- Revisiting the pharmacodynamics uroselectivity of Alpha1-Adrenergic Receptor Antagonists. [Journal Article]
- JPJ Pharmacol Exp Ther 2019 Jul 08
- α1-adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five FDA-approved α1-AR antagonists (terazosin, doxazos…
α1-adrenoceptor (AR) antagonists are widely used for the relief of urinary retention secondary to benign prostatic hyperplasia (BPH). While the five FDA-approved α1-AR antagonists (terazosin, doxazosin, alfuzosin, tamsulosin and silodosin) share similar efficacy, they differ in tolerability with reports of ejaculatory dysfunction. The aim of the present work was to revisit their α1-AR subtype selectivity as well as of LDT5, a compound previously described as a multi-target antagonist of α1A-/α1D-AR and 5-HT1A receptors, and to estimate their affinity for D2, D3 and 5-HT1A receptors, putatively involved in ejaculatory dysfunction. Competition binding assays were performed with native (D2, 5-HT1A) or transfected (human α1A-, α1B-, α1Dt-AR and D3) receptors for determination of drug's affinities. Tamsulosin and silodosin have the highest affinities for α1A-AR, but only silodosin is clearly a selective α1A-AR antagonist with Ki ratios of 25.3 and 50.2, for the α1D-AR and α1B-AR, respectively. Tamsulosin, silodosin and LDT5, but not terazosin, doxazosin and alfuzosin, have high affinity for the 5-HT1AR (K i around 5-10 nM), behaving as antagonists. We conclude that the uroselectivity of tamsulosin is not explained by its too low selectivity for the α1A- vs. α1B-AR and that its affinity for D2 and D3 receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Present data also support the design of »better-than-LDT5» new multi-target lead compounds with pharmacokinetics selectivity based on poor brain penetration and that could prevent hyperplastic cell proliferation and BPH progression. SIGNIFICANCE STATEMENT: Present work revisits the uroselectivity of the five FDA-approved α1 adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Contrarily to what has been claimed by some, our results indicate that the uroselectivity of tamsulosin is probably not fully explained by its too weak selectivity for the α1A vs. α1B adrenoceptors. We also show that tamsulosin affinity for D3 and 5-HT1A receptors is probably too low for explaining the ejaculatory dysfunction reported for this drug. Based on our lead compound LDT5, present data support the search for a multi-target antagonist of α1A-α1D and 5-HT1A receptors with poor brain penetration as an alternative for BPH treatment.
- [Sustained ventricular tachycardia in a patient with a single ventricle of the heart and a pheochromocytoma]. [Journal Article]
- PEProbl Endokrinol (Mosk) 2019 Jun 30; 65(2):107-112
- A pheochromocytoma is a rare tumor that develops from adrenomedullary chromaffin cells and produce ones or more catecholamines, including adrenaline, norepinephrine, and dopamine. On rare occasions a…
A pheochromocytoma is a rare tumor that develops from adrenomedullary chromaffin cells and produce ones or more catecholamines, including adrenaline, norepinephrine, and dopamine. On rare occasions a pheochromocytoma is hormonally inactive. Cyanotic heart disease is also a relatively rare pathology. One of its least frequently occurring variants is the single ventricle of the heart. Presumably, in patients with cyanotic heart defects, the occurrence of pheochromocytes and paragangliomas will be higher due to the presence of certain germinative and somatic mutations. In cyanotic heart defects, the development of malignant arrythmias is one of the frequent causes of death. A combination of a pheochromocytoma with a single ventricle of the heart is extremely rare: only eight such cases have been described in the literature. This article describes a young patient with a unique case of a single ventricle of the heart, pheochromocytoma and sustained ventricular tachycardia. The cause of the ventricular tachycardia, in all likelihood, was inappropriate medical care - in this case, a prescription for verapamil. The surgical excision of the pheochromocytoma and the referral of the patient for cardiac surgery became possible only after correcting the antihypertensive and antiarrhythmic therapy. Verapamil was replaced with a combination of doxazosin and amiodarone, resulting in relatively satisfactory blood pressure readings and sinus rhythm.
- Structure-based analysis of curcumin and conventionaldrugs targeting tumor-inducing protein PHF20. [Journal Article]
- BBioinformation 2018; 14(9):477-481
- Recently, the PHF20 has been reported as tumor inducer protein by suppressing the activity of tumor suppressor protein p53. Conventional drugs (albendazole, doxazosin, and propranolol) are used for t…
Recently, the PHF20 has been reported as tumor inducer protein by suppressing the activity of tumor suppressor protein p53. Conventional drugs (albendazole, doxazosin, and propranolol) are used for treatment of cancer causing side effect. The secondary metabolite curcumin is employed in various diseases treatment including cancer. The present study is to explore curcumin in comparison to selected conventional drugs by using molecular docking. The online database "Molinspiration online server" detected the physicochemical pharmacokinetics and drug likeness score of curcumin and conventional drugs. Results from Molinspiration online server showed that curcumin did not violate the "Lipinski five rule" for drug. The lead compound for molecular docking exhibited the potential interaction to the active site of PHF20. The resulted binding energy of albendazole and doxazosin were -21.97 and -26.64 respectively. The binding energy (-18.12 kcal/mol) of curcumin was higher than propranolol (17.62 kcal/mol). Thus, curumin has greater potential to interact for further consideration as an anti-cancerous regimen.
- Prostate Transition Zone Fibrosis is Associated with Clinical Progression in the Medical Therapy of Prostatic Symptoms (MTOPS) Study. [Journal Article]
- JUJ Urol 2019 Jun 12; :101097JU0000000000000385
- CONCLUSIONS: Fibrotic changes in the prostate transition zone (TZ) is associated with an increased risk for clinical progression in men treated with doxazosin+finasteride. Anti-fibrotic therapeutics might provide a new treatment approach for men with LUTD who do not respond to current medical treatment approaches.
- Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB. [Journal Article]
- JIJ Immunol Res 2019; 2019:3019794
- Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that H…
Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that HSC express adrenoreceptors (AR), and the use of AR antagonists protects experimental animals from cirrhosis. However, several studies suggest that the toxicity generated by metabolism of these antagonists would hinder its use in cirrhotic patients. In addition, liver fibrosis may be associated with a decrease of the antioxidant response of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and the overregulation of the proinflammatory pathway of nuclear factor kappa B (NF-κB). Therefore, in the present work, the capacity of doxazosin (α1 antagonist), carvedilol (nonselective beta-adrenoceptor blocker with alpha 1-blocking properties), and curcumin (antioxidant and anti-inflammatory compound) to reverse liver cirrhosis and studying the possible modulation of Nrf-2 and NF-κB were evaluated. Hamsters received CCl4 for 20 weeks, and then treatments were immediately administered for 4 weeks more. The individual administration of doxazosin or carvedilol showed less ability to reverse cirrhosis in relation to concomitantly curcumin administration. However, the best effect was the combined effect of doxazosin, carvedilol, and curcumin, reversing liver fibrosis and decreasing the amount of collagen I (Sirius red stain) without affecting the morphology of hepatocytes (hematoxylin and eosin stain), showing normal hepatic function (glucose, albumin, AST, ALT, total bilirubin, and total proteins). In addition, carvedilol treatment and the combination of doxazosin with curcumin increased Nrf-2/NF-κB mRNA ratio and its protein expression in the inflammatory cells in the livers, possibly as another mechanism of hepatoprotection. Therefore, these results suggest for the first time that α/β adrenergic blockers with curcumin completely reverse hepatic damage, possibly as a result of adrenergic antagonism on HSC and conceivably by the increase of Nrf-2/NF-κB mRNA ratio.
- Bilateral pheochromocytoma after kidney transplantation in neurofibromatosis type 1. [Journal Article]
- EDEndocrinol Diabetes Metab Case Rep 2019 May 23; 2019
- We present the case of a 25-year-old male with a history of neurofibromatosis type 1 and bilateral pheochromocytoma 4 years after kidney transplantation that was successfully treated with simultaneou…
We present the case of a 25-year-old male with a history of neurofibromatosis type 1 and bilateral pheochromocytoma 4 years after kidney transplantation that was successfully treated with simultaneous bilateral posterior retroperitoneoscopic adrenalectomy. Learning points: Hypertensive patients with NF1 should always be screened for pheochromocytoma. Pheochromocytoma is rarely associated with transplantation, but it must be ruled out in patients with genetic susceptibility. Posterior retroperitoneoscopic adrenalectomy (PRA) allows more direct access to the adrenal glands, especially in patients with previous abdominal surgeries.
- Effects of doxazosin mesylate versus nifedipine on blood pressure variability in hypertensive patients: a randomized crossover study (SIMILAR). [Journal Article]
- BPBlood Press Monit 2019 May 20
- CONCLUSIONS: Doxazosin mesylate GITS had similar therapeutic effects on BP, BP SD, and BP CV lowering as nifedipine GITS in patients with mild-to-moderate essential hypertension.
- Prospects for pharmacotherapies to treat alcohol use disorder: an update on recent human studies. [Journal Article]
- COCurr Opin Psychiatry 2019; 32(4):255-265
- CONCLUSIONS: There is a critical need to increase the armamentarium of medications for AUD. Human laboratory studies may help screen and prioritize promising targets and compounds before running large clinical trials. Given the complexity of AUD and the heterogeneity of afflicted patients, future studies should also investigate potential moderators and predictors of response to each pharmacological intervention.
- Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy. [Journal Article]
- EDEndocrinol Diabetes Metab Case Rep 2019 May 03; 2019
- Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticost…
Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed. Learning points: Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels. The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing's syndrome, Liddle's syndrome and 11-deoxycorticosterone-producing tumours. DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase. The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.
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- Polytropic Influence of TRIB3 rs2295490 Genetic Polymorphism on Response to Antihypertensive Agents in Patients With Essential Hypertension. [Journal Article]
- FPFront Pharmacol 2019; 10:236
- Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying T…
Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (251, A > G, rs2295490) G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives (6 groups, grouped by atenolol/bisoprolol, celiprolol, doxazosin, azelnidipine/nitrendipine, imidapril, and candesartan/irbesartan) were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3 (251, A > G) genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3 (251, A > G) AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved (P = 0.073 and 0.075, respectively). Against that, we found that TRIB3 (251, A > G) AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change (13 mmHg for the MAP between male and female patients with AA genotype who took ARBs). Although no significant difference in antihypertensive effect between TRIB3 (251, A > G) genotypes in patients treated with α, β-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, β-ADRs. In conclusion, our data supported that TRIB3 (251, A > G) genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.