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Pharmacology & Therapeutics Aug 2008Current guidelines describe strategies on how the potential of non-antiarrhythmic drugs to delay ventricular repolarisation should be assessed. However, the non-clinical... (Review)
Review
Current guidelines describe strategies on how the potential of non-antiarrhythmic drugs to delay ventricular repolarisation should be assessed. However, the non-clinical guidelines recommend repolarisation assays only and do not advocate experimental models that express the proarrhythmia of concern, torsades de pointes (TdP). Although the repolarisation assays may predict QT interval prolongation in man they cannot alone sufficiently predict proarrhythmia risk. Furthermore, there is also a need for more robust surrogate markers of drug-induced proarrhythmia and such validated markers are on the horizon as a result of the availability of sensitive animal models of TdP. This review will describe the methoxamine-sensitised rabbit model of TdP, one of the most frequently used proarrhythmia models, and present some of it characteristics, its pros and cons and how it historically has been used for assessing proarrhythmia liability of drugs.
Topics: Adrenergic alpha-Agonists; Animals; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Guidelines as Topic; Humans; Methoxamine; Rabbits; Torsades de Pointes; Toxicity Tests
PubMed: 18558435
DOI: 10.1016/j.pharmthera.2008.04.004 -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2023Methoxamine (Mox) is a well-known α1-adrenoceptor agonist, clinically used as a longer-acting analogue of epinephrine. 1,2-Mox (NRL001) has been also undergoing...
Methoxamine (Mox) is a well-known α1-adrenoceptor agonist, clinically used as a longer-acting analogue of epinephrine. 1,2-Mox (NRL001) has been also undergoing clinical testing to increase the canal resting pressure in patients with bowel incontinence. Here we show, that Mox hydrochloride acts as an inhibitor of base excision repair (BER). The effect is mediated by the inhibition of apurinic/apyrimidinic endonuclease APE1. We link this observation to our previous report showing the biologically relevant effect of Mox on BER - prevention of converting oxidative DNA base damage to double-stranded breaks. We demonstrate that its effect is weaker, but still significant when compared to a known BER inhibitor methoxyamine (MX). We further determined Mox's relative at 19 mmol L, demonstrating a significant effect of Mox on APE1 activity in clinically relevant concentrations.
Topics: Humans; Methoxamine; DNA Repair; Epinephrine; Receptors, Adrenergic; Endonucleases
PubMed: 37307375
DOI: 10.2478/acph-2023-0012 -
Journal of Biological Regulators and... 2020
Topics: Anesthesia, Obstetrical; Anesthesia, Spinal; Cesarean Section; Female; Humans; Methoxamine; Pregnancy; Pregnant Women
PubMed: 33322888
DOI: 10.23812/20-333-L -
Nature Nov 1959
Topics: Methoxamine; Radiation Protection; Sympathomimetics
PubMed: 13854851
DOI: 10.1038/1841729a0 -
Archives Internationales de... Jul 1959
Topics: Methoxamine; Sympathomimetics
PubMed: 13800388
DOI: No ID Found -
Physiology & Behavior 1988New Zealand albino rabbits received classical conditioning training in which a 35-sec tone conditioned stimulus was paired with a bolus injection of methoxamine...
New Zealand albino rabbits received classical conditioning training in which a 35-sec tone conditioned stimulus was paired with a bolus injection of methoxamine hydrochloride (Vasoxyl), an alpha 1-adrenergic agonist. Heart rate (HR) and blood pressure (BP) responses were recorded. Methoxamine produced a precipitous rise in BP and bradycardia as an unconditioned response (UR); pairings of tone and methoxamine over a 5-day period resulted in a gradually appearing tachycardia conditioned response (CR) which occurred shortly following tone onset. On the other hand, the BP CR was a pressor response. Accordingly, the HR CR was opposite in direction and, thus, apparently compensatory to the UR, whereas the BP CR was similar in direction to the UR. Neither of these cardiovascular changes were observed in control animals receiving either unpaired presentations of tone and methoxamine or tones paired with physiological saline. Most animals receiving either paired or unpaired infusions of methoxamine also showed consistent elevations in baseline HR as training progressed, relative to their respective day 1 levels, thus suggesting the development of compensatory HR CRs to the contextual cues associated with training.
Topics: Acoustic Stimulation; Animals; Blood Pressure; Conditioning, Classical; Female; Heart Rate; Male; Methoxamine; Rabbits; Reference Values
PubMed: 3212054
DOI: 10.1016/0031-9384(88)90235-1 -
British Journal of Anaesthesia May 1995
Topics: Blood Loss, Surgical; Humans; Male; Methoxamine; Prostatectomy; Time Factors
PubMed: 7772446
DOI: 10.1093/bja/74.5.628 -
The American Journal of the Medical... Apr 1957
Topics: Blood Pressure; Cardiovascular System; Hemodynamics; Kidney; Methoxamine; Sympathomimetics
PubMed: 13410917
DOI: 10.1097/00000441-195704000-00007 -
Methoxamine versus epinephrine on regional cerebral blood flow during cardiopulmonary resuscitation.Critical Care Medicine Jul 1987The improvement in cerebral blood flow (CBF) during CPR after epinephrine administration has been attributed to epinephrine's alpha-adrenergic properties. Methoxamine, a... (Comparative Study)
Comparative Study
The improvement in cerebral blood flow (CBF) during CPR after epinephrine administration has been attributed to epinephrine's alpha-adrenergic properties. Methoxamine, a pure alpha-1 agonist, has only been shown to be comparable to epinephrine in restoring circulation after cardiac arrest in a canine model. This study compares the effectiveness of equipotent doses of epinephrine and methoxamine in improving CBF during CPR after a prolonged cardiac arrest in a swine model. Twenty-five swine, weighing 15.9 to 28.2 kg, underwent instrumentation for regional CBF using tracer microspheres. CBF was determined during normal sinus rhythm. After 10 min of ventricular fibrillation, CPR was begun with a pneumatic compressor. CBF measurements were again made during CPR. After 3 min of CPR, the swine were randomized to receive 0.02 or 0.2 mg/kg epinephrine, 0.1, 1.0, or 10.0 mg/kg methoxamine. Five swine were allocated to each group. CBF measurements were determined after drug administration and compared using a Bonferroni multiple comparison procedure. A p-value less than .05 was considered statistically significant. This study demonstrated that, after a 10-min cardiac arrest, CBF was extremely low, averaging less than 7 ml/min X 100 g during external CPR. There were no clinically significant improvements in regional CBF after 0.02 mg/kg of epinephrine, or the two lowest doses of methoxamine. The addition of 10 mg/kg of methoxamine clinically improved blood flow only to the most caudal CNS structures, including the pons, medulla, and cervical spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Cardiac Output; Cerebrovascular Circulation; Epinephrine; Heart Arrest; Methoxamine; Random Allocation; Regional Blood Flow; Resuscitation; Swine
PubMed: 3595156
DOI: 10.1097/00003246-198707000-00011 -
The British Journal of Surgery Jul 2003Topical phenylephrine has been shown to increase resting anal canal pressure in normal and incontinent individuals. However, high concentrations of gel (10-40 per cent)... (Comparative Study)
Comparative Study
BACKGROUND
Topical phenylephrine has been shown to increase resting anal canal pressure in normal and incontinent individuals. However, high concentrations of gel (10-40 per cent) are required that may cause local side-effects. The aim of this study was to determine whether methoxamine, another alpha-1-adrenoceptor agonist, might be a more potent alternative to phenylephrine.
METHODS
Porcine internal anal sphincter (IAS) tissue was cut into strips, suspended in a superfusion organ bath and allowed to equilibrate. Strips were subjected to each drug under test for 20 s, sufficient to obtain stable tone. Phenylephrine, methoxamine (1 : 1 : 1 : 1 ratio of its four isomers) and each of the individual isomers of methoxamine were evaluated in turn.
RESULTS
In vitro, methoxamine racemate and phenylephrine were similarly potent in causing contraction of IAS strips (mean(s.e.m.) dose giving half maximal effect (EC(50)) at 74.7(16.5) versus 58.3(13.4) micro M respectively; P = 0.443). However, one of the methoxamine isomers, L-erythro-methoxamine (EC(50) 17.6(3.7) micro M), was significantly more potent than the other three isomers, methoxamine racemate and phenylephrine (P = 0.002).
CONCLUSION
L-Erythro-methoxamine is four times more potent than phenylephrine and is a possible treatment for incontinence. Trials are under way to examine the efficacy of L-erythro-methoxamine in vivo.
Topics: Adrenergic alpha-Agonists; Anal Canal; Animals; Dose-Response Relationship, Drug; Female; Methoxamine; Muscle Contraction; Phenylephrine; Pressure; Stereoisomerism; Swine
PubMed: 12854116
DOI: 10.1002/bjs.4120