamine eliminated the initial vasodepressor response. Conclusions Pralidoxime at 40 mg/kg administered with epinephrine improved restoration of spontaneous circulation rate by increasing coronary perfusion pressure in a pig model of cardiac arrest, whereas 120 mg/kg did not improve coronary perfusion pressure or restoration of spontaneous circulation rate. The pressor effect of pralidoxime was unrelated to α-adrenoceptors and buffered by its vasodepressor action mediated by sympathoinhibition.
Topics: Adrenergic alpha-Agonists; Animals; Blood Pressure; Cardiopulmonary Resuscitation; Cholinesterase Reactivators; Coronary Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Epinephrine; Heart Arrest; Pralidoxime Compounds; Rats; Rats, Wistar; Swine
PubMed: 32070203
DOI: 10.1161/JAHA.119.015076 -
BMC Veterinary Research Feb 2020Ectopic Cushing's syndrome (ECS) associated with malignant tumors, such as small cell lung carcinoma, bronchial carcinoids, and pheochromocytoma, has been reported in...
BACKGROUND
Ectopic Cushing's syndrome (ECS) associated with malignant tumors, such as small cell lung carcinoma, bronchial carcinoids, and pheochromocytoma, has been reported in human medicine. However, ECS related to pheochromocytoma has not been reported in dogs.
CASE PRESENTATION
An 11-year-old castrated, male Scottish terrier was diagnosed with a left adrenal mass. Cushing's syndrome was suspected based on clinical signs, including pot belly, polyuria, polydipsia, bilateral alopecia, recurrent pyoderma, and calcinosis cutis. Cushing's syndrome was diagnosed on the basis of consistent clinical signs and repeated adrenocorticotropic hormone (ACTH) stimulation tests. In addition, tests for fractionated plasma metanephrine/normetanephrine suggested a pheochromocytoma. Unilateral adrenalectomy was performed after medical management with trilostane and phenoxybenzamine. Histopathology confirmed a diagnosis of pheochromocytoma without cortical lesions. After surgery, fractionated metanephrine/normetanephrine and the findings of low-dose dexamethasone suppression and ACTH stimulation tests were within the normal ranges without any medication. There were no clinical signs or evidence of recurrence and metastasis on thoracic and abdominal X-rays and ultrasonography up to 8 months after surgery.
CONCLUSIONS
Pheochromocytoma should be considered a differential diagnosis for dogs with Cushing's syndrome with an adrenal tumor. A good prognosis can be expected with prompt diagnosis and surgical intervention.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Animals; Cushing Syndrome; Dihydrotestosterone; Dog Diseases; Dogs; Male; Phenoxybenzamine; Pheochromocytoma
PubMed: 32014021
DOI: 10.1186/s12917-020-2244-7 -
AACE Clinical Case Reports 2019To describe the case of a woman with a longstanding misdiagnosis of type 1 diabetes mellitus (T1DM), in whom diabetes remission was achieved following surgical resection...
OBJECTIVE
To describe the case of a woman with a longstanding misdiagnosis of type 1 diabetes mellitus (T1DM), in whom diabetes remission was achieved following surgical resection of adrenal pheochromocytoma.
METHODS
We present a case report with accompanying biochemical, histologic, and genetic investigation results.
RESULTS
We report the case of a 57-year-old woman with a 13-year history of apparent T1DM, and her presentation with intermittent exertional nausea. An abdominal ultrasound scan identified a rounded heterogeneous mass measuring 120 × 110 × 104 mm superior to her left kidney. Plasma metanephrine levels were markedly elevated with normetaneprhine at 17,856 pmol/L (reference range is 120 to 1,180 pmol/L), metanephrine >25,000 pmol/L (reference range is 80 to 510 pmol/L), 3-methoxytyramine at 1,393 pmol/L (reference range is 0 to 180 pmol/L). The mass demonstrated marked uptake on an iodine-123-meta-iodobenzylguanidine scan. The patient's hypertension was managed with phenoxybenzamine, and she underwent adrenalectomy. Following surgery, she was able to discontinue all diabetes medications and has maintained a hemoglobin A1c value <48 mmol/mol for over 12 months.
CONCLUSION
The case illustrates that remission of T1DM is possible even after prolonged insulin treatment upon surgical resection of pheochromocytoma. It highlights the potential benefits of reevaluating the diagnostic classification of T1DM in the light of new clinical information.
PubMed: 31967003
DOI: 10.4158/ACCR-2018-0091 -
BMC Veterinary Research Jan 2020Pheochromocytoma (PCC) has poor prognosis and adrenalectomy is hard to be performed, in case of caudal vena cava invasion. The long-term administration of...
BACKGROUND
Pheochromocytoma (PCC) has poor prognosis and adrenalectomy is hard to be performed, in case of caudal vena cava invasion. The long-term administration of phenoxybenzamine in PCC has not been reported in dogs.
CASE PRESENTATION
A 14-year-old castrated male Poodle dog presented with an abdominal mass. On physical examination, hypertension, increased lens opacity, calcinosis cutis, generalized alopecia, and systolic murmur were observed. Serum chemistry and urinalysis profiles revealed hyperglycemia, hypercholesterolemia, elevated liver enzymes, and glucosuria. Abdominal ultrasonography showed a right adrenal mass with invasion of the caudal vena cava, which was cytologically diagnosed as suspected PCC. An adrenal mass (width × height × length, 28 × 26 × 48 mm) was found on computed tomography and diagnosed as PCC with increased plasma metanephrines and normetanephrines. An adrenocorticotropin hormone stimulation test showed elevated adrenal hormones (androstenedione, estradiol, progesterone, and 17-OH progesterone) with normal cortisol, compatible with atypical Cushing's syndrome. The dog was managed with trilostane, phenoxybenzamine, and insulin therapy. Glycosylated hemoglobin and fructosamine levels gradually decreased, and hypertension resolved. In the 10-month follow-up period, the liver enzymes levels gradually decreased, and the clinical signs of the dog were well-controlled without deterioration.
CONCLUSIONS
This case report describes long-term medical management without adrenalectomy of PCC complicated with atypical Cushing's syndrome and DM.
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Animals; Antineoplastic Agents; Cushing Syndrome; Diabetes Mellitus; Dihydrotestosterone; Dog Diseases; Dogs; Hypoglycemic Agents; Insulin; Male; Phenoxybenzamine; Pheochromocytoma; Treatment Outcome
PubMed: 31900158
DOI: 10.1186/s12917-019-2225-x -
Laboratory Investigation; a Journal of... Apr 2020Enterovirus A71 (EV-A71) infection is primarily responsible for fatal hand, foot, and mouth disease (HFMD) cases. Infants and younger children are more likely to suffer...
Enterovirus A71 (EV-A71) infection is primarily responsible for fatal hand, foot, and mouth disease (HFMD) cases. Infants and younger children are more likely to suffer central nervous system damage as a result of EV-A71 infection, but this virus mostly does not affect older children and adults. This study investigated the possible mechanism underlying the age-dependent lethal effect of EV-A71 infection by comparing neonatal and adult mouse models of EV-A71 infection. Although viral proliferation is absent in both neonatal and adult mice, we observed that EV-A71, as a stimulus for astrocytes, elevates the levels of cytokines and monoamine neurotransmitters in neonatal mice. Then, we selected IL-6 and adrenaline as targets in a pharmacological approach to further validate the roles of these factors in mediating the mortality of neonatal mice after EV-A71 infection. Intracerebral injection of IL-6 and adrenaline enhanced the severity of EV-A71 infection, while treatment with an anti-IL-6-neutralizing antibody or the adrenergic-antagonist phenoxybenzamine reversed the lethal effect of EV-A71 in neonatal mice. These results suggest that the central nervous system (CNS) damage in neonatal cases of EV-A71 infection might be caused by an activated fetal cerebral immune response to the virus, including the disruption of brainstem function through increased levels of cytokines and neurotransmitters, rather than the typical cytopathic effect (CPE) of viral infection.
Topics: Aging; Animals; Animals, Newborn; Astrocytes; Brain; Enterovirus A, Human; Enterovirus Infections; Female; Host-Pathogen Interactions; Interleukin-6; Mice; Mice, Inbred ICR; Viral Load
PubMed: 31857694
DOI: 10.1038/s41374-019-0351-5 -
BioMed Research International 2019There is no consensus for the optimum duration of preoperative administration of phenoxybenzamine (PXB) before adrenalectomy for pheochromocytoma. The aim of this study...
The Duration of Preoperative Administration of Single -Receptor Blocker Phenoxybenzamine before Adrenalectomy for Pheochromocytoma: 18 Years of Clinical Experience from Nationwide High-Volume Center.
PURPOSE
There is no consensus for the optimum duration of preoperative administration of phenoxybenzamine (PXB) before adrenalectomy for pheochromocytoma. The aim of this study is to investigate whether perioperative hemodynamics and postoperative outcomes are related to the duration of PXB administration.
METHODS
In total, 102 patients managed preoperatively with single -receptor blocker phenoxybenzamine were enrolled from 469 consecutive patients diagnosed histologically with pheochromocytoma. The patients received surgical treatment in the Department of Urology, Peking University First Hospital, between January 2001 and July 2018. All patients were divided into three groups: Group A (<14 d), Group B (14-30 d), and Group C (>30 d). Patient and tumor characteristics, intraoperative hemodynamics, and postoperative outcomes were recorded and compared among the three groups.
RESULTS
These patients included 47 men and 55 women, with an average age of 43 years at the time of surgery. Clinical characteristics, except the status of preoperative biochemical tests (24 hr urine fractioned catecholamine or plasma-fractioned catecholamine) (=0.020), preoperative hemodynamics, and medicine management and surgical approaches, in the three groups were comparable. Multivariate analyses demonstrated that the size of the tumor (=0.034) was an independent risk factor for intraoperative hemodynamic instability. Among the three groups, we found no significant difference in intraoperative hemodynamics and postoperative outcomes.
CONCLUSION
The data from the current study indicated that the preoperative management of pheochromocytoma with single -receptor blocker PXB for more than 2 weeks, after the final dose adjustment, could not further reduce the risk of intraoperative hemodynamic instability or postoperative complications. Thus, our study supports that 14 days would be enough for the duration of preoperative management of pheochromocytoma with single -receptor blocker PXB in final dose.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adrenergic alpha-Antagonists; Adult; Catecholamines; Female; Hemodynamics; Humans; Male; Phenoxybenzamine; Pheochromocytoma; Postoperative Complications; Preoperative Care
PubMed: 31828097
DOI: 10.1155/2019/2613137