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Tolerance to the Amphetamines: An Examination of Possible Mechanisms
Published in John Caldwell, S. Joseph Mulé, Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects, 2019
John Caldwell, Jane E. Croft, Peter S. Sever
In a more comprehensive study of this phenomenon, we have confirmed these results as far as the male rat is concerned and in the same way shown that norephedrine pretreatment protects the animals against amphetamine-induced hyperthermia. Norephedrine is extensively metabolized to p-hydroxynorephedrine in the rat (see Chapter 3).However, when the identical procedures were carried out in female rats, it was found that none of these pretreatments had any influence on the hyperthermic response to amphetamine. These data are presented in Table 3.
Adrenoceptors: Classification and Distribution
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Early studies showed that the sympathomimetic compound, phenylpropanolamine (norephedrine), could be used in the treatment of obesity to produce weight loss (Hirsch 1939). This compound has consequently been available in the USA as an OTC weight-reducing remedy for many years. In spite of some controversy over its efficacy, the FDA has approved the continued sale of phenylpropranolamine-containing products for weight loss. Its combination with caffeine, however, is no longer used. Unlike amphetamine, which is closely related structurally (see Table 4.1), phenylpropranolamine does not appear to exert significant appetite supression and weight loss by a central anorexic mechanism. It is virtually free of CNS stimulant activity and therefore should not be regarded as a look-alike, amphetamine-type, stimulant drug of abuse, although it may appear on the streets as such. More recent studies showed that ephedrine reduced body lipid (but not protein) in various obese mice (Massoudi & Miller 1977). Also, phenylpropranolamine has been shown to increase thermogenic energy expenditure in normal and genetically obese mice. This was associated with decreased body weight gain, decreased total body fat and reduced food intake (Arch et al. 1982). Phenylpropanolamine stimulates BAT thermogenesis in rats, an effect that is abolished by pretreatment with reserpine to deplete endogenous catecholamines. This suggests that the effect is due to release of noradrenaline from noradrenergic neurones (Lasagna 1988).
Conditions that sometimes mimic peripheral nervous system disease
Published in James W. Albers, Stanley Berent, Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, 2005
James W. Albers, Stanley Berent
Erythromelalgia associated with a systemic disorder is referred to as ‘secondary erythromelalgia.’ Systemic disorders or physiologic conditions associated with erythromelalgia include myeloproliferative disease (including essential thrombocytosis, polycythemia vera, thrombotic thrombocytopenic purpura, and leukemia), hypertension, systemic lupus erythematosus, and even pregnancy (Confino et al., 1997; Drenth, Michiels, Van Joost, & Vuzevski, 1993; Kurzrock & Cohen, 1989; Mehle, Nedorost, & Camisa, 1990; Ongenae et al., 1996; van Genderen & Michiels, 1997; Yosipovitch, Krause, & Blickstein, 1992; Hart, 1996). The onset of erythromelalgia has on occasion begun shortly after initiation of some medication, such as bromo-criptine, nicardipine, verapamil, or nifedipine (Levesque, Cailleux, & Courtois, 1992; Hart, 1996). Erythromelalgia also has been reported in association with discontinuing norephedrine, a medication prescribed to treat obesity (Wagner, Spengel, & Middeke, 1993). The authors who reported the association hypothesized that erythromelalgia was masked by the vasoactive properties of norephedrine. Norephedrine may produce adaptive adrenergic subsensitivity of vascular smooth muscles, resulting in an enhanced vasodilatation due to an abnormal adrenergic sensitivity when the medication was discontinued (Wagner et al., 1993). The role of abnormal adrenergic sensitivity in the pathogenesis of primary erythromelalgia is unknown. At least one report linked erythromelalgia with autonomic nervous system dysfunction. That report described vascular dysregulation as producing acroerythema, increased extremity temperature, local swelling and distension, and severe burning pain (Liu, 1900).
A randomized open label, parallel-group study to evaluate the hemodynamic effects of Cafedrine/Theodrenaline vs Noradrenaline in the treatment of intraoperative hypotension after induction of general anesthesia: the “HERO” study design and rationale
Published in Current Medical Research and Opinion, 2023
Benjamin Vojnar, Götz Geldner, Susanne Huljic-Lankinen, Melanie Murst, Thomas Keller, Stephan Weber, Christine Gaik, Tilo Koch, Andreas Weyland, Peter Kranke, Sascha Kreuer, Daniel Chappell, Leopold Eberhart
The 20:1 C/T is a mixture of Noradrenaline and Norephedrine, both covalently bound to Theophylline7. Previous data indicate that the rapid onset of action seems to be based on Noradrenaline-mediated vasoconstriction, which is subsequently reduced by the delayed effect of Cafedrine, while Norephedrine leads to a positive inotropic effect, which is enhanced and prolonged by phosphodiesterase 3 inhibition mediated by Theophylline7. In sum, C/T exerts inotropic and moderate vasopressor effects, meaning the term “inopressor” best describes its mechanism of action and differentiates this medicinal product from other sympathomimetic agents. Inopressors may be particularly suitable for treatment of hypotension that occurs in association with Propofol use as they counteract both cardiac impairment and vasodilation14,15,18. The effect of C/T is long-lasting7. Noradrenaline, a well-established alternative agent for the treatment of acute hypotension8 with a short elimination half-life, has potent alpha-adrenergic and slight beta-adrenergic effects, resulting in potent vasoconstriction and less potent inotropy. Reflex bradycardia can occur16,17. The effect of NA on cardiac output has been shown to be highly variable23. In summary, the pharmacodynamic and -kinetic profiles of C/T compared to NA are described to be different.
Synthesis of some quinazolinones inspired from the natural alkaloid L-norephedrine as EGFR inhibitors and radiosensitizers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Mostafa M. Ghorab, Maged S. Abdel-Kader, Ali S. Alqahtani, Aiten M. Soliman
Quinazolines are fused heterocyclic ring systems known for their variable biological activity12–15. They are well known for their inhibitory activity towards various protein kinase enzymes and their anticancer activity16. For example, lapatinib, a dual reversible EGFR and HER2 inhibitor. Also, gefitinib and erlotinib are reversible EGFR inhibitors; they are examples of FDA approved small molecules TK inhibitors17. Methaqualone, a potent hypnotic, was considered as an important landmark in synthetic anticonvulsants18. The 3-[β-keto-gamma-(3-hydroxy-2-piperidyl)-propyl]-4-quinazolone (A) was the first isolated natural quinazolinone alkaloid known by its antimalarial activity19. The quinazolinone derivatives (B) and benzo[g]quinazolinone (C) were reported to possess potent EGFR and HER2 inhibitory activity20,21 (Figure 1). On the other hand, the Ephedra alkaloid, Norephedrine (NE) is a stereoisomer of phenylpropanolamine that is naturally occurring sympathomimetic22. Investigation revealed that long-term use of NE caused severe side effects, including fatality23. In addition to medicinal use, the properties of this alkaloid have attracted considerable attention in natural product chemistry field that leads to its use as a starting material in the preparation of chiral ligands for asymmetric catalytic synthesis24,25.
Attitude and practice of substance misuse and dietary supplements to improve performance in sport
Published in Journal of Substance Use, 2019
Doping is also known as follows: “The intentional use by the athletes of drugs or methods aimed at obtaining an improved sports performance beyond the limits possible only with training”. It has become an important topic in virtually every sport and has been discovered in athletes of all ages and at every level of competition. Importantly, performance-enhancing drugs (PEDs) are not restricted to illegal drugs or prescription medications, such as anabolic steroid and inhaled bronchodilators (Mazzeo, 2018; Perrotta, Mazzeo, & Cerqua, 2017). They include dietary supplements vitamins, minerals and more and a variety of compounds that are available at grocery and health food stores and website. These substances are increasingly used by athletes, in competitive sports, but at the same time in fitness and recreational sports (Mazzeo, Santamaria et al., 2016). It is important to know the motivation and the advantages to led the athletes to dope (Table 2). In advance, it is important to know that the prohibited substances and/or the amount of substance prohibited constantly change: some of them have been eliminated over time while others have been added. For example, pseudoephedrine and norephedrine were removed from the list in 2003 but in 2013, the first substance was reintroduced with a different dosage. Local anesthetics and caffeine were eliminated in 2004 (Strano Rossi & Botrè 2011), even if the substance has been included in the monitoring program of WADA in 2015 (Table 3).