September 2015

Anastrozole is a reversible competitive aromatase inhibitor (AI) with high specificity and affinity1,2. It has a chemical formula of C17H19N5 and a mass of 293.366 g/mol. Anastrozole, Estrogen and Testosterone This molecule binds to aromatase, which prevents the conversion of estrogen to testosterone¹. These reductions in estrogen are used in medicine and research to reduce the supply of the hormone to its receptors (ERs) on tumor cells³. A recent trial of the effects of anastrozole on murine ER-positive carcinoma cells found the AI significantly reduced cell viability and proliferation at a range of doses³. It may be intuitive therefore to assume a role for anastrozole in the effects of testosterone on its physiological and pathological effects. However, a recent study using male Fisher 344 rats found that anastrozole had little effect on the bone-conserving properties of testosterone. This study randomly allocated orchidectomized rats to dose-regimens of testosterone, anastrozole, trenbolone (a testosterone analog which cannot be converted to estrogen), both anastrozole and trenbolone or placebo⁴. The 'testosterone'and 'trenbolone' group suppressed the bone loss seen in the placebo group compared to intact animals, but this was not affected positively or negatively in the groups receiving anastrozole⁴. In addition, anastrozole did not affect the increases in fat mass and decreases in muscle mass seen in the placebo group⁴. Anastrozole is an azole, which leads to its classification as a non-steroidal third-generation aromatase inhibitor⁵. It is electrophilic, which suggests a role in ion channel activation⁵. Anastrozole and Pain Anastrozole has been found to produce the side-effect of pain when used as a treatment or intervention⁵. This adverse event most often arises in the form of joint or neuropathic (or nerve damage-related) pain⁵. This azole has demonstrated the ability to induce or increase pain in murine studies⁵. Anastrozole has been found to target the transient receptor potential ankyrin 1 (TRPA1) channel, which is a mediator of neuropathic pain, chemical irritation and pain related to inflammatory stimuli^5,6. Mouse models of genetic TRPA1 deficiency and blockade have shown that anastrozole administration resulted in the calcium response of this channel⁵. This indicates a role for anastrozole in models and studies of neuropathy, inflammatory pain and irriation in the future. References: 1. Geisler J. Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole--of clinical importance? British journal of cancer. 2011;104(7):1059-1066. 2. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014;383(9922):1041-1048. 3. Topcul M, Cetin I, Ozlem Kolusayin Ozar M. The effects of anastrozole on the proliferation of FM3A cells. J BUON. 2013;18(4):874-878. 4. Beck DT, Yarrow JF, Beggs LA, et al. Influence of aromatase inhibition on the bone-protective effects of testosterone. J Bone Miner Res. 2014;29(11):2405-2413. 5. Fusi C, Materazzi S, Benemei S, et al. Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1. Nature Communications. 2014;5:5736. 6. Trevisani M, Siemens J, Materazzi S, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007;104(33):13519-13524.

Albuterol Albuterol is an agonist of the [beta]-adrenergic receptor (β2-AR). It is commonly available in two forms, R-albuterol (or levalbuterol) and S-albuterol¹. Levalbuterol is often regarded as the active form of this molecule, as S-albuterol as been found to remain in circulation for up to twelve times longer than its other isomer¹. Albuterol and Respiration This class of drug elicits bronchodilation through the recruitment of sodium/potassium ATPases in the alveoli of animal lungs via changes in calcium concentrations². A recent study has found that this is associated with calcium release-activated calcium channels linked to stromal interaction molecule 1 (STIM1)². A rat model of acute respiratory distress syndrome (ARDS) found that the genes for sodium/potassium ATPase-α were significantly increased in response to intratracheal and intravenous albuterol, but only if alveolar ion channel and aquaporin gene expression were elevated beforehand (i.e. by experimental ARDS induction)³. Albuterol is often used as a standard when assessing the binding (and other) properties of novel β2-AR agonists⁴. It was also recently used to validate the bronchoconstrictive properties of insulin in a study using guinea pigs⁵. Albuterol has also been found to potentiate concurrently-available corticosteroids and modulate inflammatory responses when inhaled¹. Albuterol and Cardiovascular Research Albuterol has been proposed as a preventative against hypoxia (oxygen deprivation) in anesthetized animals. However, it is also linked to increased risks of cardiac complications (e.g. changes in heart rate) due to its effects on β2-ARs outside the lungs⁶. An electrophysiological study using mice with experimentally-induced heart failure found that this intervention resulted in significantly decreased bronchial tissue responses to albuterol⁷. This was most probably due to significant decreases in β2-AR expression following heart failure⁷. Albuterol and Body Composition(?) Albuterol may also have positive effects on fat accumulation and metabolism. A group of researchers have claimed that doses of albuterol, caffeine or both increased lipid breakdown in cultured lipocytes⁸. They also reported a long-term trend of increased metabolic rates in rats, although increases in lean body mass and reductions in fat mass in response to the combination of caffeine and albuterol was greater compared to those associated with albuterol alone⁸. References: 1. Ameredes BT, Calhoun WJ. Levalbuterol versus albuterol. Curr Allergy Asthma Rep. 2009;9(5):401-409. 2. Keller MJ, Lecuona E, Prakriya M, et al. Calcium release-activated calcium (CRAC) channels mediate the beta(2)-adrenergic regulation of Na,K-ATPase. FEBS Lett. 2014;588(24):4686-4693. 3. Uhlig C, Silva PL, Ornellas D, et al. The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration. Respir Res. 2014;15:56. 4. Baker JG, Proudman RG, Hill SJ. Salmeterol's extreme beta2 selectivity is due to residues in both extracellular loops and transmembrane domains. Mol Pharmacol. 2015;87(1):103-120. 5. Sharif M, Khan BT, Ajmal K, Anwar MA. Acute effect of insulin on guinea pig airways and its amelioration by pre-treatment with salbutamol. J Pak Med Assoc. 2014;64(8):932-935. 6. Casoni D, Spadavecchia C, Adami C. Cardiovascular changes after administration of aerosolized salbutamol in horses: five cases. Acta Veterinaria Scandinavica. 2014;56(1):49-49. 7. Rinaldi B, Capuano A, Gritti G, et al. Effects of chronic administration of beta-blockers on airway responsiveness in a murine model of heart failure. Pulm Pharmacol Ther. 2014;28(2):109-113. 8. Liu AG, Arceneaux KP, 3rd, Chu JT, et al. The effect of caffeine and albuterol on body composition and metabolic rate. Obesity (Silver Spring). 2015.