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1.
Endocrine ; 74(3): 676-684, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34373995

RESUMO

PURPOSE: To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery. METHODS: A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale. RESULTS: One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P = 0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2 ± 11.16 vs 6.2 ± 6.82, P < 0.001) than those treated with doxazosin. Hypertension resolution was observed in 78.7% and biochemical cure in 96.6% of the patients. Thirty-one patients (19.1%) had postsurgical complications. Prolonged hypotension was the most common, in 9.9% (n = 16), followed by hypoglycaemia in six patients and acute renal failure in four patients. 13.0% of complications had a score ≥3 in the Clavien-Dindo scale. Postsurgical complications were more common in patients with diabetes, cerebrovascular disease, higher plasma glucose levels, higher urinary free metanephrine and norepinephrine, and with pheochromocytomas larger than 5 cm. CONCLUSION: Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications.


Assuntos
Neoplasias das Glândulas Suprarrenais , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/cirurgia , Humanos , Fenoxibenzamina/uso terapêutico , Feocromocitoma/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
2.
J Pharm Biomed Anal ; 191: 113618, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32942108

RESUMO

The current United States Pharmacopeia-National Formulary (USP-NF) and the British Pharmacopoeia phenoxybenzamine (PBA) hydrochloride drug substance and drug product monographs describe an HPLC procedure for the determination of a specified impurity "tertiary amine phenoxybenzamine" and use the resolution of an "unknown related substance" from PBA as a system suitability criterion; however, neither structural information of the "unknown related substance" is provided nor reference standards of the two impurities are available. The ambiguity in pharmacopeias poses difficulties in implementing the procedure for quality control. To clarify the degradation pathways, and incorporate the impurity profile of PBA into the USP monographs, the degradation of PBA was revisited. PBA undergoes rapid degradation in neutral or basic aqueous solutions to generate the "tertiary amine phenoxybenzamine" as the predominant degradation product, which was confirmed as phenoxybenzamine hydroxide (PBA-OH). In addition, the "unknown related substance" was proposed as the phenoxybenzamine nitrile (PBA-CN) on the basis of LC-MS studies. The identity of PBA-CN was unambiguously verified via chemical synthesis, HPLC and NMR analyses. A stability-indicating method was developed and validated for the determination of PBA and its impurities, and was used to support USP monograph modernization.


Assuntos
Contaminação de Medicamentos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Espectrometria de Massas , Fenoxibenzamina
4.
J Sep Sci ; 43(11): 2209-2216, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32160391

RESUMO

Inspired by the distinct chemical and physical properties of nanoparticles, here a novel open-tubular capillary electrochromatography column was prepared by electrostatic assembly of poly(diallydimethylammonium chloride) onto the inner surface of a fused-silica capillary, followed by self-adsorption of negatively charged SH-ß-cyclodextrin/gold nanoparticles. The formation of the SH-ß-cyclodextrin/gold nanoparticles coated capillary was confirmed and characterized by scanning electron microscopy and energy dispersive spectrometry. The results of scanning electron microscopy and energy dispersive spectrometry studies indicated that SH-ß-cyclodextrin/gold nanoparticles were successfully coated on the inner wall of the capillary column. The performance of the SH-ß-cyclodextrin/gold nanoparticles coated capillary was validated by the analysis of six pairs of chiral drugs, namely zopiclone, carvedilol, salbutamol, terbutaline sulfate, phenoxybenzamine hydrochloride, and ibuprofen. Satisfactory enantioseparation results were achieved, confirming the use of gold nanoparticles as the support could enhance the phase ratio of the open-tubular capillary column. Additionally, the stability and reproducibility of the SH-ß-cyclodextrin/gold nanoparticles coated capillary column were also investigated. Then, this proposed method was well validated with good linearity (≥0.999), recovery (90.0-93.5%) and repeatability, and was successfully used for enantioseparation of ibuprofen in spiked plasma samples, which indicated the new column's potential usage in biological analysis.


Assuntos
Eletrocromatografia Capilar , Ouro/química , Nanopartículas Metálicas/química , beta-Ciclodextrinas/química , Albuterol/química , Albuterol/isolamento & purificação , Compostos Azabicíclicos/química , Compostos Azabicíclicos/isolamento & purificação , Carvedilol/química , Carvedilol/isolamento & purificação , Ibuprofeno/química , Ibuprofeno/isolamento & purificação , Fenoxibenzamina/química , Fenoxibenzamina/isolamento & purificação , Piperazinas/química , Piperazinas/isolamento & purificação , Estereoisomerismo , Terbutalina/química , Terbutalina/isolamento & purificação
5.
BMC Vet Res ; 16(1): 35, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014021

RESUMO

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.


Assuntos
Neoplasias das Glândulas Suprarrenais/veterinária , Síndrome de Cushing/veterinária , Doenças do Cão/diagnóstico , Feocromocitoma/veterinária , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia/veterinária , Animais , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiologia , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/uso terapêutico , Doenças do Cão/etiologia , Doenças do Cão/terapia , Cães , Masculino , Fenoxibenzamina/uso terapêutico , Feocromocitoma/complicações , Feocromocitoma/diagnóstico
6.
BMC Vet Res ; 16(1): 3, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900158

RESUMO

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 mm3) 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.


Assuntos
Neoplasias das Glândulas Suprarrenais/veterinária , Doenças do Cão/diagnóstico , Feocromocitoma/veterinária , Neoplasias das Glândulas Suprarrenais/diagnóstico , Antagonistas Adrenérgicos alfa/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Síndrome de Cushing , Diabetes Mellitus/tratamento farmacológico , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Fenoxibenzamina/uso terapêutico , Feocromocitoma/diagnóstico , Feocromocitoma/tratamento farmacológico , Resultado do Tratamento
7.
J Clin Endocrinol Metab ; 105(7)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31714582

RESUMO

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with nonmetastatic PPGL. INTERVENTION: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.


Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Antagonistas Adrenérgicos alfa/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Feocromocitoma/cirurgia , Antagonistas Adrenérgicos alfa/administração & dosagem , Doxazossina/administração & dosagem , Doxazossina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenoxibenzamina/administração & dosagem , Fenoxibenzamina/uso terapêutico , Resultado do Tratamento
8.
Biomed Res Int ; 2019: 2613137, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828097

RESUMO

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 α-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) (p=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 (p=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 α-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 α-receptor blocker PXB in final dose.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Antagonistas Adrenérgicos alfa/uso terapêutico , Fenoxibenzamina/uso terapêutico , Feocromocitoma/tratamento farmacológico , Adrenalectomia/métodos , Adulto , Catecolaminas/uso terapêutico , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios
9.
J Vet Intern Med ; 33(5): 2117-2123, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400046

RESUMO

BACKGROUND: Urethral obstruction (UO) is a common complication of feline idiopathic cystitis (FIC). Robust treatment recommendations to prevent its recurrence are scarce. OBJECTIVES: To evaluate meloxicam treatment for prevention of clinical recrudescence in male cats with obstructive FIC. ANIMALS: Fifty-one client-owned cats. METHODS: Prospective, randomized clinical trial. Every male cat with FIC-associated UO was deemed eligible for the study and was recruited during hospitalization. After discharge, cats were treated with phenoxybenzamine and alprazolam for 2 weeks, with (24 cats) or without (27 cats) low-dose meloxicam (0.025 mg/kg/day PO) and monitored for 6 months. RESULTS: Cumulative number (%) of cats with recurrent UO at 10 days, 1-, 2-, and 6-months after discharge was 1 (2%), 2 (4%), 4 (8%), and 8 (16%), respectively. Overall, 12 (24%) cats experienced signs of recurrent FIC within 6 months, with (8 cats) or without (4 cats) concurrent UO. No difference in the cumulative incidence of UO within 6 months was detected with addition of meloxicam (odds ratio [95% confidence interval], 0.63 [0.13-2.97]; P = .70). All cats were alive at 6 months. CONCLUSIONS AND CLINICAL IMPORTANCE: No clinical benefit was detected with the addition of low-dose meloxicam to phenoxybenzamine and alprazolam treatment for 2 weeks after discharge. Nevertheless, this study was underpowered to identify potential differences, and its findings must be corroborated in larger studies.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças do Gato/prevenção & controle , Cistite/veterinária , Meloxicam/uso terapêutico , Obstrução Uretral/veterinária , Antagonistas Adrenérgicos alfa/uso terapêutico , Alprazolam/uso terapêutico , Animais , Doenças do Gato/tratamento farmacológico , Gatos , Protocolos Clínicos , Cistite/tratamento farmacológico , Cistite/prevenção & controle , Hipnóticos e Sedativos/uso terapêutico , Masculino , Fenoxibenzamina/uso terapêutico , Estudos Prospectivos , Recidiva , Obstrução Uretral/tratamento farmacológico , Obstrução Uretral/prevenção & controle
10.
J Recept Signal Transduct Res ; 39(2): 106-113, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31322035

RESUMO

Context: Drugs such as positive allosteric modulators (PAMs) produce complex behaviors when acting on tissues in different physiological contexts in vivo. Objective: This study describes the use of functional assays of varying receptor sensitivity to unveil the various behaviors of PAMs and thus quantify allosteric effect through system independent scales. Materials and methods: Muscarinic receptor activation with acetylcholine (ACh) was used to the demonstrate activity of the PAM agonist 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, Benzyl quinolone carboxylic acid (BQCA) in terms of direct agonism, potentiation of ACh affinity, and ACh efficacy. Concentration-response curves were fit to the functional allosteric model to yield indices of agonism (τB), effects on affinity (α cooperativity), and efficacy (ß cooperativity). Results: It is shown that a highly sensitive functional assay revealed the direct efficacy of BQCA as an agonist and relatively insensitive cells (produced by chemical alkylation of muscarinic receptor with phenoxybenzamine) revealed a positive allosteric effect of BQCA on ACh efficacy. A wide range of functional assay sensitivities produced a complex pattern of behavior for BQCA all of which was accurately quantified through the system-independent parameters of the functional allosteric model. Conclusions: The study of complex allosteric molecules in a range of functional assays of varying sensitivity allows the measurement of the complete array of activities of these molecules on receptors and also better predicts which will be seen with these in vivo where a range of tissue sensitivities is encountered.


Assuntos
Acetilcolina/química , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/química , Agonistas Muscarínicos/química , Quinolinas/química , Receptor Muscarínico M1/química , Acetilcolina/agonistas , Regulação Alostérica/efeitos dos fármacos , Animais , Células CHO , Cricetinae , Cricetulus , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Agonistas Muscarínicos/farmacologia , Fenoxibenzamina/química , Fenoxibenzamina/farmacologia , Quinolinas/farmacologia , Receptor Muscarínico M1/agonistas , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 29(13): 1605-1608, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31053508

RESUMO

Histone deacetylase (HDAC) inhibitors as an important epigenetic therapeutic strategy affect signaling networks and act synergistically with kinase inhibitors for the treatment of cancer. Herein we presented a series of novel phenoxybenzamide analogues with inhibition of Raf and HDAC. Among them, compound 10e showed potent antiproliferative activities against Hepg2 and MDA-MB-468 in cellular assays. This work may lay the foundation for developing novel dual Raf/HDAC inhibitors as potential anticancer therapeutics.


Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Fenoxibenzamina/análogos & derivados , Inibidores de Histona Desacetilases/farmacologia , Humanos , Relação Estrutura-Atividade
14.
Protein Cell ; 10(3): 178-195, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29542010

RESUMO

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HT2AR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HT2AR and clinically available 5-HT2AR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process. The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1). Moreover, phenoxybenzamine (PBZ), an FDA-approved 5-HT2AR antagonist, inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs. The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice. Our results not only expand the understanding of HCV entry, but also present a promising target for the invention of HCV entry inhibitor.


Assuntos
Hepacivirus/fisiologia , Hepatite C/virologia , Fenoxibenzamina/farmacologia , Receptor 5-HT2A de Serotonina/fisiologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Internalização do Vírus , Animais , Antivirais/farmacologia , Claudina-1/metabolismo , Células HEK293 , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Camundongos , Fenoxibenzamina/uso terapêutico , Receptor 5-HT2A de Serotonina/genética , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Internalização do Vírus/efeitos dos fármacos
18.
Br J Pharmacol ; 175(16): 3394-3406, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29859008

RESUMO

BACKGROUND AND PURPOSE: Development of combination therapies has received significant interest in recent years. Previously, a two-receptor one-transducer (2R-1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R-1T model to characterize the interaction of noradrenaline and arginine-vasopressin on vasoconstriction and performed inter-species scaling to humans using this mechanism-based model. EXPERIMENTAL APPROACH: Contractile data were obtained from in vitro rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine-vasopressin with or without pretreatment with the irreversible α-adrenoceptor antagonist, phenoxybenzamine. Data were analysed using the 2R-1T model to characterize the observed exposure-response relationships and drug-drug interaction. The model was then scaled to humans by accounting for differences in receptor density. KEY RESULTS: With receptor affinities set to published values, the 2R-1T model satisfactorily characterized the interaction between noradrenaline and arginine-vasopressin in rat small mesenteric arteries (relative standard error ≤20%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries. CONCLUSIONS AND IMPLICATIONS: The 2R-1T model can be of relevance to quantitatively characterize the interaction between two drugs that interact via different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments.


Assuntos
Arginina Vasopressina/farmacologia , Modelos Biológicos , Norepinefrina/farmacologia , Vasoconstrição/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Interações Medicamentosas , Humanos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Fenoxibenzamina/farmacologia , Ratos Wistar , Artéria Renal/efeitos dos fármacos , Artéria Renal/fisiologia , Biologia de Sistemas
19.
PLoS One ; 13(6): e0198514, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29897996

RESUMO

The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several "off label" indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact that certain types of neuropathic pain, in particular complex regional pain syndrome, demonstrate a proliferative nature, with the capacity to spread from an injured limb, for example, to a non-injured limb and perhaps to essentially the entire body. Sensory neuronal sprouting in the spinal cord has been observed under conditions where there is a high sensory input from painful stimuli. Searches of gene expression signatures in the BroadBuild02 Molecular Signature Database using their connectivity map software suggested that phenoxybenzamine may have histone deacetylase inhibitory activity. Studies by others have reported inhibitory effects of phenoxybenzamine on growth, invasion and migration of human tumor cell cultures and, in one study, inhibition of tumor expansion in animal experiments. Inhibitory effects on human tumor cell cultures are also reported in the present study. Phenoxybenzamine was also found to have histone deacetylase inhibitory activity; histone deacetylase isoforms 5, 6, and 9 were the most sensitive to inhibition by phenoxybenzamine. The importance of elevated levels of these isoforms as biomarkers of poor prognosis in human malignant disease, and the recognized suppression of tumor growth that may accrue from their inhibition, opens consideration of possible translation of phenoxybenzamine to new clinical applications. This might be facilitated by the fact that phenoxybenzamine is already an approved drug entity. There appears to be no previous report of the activity of phenoxybenzamine as a histone deacetylase inhibitor.


Assuntos
Antineoplásicos/metabolismo , Histona Desacetilases/metabolismo , Fenoxibenzamina/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Bases de Dados Factuais , Histona Desacetilases/química , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Neoplasias , Fenoxibenzamina/química , Fenoxibenzamina/farmacologia
20.
Medicine (Baltimore) ; 97(19): e0614, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29742697

RESUMO

RATIONALE: Malignant pheochromocytoma is a rare disease and surgical resection is the only curative treatment. PATIENT CONCERNS: An 81-year-old man of Chinese ethnicity was found to have a giant retroperitoneal tumor. DIAGNOSES: B-scan ultrasonography and CT scan presented a mass above the left kidney, measuring 13.5 × 10 .6 × 9.8 cm. Subsequent analysis of 24-h urinary catecholamines and vanillylmandelic acid, as well as of blood catecholamines and blood cortisol, showed no elevated levels. INTERVENTIONS: The patient was treated with surgery. OUTCOMES: The result from immunohistochemical staining confirmed the presence of malignant pheochromocytoma. After three months follow-up, the blood pressure and serum potassium were all within normal limits, no post-operative complications, no tumor recurrence and metastasis were found. LESSONS: This is the oldest patient known to have histologic documentation of this disease. Giant malignant pheochromocytomas are rare entities requiring clinical suspicion coupled with strategic diagnostic evaluation to confirm the diagnosis, personalized therapeutic treatment is required, particularly among elderly population.


Assuntos
Neoplasias das Glândulas Suprarrenais , Adrenalectomia/métodos , Hipertensão , Complicações Intraoperatórias/prevenção & controle , Fenoxibenzamina/administração & dosagem , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/fisiopatologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Idoso de 80 Anos ou mais , Humanos , Hipertensão/diagnóstico , Hipertensão/etiologia , Hipertensão/prevenção & controle , Masculino , Estadiamento de Neoplasias , Duração da Cirurgia , Feocromocitoma/complicações , Feocromocitoma/patologia , Feocromocitoma/fisiopatologia , Feocromocitoma/cirurgia , Cuidados Pré-Operatórios/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Carga Tumoral , Ultrassonografia/métodos , Vasodilatadores/administração & dosagem
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