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Endocrine May 2024Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial... (Observational Study)
Observational Study
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.
Topics: Humans; Doxazosin; Female; Male; Pheochromocytoma; Middle Aged; Adrenal Gland Neoplasms; Retrospective Studies; Paraganglioma; Adult; Aged; alpha-Methyltyrosine; Adrenergic alpha-1 Receptor Antagonists; Drug Therapy, Combination; Preoperative Care; Treatment Outcome
PubMed: 38206436
DOI: 10.1007/s12020-023-03681-4 -
Nutrients Dec 2023Deoxycholic acid (DCA) is a secondary bile acid produced by gut bacteria. Elevated serum concentrations of DCA are observed in cardiovascular disease (CVD). We...
BACKGROUND
Deoxycholic acid (DCA) is a secondary bile acid produced by gut bacteria. Elevated serum concentrations of DCA are observed in cardiovascular disease (CVD). We hypothesized that DCA might influence hemodynamic parameters in rats.
METHODS
The concentration of DCA in systemic blood was measured with liquid chromatography coupled with mass spectrometry. Arterial blood pressure (BP), heart rate (HR) and echocardiographic parameters were evaluated in anesthetized, male, 3-4-month-old Sprague-Dawley rats administered intravenously (IV) or intracerebroventricularly (ICV) with investigated compounds. Mesenteric artery (MA) reactivity was tested ex vivo.
RESULTS
The baseline plasma concentration of DCA was 0.24 ± 0.03 mg/L. The oral antibiotic treatment produced a large decrease in the concentration. Administered IV, the compound increased BP and HR in a dose-dependent manner. DCA also increased heart contractility and cardiac output. None of the tested compounds-prazosin (an alpha-blocker), propranolol (beta-adrenolytic), atropine (muscarinic receptor antagonist), glibenclamide (K-ATP inhibitor) or DY 268 (FXR antagonist), glycyrrhetinic acid (11HSD2 inhibitor)-significantly diminished the DCA-induced pressor effect. ICV infusion did not exert significant HR or BP changes. DCA relaxed MAs. Systemic vascular resistance did not change significantly.
CONCLUSIONS
DCA elevates BP primarily by augmenting cardiac output. As a metabolite derived from gut bacteria, DCA potentially serves as a mediator in the interaction between the gut microbiota and the host's circulatory system.
Topics: Male; Rats; Animals; Blood Pressure; Rats, Sprague-Dawley; Cardiac Output; Bile Acids and Salts; Deoxycholic Acid
PubMed: 38201862
DOI: 10.3390/nu16010032 -
The Korean Journal of Pain Jan 2024Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of...
BACKGROUND
Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity.
METHODS
Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/K pathway in the antinociceptive effect of sitagliptin (5 mg/kg).
RESULTS
Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly ( < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect.
CONCLUSIONS
NO/cGMP/K, 5HT and D pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.
PubMed: 38123184
DOI: 10.3344/kjp.23262 -
Heliyon Dec 2023To determine the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma through QuEChERS pre-treatment combined with...
To determine the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma through QuEChERS pre-treatment combined with ultra-performance liquid chromatography-tandem mass spectrometry. Plasma samples were extracted with 3 mL of acetonitrile, 400 mg of anhydrous magnesium sulfate as a salting agent, and 20 mg of C18 as a sorbent. An Agilent Poroshell 120 EC-C18 column (4.6 × 100 mm, 2.7 μm) was selected and methanol-0.1 % water was used as the mobile phase, and ESI positive ion detection mode was selected. Results: The plasma concentrations of nisoldipine, metoprolol, and prazosin exhibited good linearity within the range of 0.05-4.0 ng/mL (r > 0.99), while atenolol, bisoprolol, propranolol, rosuvastatin, and atorvastatin showed linearity within the range of 0.5-40 ng/mL (r > 0.99). Fluvastatin showed good linearity within the range of 5.0-400 ng/mL. The accuracy of the method ranged from 94.15 to 110.62 %, while the recovery levels were in the range of 85.23 %-115.13 %. The matrix effects were observed between-6.54 % and 12.43 %. The intra-day and inter-day RSD was <15 % for the three concentrations of low, medium, and high. Conclusion The proposed method is rapid, accurate, specific, simple, reproducible, and suitable for the simultaneous measurement of the concentrations of nine drugs used in the treatment of cardiovascular diseases in human plasma.
PubMed: 38094060
DOI: 10.1016/j.heliyon.2023.e22543 -
International Journal of Molecular... Nov 2023In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (-) was designed....
In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (-) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds -. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α-adrenergic receptors (α-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α and α, was conducted. Selected compounds were tested for their activity towards two α-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds ( and ), which possess o-methoxyphenylpiperazine fragments, strong activity (IC < 100 nM) was observed. Some representatives ( and ), which contain alkyl linker, proved selectivity towards α-AR, while two compounds with 2-hydroxypropyl linker ( and ) to α-AR. Finally, hypotensive activity was examined in rats. The most active compound () proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.
Topics: Rats; Animals; Prazosin; Antihypertensive Agents; Radioligand Assay; Receptors, Adrenergic, alpha-1; Hypotension; Adrenergic alpha-1 Receptor Antagonists
PubMed: 38068933
DOI: 10.3390/ijms242316609 -
AACE Clinical Case Reports 2023Documented symptomatic progression of a paraganglioma (PGL) over many years is unusual. Our objective is to report a young man with such an occurrence.
BACKGROUND
Documented symptomatic progression of a paraganglioma (PGL) over many years is unusual. Our objective is to report a young man with such an occurrence.
CASE REPORT
A 27-year-old male presented with headache, sweating, and palpitation. He had a history of cyanotic congenital heart disease. Five years before presentation, he had 24-hour urine metanephrines 43 mcg/d (25-222), vanillylmandelic acid 3 mg/d (<6), and homovanillic acid 2.4 mg/d (1.6-7.5) levels and a 3.13 cm mass in the upper aortocaval space. Subsequent imaging showed slow growth of the mass. On admission, his blood pressure was 197/134 mm Hg, heart rate was 163 beats per minute, respiratory rate was 25 per minute, and oxygen saturation was 76% on room air. His 24-hour urine normetanephrine level was 2644 mcg/d (81-667) while metanephrine was 405 mcg/d (55-320). Plasma free metanephrine level was 0.92 nmol/L (0-0.49) and normetanephrine was 11.85 nmol/L (0-0.89). DOTATATE positron emission tomography-computed tomography revealed a 4.3 × 3.1 × 4.9 cm mass with activity in the right upper aortocaval space. He was treated with Prazosin. Two months later, he underwent resection of the mass. Pathology diagnosed a 4.9 cm PGL. He had improvement in metanephrine levels.
DISCUSSION
PGL is diagnosed by documenting excess catecholamines and identifying a lesion on imaging. False negative laboratory testing is rare but can occur. Patients with cyanotic congenital heart disease have a greater risk of developing PGL.
CONCLUSION
It is crucial to evaluate a patient for PGL if clinical conditions suggest catecholamine excess, especially if a retroperitoneal tumor has grown or the patient has risk factors.
PubMed: 38045797
DOI: 10.1016/j.aace.2023.09.003 -
Journal of Ethnopharmacology Mar 2024Melissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this...
ETHNOPHARMACOLOGICAL RELEVANCE
Melissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain.
AIM OF THE STUDY
To assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (K) mechanisms in its anti-nociceptive effects.
MATERIAL AND METHODS
We employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1-, α2- and β-adrenergic, potassium adenosine triphosphate (K), opioidergic and serotonergic systems, respectively.
RESULTS
MO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception.
CONCLUSIONS
MO contains biologically active compounds with potential anti-nociceptive properties that modulate K opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents.
Topics: Rats; Animals; Oils, Volatile; Melissa; Plant Extracts; Chronic Pain; Metergoline; Plants, Medicinal; Formaldehyde; Yohimbine; Adrenergic Agents; Acetates; Adenosine Triphosphate; Naloxone; Potassium; Prazosin
PubMed: 38030022
DOI: 10.1016/j.jep.2023.117500 -
Frontiers in Cell and Developmental... 2023Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this...
Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this process by promoting the intravascular migration of endothelial cells in developing networks, such as in the yolk sac, zebrafish brain or postnatal mouse retina. In this study, we have implemented innovative tools to recognize capillary pruning in the complex 3D coronary microvasculature of the postnatal mouse heart. We have also experimentally tested the impact of decreasing pruning on the structure and function of this network by altering blood flow with two different vasodilators: losartan and prazosin. Although both drugs reduced capillary pruning, a combination of experiments based on imaging, proteomics, electron microscopy and functional approaches showed that losartan treatment resulted in an inefficient coronary network, reduced myocardial oxygenation and metabolic changes that delayed the arrest of cardiomyocyte proliferation, in contrast to the effects of prazosin, probably due to its concomitant promotion of capillary expansion. Our work demonstrates that capillary pruning contributes to proper maturation and function of the heart and that manipulation of blood flow may be a novel strategy to refine the microvasculature and improve tissue perfusion after damage.
PubMed: 38020883
DOI: 10.3389/fcell.2023.1256127 -
Metabolites Nov 2023Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors...
Manifestations of Liver Impairment and the Effects of MH-76, a Non-Quinazoline α1-Adrenoceptor Antagonist, and Prazosin on Liver Tissue in Fructose-Induced Metabolic Syndrome.
Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors antagonists are antihypertensive agents that exert mild beneficial effects on the metabolic profile in hypertensive patients. However, they are no longer used as a first-line therapy for hypertension based on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) outcomes. Later studies have shown that quinazoline-based α1-adrenolytics (prazosin, doxazosin) induce apoptosis; however, this effect was independent of α1-adrenoceptor blockade and was associated with the presence of quinazoline moiety. Recent studies showed that α1-adrenoceptors antagonists may reduce mortality in COVID-19 patients due to anti-inflammatory properties. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted anti-inflammatory, antihypertensive properties and reduced insulin resistance and visceral adiposity. In this study, we aimed to evaluate the effect of fructose consumption and treatment with α1-adrenoceptor antagonists of different classes (MH-76 and prazosin) on liver tissue of fructose-fed rats. Livers were collected from four groups (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical and histopathological studies. Both α1-adrenolytics reduced macrovesicular steatosis and triglycerides content of liver tissue and improved its antioxidant capacity. Treatment with MH-76, contrary to prazosin, reduced leucocytes infiltration as well as decreased elevated IL-6 and leptin concentrations. Moreover, the MH-76 hepatotoxicity in hepatoma HepG2 cells was less than that of prazosin. The use of α1-adrenolytics with anti-inflammatory properties may be an interesting option for treatment of hypertension with metabolic complications.
PubMed: 37999226
DOI: 10.3390/metabo13111130 -
Georgian Medical News Sep 2023The aim of this study was to evaluate current approaches to the pharmacotherapy of posttraumatic stress disorder. An information search was carried out in the databases...
The aim of this study was to evaluate current approaches to the pharmacotherapy of posttraumatic stress disorder. An information search was carried out in the databases PubMed, Ovid, EMBASE by keywords: "posttraumatic stress disorder", "treatment", and "medications". Search depth 2012-2022 years. From the general data (4877 articles) there were selected 14 articles with the highest degree of relevance. A content analysis of selected articles was carried out with the formation of recommendations for the use of pharmacotherapy in posttraumatic stress disorder. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Antidepressants (SSRI SNRIs) are primarily considered as first-line drugs, but only sertraline, paroxetine, and fluoxetine are approved by the FDA. But these drugs have a fairly wide range of side effects, including suicidal thoughts. The use of benzodiazepines should be limited as they increase the risk of developing posttraumatic stress disorder. Vortioxetine becomes a very promising option. The most significant benefits of vortioxetine are the significant positive effects of vortioxetine on attention, memory, and executive function. There is some evidence for the use of alpha-1 adrenoceptor antagonists and alpha-2 adrenoceptor agonists in therapy. In insomnia the use of prazosin and trazodone is recommended. Pharmacotherapy of posttraumatic stress disorder requires administration of medications with multimodal action. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Further randomized clinical trials are necessary for developing effective treatment of posttraumatic stress disorder.
Topics: Humans; Antidepressive Agents; Receptors, Adrenergic; Stress Disorders, Post-Traumatic; Vortioxetine
PubMed: 37991966
DOI: No ID Found