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Annals of Medicine Dec 2023The sympathetic nervous system and the immune system are responsible for producing neurotransmitters and cytokines that interact by binding to receptors; due to this,... (Review)
Review
The sympathetic nervous system and the immune system are responsible for producing neurotransmitters and cytokines that interact by binding to receptors; due to this, there is communication between these systems. Liver immune cells and nerve fibres are systematically distributed in the liver, and the partial overlap of both patterns may favour interactions between certain elements. Dendritic cells are attached to fibroblasts, and nerve fibres are connected via the dendritic cell-fibroblast complex. Receptors for most neuroactive substances, such as catecholamines, have been discovered on dendritic cells. The sympathetic nervous system regulates hepatic fibrosis through sympathetic fibres and adrenaline from the adrenal glands through the blood. When there is liver damage, the sympathetic nervous system is activated locally and systemically through proinflammatory cytokines that induce the production of epinephrine and norepinephrine. These neurotransmitters bind to cells through α-adrenergic receptors, triggering a cellular response that secretes inflammatory factors that stimulate and activate hepatic stellate cells. Hepatic stellate cells are key in the fibrotic process. They initiate the overproduction of extracellular matrix components in an active state that progresses from fibrosis to liver cirrhosis. It has also been shown that they can be directly activated by norepinephrine. Alpha and beta adrenoblockers, such as carvedilol, prazosin, and doxazosin, have recently been used to reverse CCl-induced liver cirrhosis in rodent and murine models.KEY MESSAGESNeurotransmitters from the sympathetic nervous system activate and increase the proliferation of hepatic stellate cells.Hepatic fibrosis and cirrhosis treatment might depend on neurotransmitter and hepatic nervous system regulation.Strategies to reduce hepatic stellate cell activation and fibrosis are based on experimentation with α-adrenoblockers.
Topics: Mice; Humans; Animals; Hepatic Stellate Cells; Neuroimmunomodulation; Liver Cirrhosis; Liver; Norepinephrine; Fibrosis; Cytokines; Neurotransmitter Agents
PubMed: 36826975
DOI: 10.1080/07853890.2022.2164047 -
Minerva Urology and Nephrology Aug 2023Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and...
BACKGROUND
Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and sexual AEs associated with ABs based on Eudra-Vigilance reported AEs.
METHODS
Eudra-Vigilance (EV) database is the system for managing and analyzing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area (EEA). We recorded the number of sexual and neuro-vascular AEs for tamsulosin, alfuzosin, silodosin, prazosin and doxazosin per category and severity until July 30, 2022. Pooled Relative Risk (PRR) was used to compare data between drugs.
RESULTS
Overall the number of AEs were 2842 for Alfuzosin, 11,086 for tamsulosin, 792 for terazosin, 572 for prazosin and 4641 for doxazosin. Different percentages of AEs were obtained for each drug and in different age groups according to EV sub-groups (≤65, 65-85, ≥85). On PRR analysis, the risk of ejaculatory disorders for Silodosin (11%) is 18.5 times higher (PRR 18.5 95%CI; 10.7-31.8; P<0.05) when compared to alfuzosin and the risk of orthostatic hypotension is 2 times lower (PRR=1,84 95%CI 1.32-2.57; P<0.05).
CONCLUSIONS
Real life data is consistent with registry studies regarding side effects related to alpha-blockers. Alfuzosin is safer in terms of ejaculatory disorders while silodosin and tamsulosin in terms of orthostatic hypotension. Clinicians should consider these data when prescribing ABs especially in younger and older patients.
Topics: Humans; Doxazosin; Tamsulosin; Hypotension, Orthostatic; Adrenergic alpha-Antagonists; Prazosin; Urogenital Diseases
PubMed: 37067186
DOI: 10.23736/S2724-6051.23.05225-4 -
Journal of Experimental & Clinical... Nov 2023Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and...
BACKGROUND
Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC.
METHODS
The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA.
RESULTS
DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44/CD24 subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function.
CONCLUSIONS
Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.
Topics: Humans; Cell Line, Tumor; Cell Proliferation; Doxazosin; ErbB Receptors; Molecular Docking Simulation; Neoplastic Stem Cells; Triple Negative Breast Neoplasms
PubMed: 37924112
DOI: 10.1186/s13046-023-02866-z -
World Journal of Surgical Oncology Jun 2023Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of...
BACKGROUND
Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of catecholamines. Patients may develop cardiovascular complications in the perioperative phase due to the massive release of catecholamines, particularly during anesthetic induction and surgical manipulation of the tumor. The aim of this retrospective study was to evaluate the risk factors involved in perioperative hemodynamic instability in patients who underwent surgery for chromaffin tumors.
METHODS
Forty patients (median age 55 [36.50-64.50]) undergone surgery for PHEO/abdominal PGL from January 2011 to December 2016 at the AOU Careggi (Florence, Italy) were retrospectively evaluated. Systolic, diastolic, and mean blood pressure were considered at baseline and during surgery. Patients with blood pressure steadily < 140/90 mmHg before surgery were considered "adequately prepared". A preoperative therapy with doxazosin, a selective alpha-1 blocker, was started in all patients for at least 14 days prior to the surgery. The presence of hemodynamic instability was reported.
RESULTS
Comparing males and females, a significant difference in doxazosin daily dose (p = 0.018), systolic blood pressure (p = 0.048), and in the proportion of adequately prepared patients (p = 0.031) emerged. A positive correlation between preoperative daily dose of doxazosin, tumor size (B = 0.60, p < 0.001), and urinary normetanephrine levels (B = 0.64, p < 0.001) was also observed. Hemodynamic instability occurred in 30.0% of patients. The absence of adequate preparation (p = 0.012) before surgery, urinary normetanephrine levels (NMNur p = 0.039), and surgery time (minutes) (p = 0.021) resulted as risk factors of hemodynamic instability in our series. The use of intraoperative drugs was higher in patients with hemodynamic instability (p < 0.001). A pre-surgical SBP level of > 133 mmHg (OR = 6 CI95% 1.37-26.20, p = 0.017) and an intraoperative SBP and MBP levels of > 127 mmHg (OR = 28.80 CI95% 2.23-371.0, p = 0.010) and > 90 mmHg (OR = 18.90 CI95% 1.82-196.0, p = 0.014), respectively, were identified as effective thresholds to recognize patients at higher risk of HI.
CONCLUSIONS
A preoperative therapy with alpha-blockers is useful, but not sufficient to avoid surgical risks. Patients with higher pre-surgical levels of NMNur, pre-surgical SBP > 133 mmHg, and/or intraoperative SBP > 127 mmHg and MBP > 90 mmHg, should be carefully monitored. A multidisciplinary approach is indispensable to optimize the management of PHEOs/abdominal PGLs in order to reduce surgical complications.
Topics: Male; Female; Humans; Middle Aged; Pheochromocytoma; Retrospective Studies; Doxazosin; Normetanephrine; Paraganglioma; Hemodynamics; Adrenal Gland Neoplasms; Catecholamines; Vascular Diseases
PubMed: 37370080
DOI: 10.1186/s12957-023-03072-z -
Journal of Clinical Medicine Jun 2023Laparoscopic adrenalectomy (LA), which avoids large abdomen incisions, is considered the gold standard technique for the treatment of benign small- and medium-size... (Review)
Review
BACKGROUND
Laparoscopic adrenalectomy (LA), which avoids large abdomen incisions, is considered the gold standard technique for the treatment of benign small- and medium-size adrenal masses (<6 cm) and weighing < 100 g. A trascurable mortality and morbidity rate, short hospitalization and patient rapid recovery are the main advantages compared to traditional surgery. During the past decade, a new surgical technology has been developed that expedites a "clipless" adrenalectomy. Here, the authors analyze a clinical series of 254 consecutive patients who were affected by adrenal gland neoplasms and underwent LA by the transabdominal lateral approach over the two last decades. A literature review is also presented.
METHODS
Preoperative, intraoperative and postoperative data from 254 patients who underwent LA between January 2003 and December 2022 were retrospectively collected and reviewed. Diagnosis was obtained on the basis of clinical examination, laboratory values and imaging techniques. Doxazosin was preoperatively administered in the case of pheochromocytoma (PCC) while spironolactone and potassium were employed to treat Conn's disease. The same surgeon (CG) performed all the LA and utilized the same laparoscopic transabdominal lateral approach. Different dissection tools-ultrasonic, bipolar or mixed scissors-and hemostatic agents were used during this period. The following results were obtained: 254 patients were included in the study; functioning tumors were diagnosed in 155 patients, 52 patients were affected by PCCs, 55 by Conn's disease, 48 by Cushing's disease. Surgery mean operative time was 137.33 min (range 100-180 min) during the learning curve adrenalectomies and 98.5 min (range 70-180) in subsequent procedures. Mean blood loss was respectively 160.2 mL (range 60-280) and 96.98 mL (range 50-280) in the first 30 procedures and the subsequent ones. Only three conversions (1.18%) to open surgery occurred. No mortality or postoperative major complications were observed, while minor complications occurred in 19 patients (3.54%). In 153 out of 155 functioning neoplasms, LA was effective in the normalization of the endocrine profile. According to our experience, a learning curve consisting of 30 cases was identified. In fact, a lower operative time and a lower complication rate was reported following 30 LA.
CONCLUSIONS
LA is a safe procedure, even for masses larger than 6 cm and PCCs. Undoubtedly, the development of surgical technology has made it possible reducing operative times, performing a "clipless" adrenalectomy and extending the indications in the treatment of more complex patients. A multidisciplinary team, in referral high-volume centers, is recommended in the management of adrenal pathology. A 30-procedure learning curve is necessary to improve surgical outcomes.
PubMed: 37445419
DOI: 10.3390/jcm12134384 -
Brain, Behavior, & Immunity - Health Oct 2023Bile acids have been known to have both beneficial and detrimental effects on heart function, and as a consequence this can affect the brain. Inflammation is a key... (Review)
Review
Bile acids have been known to have both beneficial and detrimental effects on heart function, and as a consequence this can affect the brain. Inflammation is a key factor linking the heart and the brain, bile acids can reduce inflammation in the heart and, as a consequence, neuroinflammation, which may be due to the activation of different peripheral and central cellular and molecular mechanisms. Herein, we compile data published so far and summarise evidence demonstrating the effects of bile acids on myocardial cell viability and function, and its related mechanisms, in and studies conducted in homeostatic state or in models of cardiovascular diseases. Studies show that ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) do not affect the viability or contraction of cardiomyocytes in homeostatic state, and while UDCA has the capability to prevent the effect of hypoxia on reduced cell viability and beating rate, TUDCA can protect endoplasmic reticulum (ER) stress-induced apoptosis and cardiac contractile dysfunction. In contrast, deoxycholic acid (DCA) decreases contraction rate in homeostatic state, but it also prevents hypoxia-induced inflammation and oxidative stress, whereas lithocholic acid (LCA) can rescue doxazosin-induced apoptosis. Moreover, glycodeoxycholic acid (GDCA), cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) and taurodeoxycholic acid (TDCA) decrease contraction, whereas CDCA decreases cell viability in homeostatic conditions. The mechanisms underlying the aforementioned contrasting effects involve a differential regulation of the TGR5, MR and FXR receptors, as well as the cAMP signalling pathway. Overall, this review confirms the therapeutic potential of certain types of bile acids: UDCA, TUDCA, and potentially LCA, in cardiovascular diseases. By reducing inflammation in the heart, bile acids can improve heart-brain communication and promote overall health. Additional investigations are required to better elucidate mechanisms of action and more personalized clinical therapeutic doses.
PubMed: 37593199
DOI: 10.1016/j.bbih.2023.100674 -
ADMET & DMPK 2024Doxazosin mesylate (DOX) is an antihypertensive drug that possesses poor water solubility and, hence, poor release properties. Both nanosuspensions and...
BACKGROUND AND PURPOSE
Doxazosin mesylate (DOX) is an antihypertensive drug that possesses poor water solubility and, hence, poor release properties. Both nanosuspensions and self-nanoemulsifying drug delivery systems (SNEDDS) are becoming nanotechnology techniques for the enhancement of water solubility of different drugs.
EXPERIMENTAL APPROACH
The study's goal was to identify the best drug delivery system able to enhance the release and antihypertensive effect of DOX by comparing the physical characteristics such as particle size, zeta potential, entrapment efficiency, release rate, and main arterial blood pressure of DOX-loaded nanosuspensions and SNEDDS in liquid and solid form.
KEY RESULTS
DOX nanosuspension preparation had a particle size of 385±13 nm, poly-dispersity index of 0.049±3, zeta potential of 50 ± 4 mV and drug release after 20 min (91±0.43 %). Liquid SNEDDS had a droplet size of 224±15 nm, poly-dispersity index of (0.470±0.01), zeta potential of -5±0.10 mV and DR20min of 93±4 %. Solid SEDDS showed particle size of 79±14 nm, poly-dispersity index of 1±0.00, a zeta potential of -18 ±0.26 mv and DR20min of 100 ±2.72 %.
CONCLUSION
Finally, in terms of the mean arterial blood pressure lowering, solid SNEDDS performed better effect than both liquid SNEDDS and nanosuspension ( >0.05).
PubMed: 38560714
DOI: 10.5599/admet.2022 -
Journal of Pharmaceutical and... Jan 2024A number of medical conditions are identified as risk factors for suicide death; in particular, cardiovascular illnesses are recognized as a major suicide risk factor....
A number of medical conditions are identified as risk factors for suicide death; in particular, cardiovascular illnesses are recognized as a major suicide risk factor. In this case, self-poisoning is the common method of suicide and cardiovascular drugs are among the major medications associated with fatal overdose, with calcium channel blockers being one of the most common agents. The present study describes two different fatal suicide cases involving four cardiovascular drugs: carvedilol, doxazosin and amlodipine (case 1) and diltiazem (case 2). The concentrations of the target cardiovascular drugs in the different biological specimens (central and femoral blood, urine, liver, brain) are presented, giving information about the potentially fatal data and the distribution of the drugs in the body. The study led to the implementation of a fast, sensitive and simple method for the detection and quantification of the four commonly prescribed cardiovascular drugs in post-mortem specimens including fluids and tissues for forensic purposes. The method was fully validated. The toxicological results of the studied cases are discussed, along with the autopsy results, histopathological evidence, and circumstances of death. The toxicological findings presented in the study provide new data regarding cardiovascular drugs in different post-mortem specimens, which will contribute to the currently limited knowledge about the toxicological profile of cardiovascular drugs and their distribution.
Topics: Humans; Amlodipine; Diltiazem; Carvedilol; Doxazosin; Cardiovascular Agents; Suicide
PubMed: 37980865
DOI: 10.1016/j.jpba.2023.115831 -
Actas Dermo-sifiliograficas Jan 2024Systemic adverse effects (AE) are a major concern of low-dose oral minoxidil (LDOM) treatment, especially in patients with arterial hypertension or arrhythmia. The...
BACKGROUND AND OBJECTIVE
Systemic adverse effects (AE) are a major concern of low-dose oral minoxidil (LDOM) treatment, especially in patients with arterial hypertension or arrhythmia. The objective of this study was to evaluate the safety of LDOM in patients with hypertension or arrhythmia.
PATIENTS AND METHODS
Retrospective multicenter study of patients with hypertension or arrhythmia treated with LDOM for any type of alopecia.
RESULTS
A total of 254 patients with hypertension [176 women (69.3%) and 78 men (30.7%)] with a mean age of 56.9 years (range 19-82) were included. From them, the dose of LDOM was titrated in 128 patients, allowing the analysis of 382 doses. Patients were receiving a mean of 1.45 (range 0-5) antihypertensive drugs. Systemic AE were detected in 26 cases (6.8%) and included lightheadedness (3.1%), fluid retention (2.6%), general malaise (0.8%), tachycardia (0.8%) and headache (0.5%), leading to LDOM discontinuation in 6 cases (1.5%). Prior treatment with doxazosin (P<0.001), or with three or more antihypertensive drugs (P=0.012) was associated with a higher risk of discontinuation of LDOM.
CONCLUSIONS
LDOM treatment showed a favorable safety profile in patients with hypertension or arrhythmia, similar to general population.
Topics: Male; Humans; Female; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Minoxidil; Antihypertensive Agents; Alopecia; Hypertension; Arrhythmias, Cardiac; Treatment Outcome
PubMed: 37923070
DOI: 10.1016/j.ad.2023.10.033