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Clinical Drug Investigation Sep 2015Phenylephrine HCl 10 mg has been used as a nasal decongestant for over 50 years, yet only limited pharmacokinetic and metabolic data are available. The purpose of this... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Phenylephrine HCl 10 mg has been used as a nasal decongestant for over 50 years, yet only limited pharmacokinetic and metabolic data are available. The purpose of this study was to evaluate single-dose pharmacokinetics and safety of phenylephrine HCl 10, 20, and 30 mg and to assess cardiovascular tolerability compared with baseline and placebo in healthy volunteers.
METHODS
Twenty-eight adults were enrolled in this randomized, double-blind, placebo-controlled, single-dose, four-treatment crossover study. Subjects remained housed for 6 days to permit time-matched, serial measurements of pulse, blood pressure, and electrocardiograms (ECGs) for baseline and complete treatments on consecutive days. After fasting overnight, subjects were dosed with oral phenylephrine HCl 10, 20, or 30 mg or placebo. Pharmacokinetic blood samples were collected over 7 h, whereas pulse, blood pressure, and ECGs were measured over 12 h. Urine was collected over each 24-h period to quantify phenylephrine and metabolites.
RESULTS
After oral administration, phenylephrine was rapidly absorbed with median times to maximum plasma concentrations (t max) from 0.33 to 0.5 h. For phenylephrine HCl 10, 20, and 30 mg, the mean (standard deviation) maximum concentration (C max) was 1354 (954), 2959 (2122), and 4492 (1978) pg/mL, and total systemic exposure [area under the plasma concentration-time curve from time zero to infinity (AUC∞)] was 955.8 (278.5), 2346 (983.8), and 3900 (1764) pg·h/mL, respectively. Both parameters increased disproportionally with increasing dose, as β >1 in the power model. Negligible amounts of phenylephrine and phenylephrine glucuronide were excreted in urine. With increasing dose, percentages by dose of phenylephrine sulfate decreased, whereas percentages of 3-hydroxymandelic acid increased. Eight subjects reported nine mild adverse events; one (somnolence) was deemed to be treatment related. Means of time-matched differences in pulse and blood pressure from baseline showed similar fluctuations over 12 h among phenylephrine HCl doses and placebo, although small differences in systolic pressure were observed during the initial 2 h. No apparent dose-related effects were observed for Fridericia-corrected QT interval (QTcF) values, and individual changes from time-matched baseline (DQTcF).
CONCLUSIONS
Maximum and total systemic exposures following singe doses of phenylephrine HCl 10, 20, and 30 mg increased disproportionally with increasing dose. Safety and cardiovascular tolerability were comparable among doses and placebo.
Topics: Administration, Oral; Adult; Area Under Curve; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Phenylephrine; Pilot Projects
PubMed: 26267590
DOI: 10.1007/s40261-015-0311-9 -
Anesthesiology Sep 2009Use of ephedrine in obstetric patients is associated with depression of fetal acid-base status. The authors hypothesized that the mechanism underlying this is transfer... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Use of ephedrine in obstetric patients is associated with depression of fetal acid-base status. The authors hypothesized that the mechanism underlying this is transfer of ephedrine across the placenta and stimulation of metabolism in the fetus.
METHODS
A total of 104 women having elective Cesarean delivery under spinal anesthesia randomly received infusion of phenylephrine (100 microg/ml) or ephedrine (8 mg/ml) titrated to maintain systolic blood pressure near baseline. At delivery, maternal arterial, umbilical arterial, and umbilical venous blood samples were taken for measurement of blood gases and plasma concentrations of phenylephrine, ephedrine, lactate, glucose, epinephrine, and norepinephrine.
RESULTS
In the ephedrine group, umbilical arterial and umbilical venous pH and base excess were lower, whereas umbilical arterial and umbilical venous plasma concentrations of lactate, glucose, epinephrine, and norepinephrine were greater. Umbilical arterial Pco2 and umbilical venous Po2 were greater in the ephedrine group. Placental transfer was greater for ephedrine (median umbilical venous/maternal arterial plasma concentration ratio 1.13 vs. 0.17). The umbilical arterial/umbilical venous plasma concentration ratio was greater for ephedrine (median 0.83 vs. 0.71).
CONCLUSIONS
Ephedrine crosses the placenta to a greater extent and undergoes less early metabolism and/or redistribution in the fetus compared with phenylephrine. The associated increased fetal concentrations of lactate, glucose, and catecholamines support the hypothesis that depression of fetal pH and base excess with ephedrine is related to metabolic effects secondary to stimulation of fetal beta-adrenergic receptors. Despite historical evidence suggesting uteroplacental blood flow may be better maintained with ephedrine, the overall effect of the vasopressors on fetal oxygen supply and demand balance may favor phenylephrine.
Topics: Adult; Anesthesia, Spinal; Apgar Score; Biomarkers; Blood Gas Analysis; Blood Glucose; Cesarean Section; Double-Blind Method; Ephedrine; Female; Fetus; Fluid Therapy; Hemodynamics; Humans; Infant, Newborn; Lactic Acid; Maternal-Fetal Exchange; Phenylephrine; Pregnancy; Vasoconstrictor Agents
PubMed: 19672175
DOI: 10.1097/ALN.0b013e3181b160a3 -
American Journal of Veterinary Research Jun 2012To determine cardiopulmonary effects of incremental doses of dopamine and phenylephrine during isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy... (Clinical Trial)
Clinical Trial
Cardiovascular and respiratory effects of incremental doses of dopamine and phenylephrine in the management of isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy.
OBJECTIVE
To determine cardiopulmonary effects of incremental doses of dopamine and phenylephrine during isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy (HCM).
ANIMALS
6 adult cats with severe naturally occurring HCM.
PROCEDURES
Each cat was anesthetized twice (once for dopamine treatment and once for phenylephrine treatment; treatment order was randomized). Hypotension was induced by increasing isoflurane concentration. Cardiopulmonary data, including measurement of plasma concentration of cardiac troponin I (cTnI), were obtained before anesthesia, 20 minutes after onset of hypotension, and 20 minutes after each incremental infusion of dopamine (2.5, 5, and 10 μg/kg/min) or phenylephrine (0.25, 0.5, and 1 μg/kg/min).
RESULTS
Mean ± SD end-tidal isoflurane concentration for dopamine and phenylephrine was 2.44 ± 0.05% and 2.48 ± 0.04%, respectively. Cardiac index and tissue oxygen delivery were significantly increased after administration of dopamine, compared with results after administration of phenylephrine. Systemic vascular resistance index was significantly increased after administration of phenylephrine, compared with results after administration of dopamine. Oxygen consumption remained unchanged for both treatments. Systemic and pulmonary arterial blood pressures were increased after administration of both dopamine and phenylephrine. Acid-base status and blood lactate concentration did not change and were not different between treatments. The cTnI concentration increased during anesthesia and infusion of dopamine and phenylephrine but did not differ significantly between treatments.
CONCLUSIONS AND CLINICAL RELEVANCE
Dopamine and phenylephrine induced dose-dependent increases in systemic and pulmonary blood pressure, but only dopamine resulted in increased cardiac output. Hypotension and infusions of dopamine and phenylephrine caused significant increases in cTnI concentrations.
Topics: Animals; Blood Pressure; Cardiomyopathy, Hypertrophic; Cat Diseases; Cats; Cross-Over Studies; Dopamine; Dose-Response Relationship, Drug; Hypotension; Isoflurane; Oxygen; Oxygen Consumption; Phenylephrine; Prospective Studies; Troponin I; Vascular Resistance
PubMed: 22620707
DOI: 10.2460/ajvr.73.6.908 -
Journal of Neurosurgical Anesthesiology Jan 2023One of the main concerns of intraoperative hypotension is adequacy of cerebral perfusion, as cerebral blood flow decreases passively when mean arterial pressure falls... (Meta-Analysis)
Meta-Analysis Review
One of the main concerns of intraoperative hypotension is adequacy of cerebral perfusion, as cerebral blood flow decreases passively when mean arterial pressure falls below the lower limit of cerebral autoregulation. Treatment of intraoperative hypotension includes administration of drugs, such as inotropes and vasopressors, which have different pharmacological effects on cerebral hemodynamics; there is no consensus on the preferred drug to use. We performed a network meta-analysis (NMA) to pool and analyze data comparing the effect on cerebral oxygen saturation (ScO 2 ) measured by cerebral oximetry of various inotropes/vasopressors used to treat intraoperative hypotension. We searched randomized control trials in Embase, Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science. We included studies that enrolled adult patients undergoing surgery under general/spinal anesthesia that compared at least 2 inotropes/vasopressors to treat hypotension. We reviewed 51 full-text manuscripts and included 9 randomized controlled trials in our study. The primary outcome was change in ScO 2 . Our results showed the likelihood that dopamine, ephedrine, and norepinephrine had the lowest probability of decreasing ScO 2 . The suggested rank order to maintain ScO 2 , from higher to lower, was dopamine
phenylephrine. Drugs in the lower rank order, like phenylephrine, produce higher reductions in ScO 2 . Compared with dopamine, the mean difference (95% credible interval) of ScO 2 reduction was: ephedrine -3.19 (-15.74, 8.82), norepinephrine -4.44 (-18.23, 9.63) and phenylephrine -6.93 (-18.31, 4.47). The results of our NMA suggest that dopamine and ephedrine are more likely to preserve ScO 2 , followed by norepinephrine. Compared with the other inotropes/vasopressors, phenylephrine decreased ScO 2 . Because of the inherent imprecision of direct/indirect comparisons, the rank orders are possibilities, not absolute ranks. Therefore the results of this NMA should be interpreted with caution. Topics: Adult; Humans; Ephedrine; Dopamine; Network Meta-Analysis; Bayes Theorem; Cerebrovascular Circulation; Oxygen Saturation; Oximetry; Vasoconstrictor Agents; Hypotension; Phenylephrine; Norepinephrine; Anesthesia, Spinal; Randomized Controlled Trials as Topic
PubMed: 34116546
DOI: 10.1097/ANA.0000000000000783 -
Experimental Physiology Dec 2023What is the central question of this study? What are the biggest challenges in performing in vitro studies on isolated human umbilical arteries? What is the main finding...
NEW FINDINGS
What is the central question of this study? What are the biggest challenges in performing in vitro studies on isolated human umbilical arteries? What is the main finding and its importance? The protocols presented in this study indicate some potential outcomes important for interpretation of the vascular responsivities of human umbilical arteries and could be useful for planning future in vitro studies with human umbilical arteries.
ABSTRACT
Human umbilical artery (HUA) preparations are of particular importance for in vitro studies on isolated blood vessels because their sampling is not risky for the patient, and they can provide the closest possible impression of changes related to the uteroplacental circulation during pre-eclampsia. Using organ bath techniques, useful experimental protocols are provided for measuring some pathophysiological phenomena in the vascular responses of HUAs. Several vasoconstrictors (serotonin, prostaglandin F and phenylephrine) and vasodilators (acetylcholine and minoxidil) were seleted for determination of their vasoactivity in HUAs. The role of L-type voltage-operated calcium channels and different types of potassium channels (K , BK and K ) were assessed, as was the impact of homocysteine. Serotonin was confirmed to be the most potent vasoconstrictor, while acetylcholine and phenylephrine caused variability in the relaxation and contraction response of HUA, respectively. The observed increase in serotonin-induced contraction and a decrease in minoxidil-induced relaxation in the presence of homocysteine suggested its procontractile effect on HUA preparations. Using selective blockers, it was determined that K and K channels participate in the minoxidil-induced relaxation, while L-type voltage-dependent Ca channels play an important role in the serotonin-induced contraction. The presented protocols reveal some of the methodological challenges related to HUA preparations and indicate potential outcomes in interpreting the vascular effects of the investigated substances, both in physiological conditions and in the homocysteine-induced pre-eclampsia model.
Topics: Pregnancy; Female; Humans; Umbilical Arteries; Serotonin; Acetylcholine; Minoxidil; Pre-Eclampsia; Vasodilation; Vasoconstrictor Agents; Phenylephrine; Homocysteine; Adenosine Triphosphate
PubMed: 37837634
DOI: 10.1113/EP091374 -
The British Journal of Ophthalmology Aug 1977During the course of negative provocative test for closed-angle glaucoma using pilocarpine and phenylephrine 60% of eyes develop significant reductions in outflow...
During the course of negative provocative test for closed-angle glaucoma using pilocarpine and phenylephrine 60% of eyes develop significant reductions in outflow facility at some stage during the test. It is shown that these reductions can be explained by postulating the presence of partial-angle closure since: (1) A random sample (6) of 53 eyes showing an abnormal response subsequently had a peripheral iridectomy. On reprovoking they then behaved as normal eyes with a uniform increase in outflow. (2) Fifty-eight eyes that had a peripheral iridectomy for closed-angle glaucoma (spontaneous or induced) responded to provocative testing as do normal eyes.
Topics: Drug Combinations; Glaucoma; Humans; Intraocular Pressure; Iris; Phenylephrine; Pilocarpine
PubMed: 911732
DOI: 10.1136/bjo.61.8.525 -
The Journal of Thoracic and... Jun 2023Cardioplegia and cardiopulmonary bypass dysregulate coronary vasomotor tone, which can be further affected by common comorbidities in patients undergoing cardiac...
OBJECTIVE
Cardioplegia and cardiopulmonary bypass dysregulate coronary vasomotor tone, which can be further affected by common comorbidities in patients undergoing cardiac surgery. This study investigates differences in coronary myogenic tone and vasomotor responses to phenylephrine before and after cardioplegia and cardiopulmonary bypass based on hypertension history.
METHODS
Coronary arterioles before and after cardioplegia and cardiopulmonary bypass were dissected from atrial tissue samples in patients with no hypertension, well-controlled hypertension, or uncontrolled hypertension, as determined by documented history of hypertension, antihypertensive agent use, and clinical blood pressure measurements averaged over 1 year. Myogenic tone in response to stepwise increases in intraluminal pressure was studied between pressure steps. Microvascular reactivity in response to phenylephrine was assessed via vessel myography. Protein expression was measured with immunoblotting.
RESULTS
Coronary myogenic tone was significantly increased in the uncontrolled hypertension group compared with the no hypertension and well-controlled hypertension groups before cardioplegia and cardiopulmonary bypass at higher intraluminal pressures, and after cardioplegia and cardiopulmonary bypass across all intraluminal pressures (P < .05). Contractile responses to phenylephrine were significantly enhanced in patients in the uncontrolled hypertension group compared with the well-controlled hypertension group before cardioplegia and cardiopulmonary bypass, and in the uncontrolled hypertension group compared with the no hypertension and well-controlled hyertension groups after cardioplegia and cardiopulmonary bypass (P < .05). There were no differences in myogenic tone or phenylephrine-induced reactivity between the no hypertension and well-controlled hypertension groups (P > .05). There was increased expression of phosphorylated protein kinase C alpha in the uncontrolled hypertension group after cardiopulmonary bypass compared with before cardiopulmonary bypass and increased phosphorylated extracellular signal-regulated kinase 1/2 in the uncontrolled hypertension compared with the no hypertension group after cardiopulmonary bypass (P < .05).
CONCLUSIONS
Uncontrolled hypertension is associated with increased coronary myogenic tone and vasoconstrictive response to phenylephrine that persists after cardioplegia and cardiopulmonary bypass.
Topics: Humans; Cardiopulmonary Bypass; Heart Arrest, Induced; Phenylephrine; Arterioles
PubMed: 36008180
DOI: 10.1016/j.jtcvs.2022.07.022 -
Anesthesiology Aug 2020Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the effects of phenylephrine and ephedrine on cerebral blood flow and cerebral metabolic rate of oxygen in brain tumor patients. The authors hypothesized that phenylephrine reduces cerebral metabolic rate of oxygen in selected brain regions compared with ephedrine.
METHODS
In this double-blinded, randomized clinical trial, 24 anesthetized patients with brain tumors were randomly assigned to ephedrine or phenylephrine treatment. Positron emission tomography measurements of cerebral blood flow and cerebral metabolic rate of oxygen in peritumoral and normal contralateral regions were performed before and during vasopressor infusion. The primary endpoint was between-group difference in cerebral metabolic rate of oxygen. Secondary endpoints included changes in cerebral blood flow, oxygen extraction fraction, and regional cerebral oxygen saturation.
RESULTS
Peritumoral mean ± SD cerebral metabolic rate of oxygen values before and after vasopressor (ephedrine, 67.0 ± 11.3 and 67.8 ± 25.7 μmol · 100 g · min; phenylephrine, 68.2 ± 15.2 and 67.6 ± 18.0 μmol · 100 g · min) showed no intergroup difference (difference [95% CI], 1.5 [-13.3 to 16.3] μmol · 100 g · min [P = 0.839]). Corresponding contralateral hemisphere cerebral metabolic rate of oxygen values (ephedrine, 90.8 ± 15.9 and 94.6 ± 16.9 μmol · 100 g · min; phenylephrine, 100.8 ± 20.7 and 96.4 ± 17.7 μmol · 100 g · min) showed no intergroup difference (difference [95% CI], 8.2 [-2.0 to 18.5] μmol · 100 g · min [P = 0.118]). Ephedrine significantly increased cerebral blood flow (difference [95% CI], 3.9 [0.7 to 7.0] ml · 100 g · min [P = 0.019]) and regional cerebral oxygen saturation (difference [95% CI], 4 [1 to 8]% [P = 0.024]) in the contralateral hemisphere compared to phenylephrine. The change in oxygen extraction fraction in both regions (peritumoral difference [95% CI], -0.6 [-14.7 to 13.6]% [P = 0.934]; contralateral hemisphere difference [95% CI], -0.1 [- 12.1 to 12.0]% [P = 0.989]) were comparable between groups.
CONCLUSIONS
The cerebral metabolic rate of oxygen changes in peritumoral and normal contralateral regions were similar between ephedrine- and phenylephrine-treated patients. In the normal contralateral region, ephedrine was associated with an increase in cerebral blood flow and regional cerebral oxygen saturation compared with phenylephrine.
Topics: Adult; Aged; Anesthesia; Brain Neoplasms; Cerebrovascular Circulation; Double-Blind Method; Ephedrine; Female; Humans; Male; Middle Aged; Oxygen Consumption; Phenylephrine; Prospective Studies; Treatment Outcome; Vasoconstrictor Agents
PubMed: 32482999
DOI: 10.1097/ALN.0000000000003377 -
Investigative Ophthalmology & Visual... Aug 2022The superior and inferior tarsal muscles are sympathetically innervated smooth muscles. Long-term diabetes often leads to microvascular complications, such as,...
PURPOSE
The superior and inferior tarsal muscles are sympathetically innervated smooth muscles. Long-term diabetes often leads to microvascular complications, such as, retinopathy and autonomic neuropathy. We hypothesized that diabetes induces (1) sympathetic paresis in the superior and inferior tarsal muscles and that this measure is associated with (2) the severity of diabetic retinopathy, (3) the duration of diabetes, and (4) autonomic function. In addition, association between the severity of retinopathy and autonomic function was investigated.
METHODS
Forty-eight participants with long-term type 1 diabetes and confirmed distal symmetrical polyneuropathy were included. Palpebral fissure heights were measured bilaterally in response to topically applied 10% phenylephrine to the right eye. The presence of proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy and disease duration were denoted. Time and frequency derived heart rate variability parameters obtained from 24-hour continuous electrocardiography were recorded.
RESULTS
The difference in palpebral fissure heights between phenylephrine treated and untreated eyes (∆PFH) was 1.02 mm ± 0.29 (P = 0.001). The ∆PFH was significantly lower in the PDR group (0.41 mm ± 0.43 vs. 1.27 mm ± 1.0), F(1,35) = 5.26, P = 0.011. The ∆PFH was lower with increasing diabetes duration, r(37) = -0.612, P = 0.000. Further, the ∆PFH was lower with diminished autonomic function assessed as total frequency power in electrocardiogram (r = 0.417, P = 0.014), and sympathetic measures of very low (r = 0.437, P = 0.010) and low frequency power (r = 0.384, P = 0.025).
CONCLUSIONS
The ∆PFH is a simple ambulatory sympathetic measure, which was associated with the presence of PDR, disease duration, and autonomic function. Consequently, ∆PFH could potentially be an inexpensive and sensitive clinical indicator of autonomic dysfunction.
Topics: Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Diabetic Retinopathy; Eyelids; Humans; Phenylephrine; Polyneuropathies
PubMed: 35980646
DOI: 10.1167/iovs.63.9.21 -
Scientific Reports Aug 2023The present work examined the effect of oral administration of rutin and its combination with metformin, an antidiabetic drug on blood glucose, total cholesterol and...
The present work examined the effect of oral administration of rutin and its combination with metformin, an antidiabetic drug on blood glucose, total cholesterol and triglycerides level and vascular function in streptozotocin (STZ) -induced diabetic rats. Male Sprague Dawley rats were rendered diabetic by a single intraperitoneal injection of STZ (50 mg/kg). Rutin and metformin were orally administered to diabetic rats at a dose of 100 mg/kg and 300 mg/kg body weight/day, respectively, for 4 weeks. Plasma analysis was conducted to determine changes in the plasma glucose and lipid levels. Rat aortic ring reactivity in response to endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) relaxants, and to the α1-adrenergic agonist phenylephrine (PE) were recorded. Histology of pancreas, liver and kidney were evaluated. In results, rutin and metformin alone and in combination has led to significant improvements in blood glucose, cholesterol and triglyceride levels compared to diabetic group. Diabetic aortic rings showed significantly greater contraction in response to PE, and less relaxation in response to ACh and SNP. Treatment with rutin and metformin in combination significantly reduced PE-induced contraction and increased ACh-induced and SNP-induced relaxation in diabetes when compared to rutin or metformin alone. Significant histological improvements were seen with combination therapy. In conclusion, rutin and metformin combination therapy has the most potentiality for restoring blood glucose and lipid level as well as vascular function.
Topics: Rats; Male; Animals; Metformin; Rats, Sprague-Dawley; Diabetes Mellitus, Type 1; Rutin; Diabetes Mellitus, Experimental; Blood Glucose; Phenylephrine; Acetylcholine; Cholesterol; Lipids; Endothelium, Vascular
PubMed: 37528147
DOI: 10.1038/s41598-023-39442-6