WCO Explanatory Notes reproduced for reference. © World Customs Organization. Verify against official WCO publication.
29.37 - Hormones,, prostaglandins, thromboxanes and leukotrienes, natural or reproduced by synthesrs; derivatives and structural analogues thereof, including chain moditied polypeptides, used primarily as hormones. - Polpeptide hormones,, rotein hormones and glycoprotein hormones, their P denvatives and structura analogues : - - Somatotropin, its derivatives and structural analogues 2937.12 - - Insulin and its salts 2937.19 - - Other - Steroidal hormones, their derivatives and structural analogues : 2937.2 1 - - Cortisone, h drocortisone, prednisone (dehydrocortisone) and prednisolone 2937.1 1 d: (dehydrohy ocortisone) - - Halogenated derivatives of corticosteroidal hormones 2937.23 - - Oestrogens and progestogens 2937.29 - - Other 2937.50 - Prostaglandins, thromboxanes and leukotrienes, their derivatives and 2937.22 structural analogues 2937.90 - Other This heading includes : (I) Natural hormones, which are active substances produced in the living tissues of man or animals, extremely small amounts of which are capable of inhibitin or stimulating the fimctioning of particular organs b acting directly on them or control ing the synthesis or secretion of secondary or tertiary ormone systems. A fundamental defining characteristic of a hormone is that ~tbinds to a stereos ecific molecular receptor to activate a res onse. The secretion of these substances, usua ly by the endocrine glands, is overned y the sympathetic and para-s athetic systems. Hormones are c m e d b the lood, lymph or other fluids of the b o r R e y may also originate .in lands whic are both endo- and exocrinal or in various cellular tissues. Transport in t e blood is not a ~equisjtefor a hormonal response. Responses can occur after release of hormones into the Interstitial fluid with binding to receptors in nearby cells (paracrine control) or to receptors on the cell that released the hormone (autocrine control). H E f i H % E (10 Natural prostaglandins, thromboxanes and leukotrienes, compounds which are secreted by the body and behave like locally-acting hormones. Prostaglandins are a class of hormones or hormone-like substances which are synthesised by the tissue in which they act (or act in the local cellular environment) by binding to specific cellular receptors and act as important modulators of cell activity in many tissues. These three related chemical families (arachidonic acid derivatives) are said to have "hormone-like action". (HI) Natural hormones, prostaglandins, thromboxanes and leukotrienes reproduced by synthesis (including biotechnological processes), that is, having the same chemical structure as the natural substance. (1V)Derivatives of natural or synthetically reproduced hormones, prostaglandins, thromboxanes and leukotrienes, such as salts, halo enated derivatives, cyclic acetals, esters, etc., includine mixed derivatives (e.g., esters of%alogenated derivatives), provided that they are used pnmarily as hormones. (V) Analogues of hormones, prosta landins, thromboxanes and leukotrienes. The term "analogue" refers to chemicals 8avin8 a close structural relationship to the parent compound, but which are not considere to be derivatives. It includes compounds which have a structural resemblance to the natural compounds, but have had one or more atoms in the structure replaced by others. (a) Analogues of polypeptide hormones are formed by adding, se arating, replacing or altering certain armno acids in the natural polype tide chain. omatrem (INN), an analogue of the growth hormone somatohopin, is tfe result of adding a terminal amino acid to the natural somatotropin molecule. Ornipressin (INN), an analogue of natural argi ressin (INN) and 1 ressin (INN), is the result of replacing an internal amino acid in t e argl ressln or ressin molecule. The synthetic onadoliberins, buserelin (INN), na areIrn . (d f e r t i r e l i n INN) leu rorelin (&and lutrelin (INN), analogues of gonadorelin (INN are t e result o altering and r lacing certain amino acids ln the pol e tide chain o natural gonadorelia ~ i r a e t i d e e fan ~ ,analogue of eorticotrop~n has the same structure as the first 18 amino acids of natural corticotropin, with the first amino acid replaced. Metreleptin (INN),an analo e of le tin, is the recombinant methionyl denvative of human leptin. Saralasin w ich contains three different amino acids in comparison to the molecule of angiotensin 11, should be considered as a strucfmal analogue of angiotensin 11, although with antagonist effects (the former is a hypotensor and the latter an hypertensor). i R @%) rW, R (b) Analogues of steroid hormones must have the gonane structure, which can be altered b ring contraction or extension or by replacing some atoms in the ring by others (ietero-atoms). Domoprednate (INN) and oxandrolone (INN represent two examples of this kind of analogues. The family of analogues and erivatives, which retain the fundamental structure of the gonane described, contains a large number of substances used as hormone inhibitors and anta onists (antihormones). Examples are c roterone (INN), an antiandrogen, danazol &N), an antigonadotropin, epostane which inhibits progesterone production. d 0, (c) Analogues of prostaglandins, thromboxanes and leukotrienes may be formed by substitution of atoms in a chain, or formation or elimination of rings. In tilsuprost (INN),a prostaglandin analogue, oxygen and carbon atoms are replaced by nitrogen and sulphur atoms and one ring is closed. (VI) Natural mixtures of hormones or their derivatives or of steroids recognised as having a hormonal effect (e.g., a natural mixture of corticosteroid hormones or of conju ated oestrogens). Deliberate mixtures or preparations are excluded (generally heading 30. 3 or 30.04). % Hormone-releasing factors (hormone-stimulatin factors), hormone inhibitors and hormone anta onists (antihornones) are also included in k s heading see Note 8 to this Chapter). The hea ing also includes derivatives and structural analo es of ormones, rovided that they are based on natural hormones, or on those reproduceLYby synthesis, an$ that they act using mechanisms similar to those of hormones. f I, A list of the products of this heading, arranged according to chemical structure, is given below. This list is not exhaustive. List of products which are to be classified as products of heading 29.37 (*) (A POLYPEPTIDE HORMONES, PROTEIN HORMONES AND d L Y c o m o T E m H o z t M o m s , THEIR DERIVATIVES m D STRUCTURAL ANALOGUES This part includes, inter alia : (1) Somatotro in, its derivatives and structural analo es. Somatotropin (growth hormone, STH (somatotro ic hormone ). Water so uble protein wh~chpromotes growth of tissues and is involve in the regu ation of other phases of protein metabolism. It is secreted by the somatotropic cells of the anterior pituitary gland. Secretion is regulated by a releasing factor (growth hormone-releasing hormone) and by an inhibitory factor, somatostatin. Human growth hormone (hGH) is a single olypeptide chain of 191 amino acids manufactured almost exclusively by recombinant I!NA technolo This p a r t includes derivatives and analogues such as somatrem (INN) (methionyl GH), ace lated hGH, desamido hGH and somenopor (INN) and antagonists such as pegvisomant JH, l S P ,y. (2) insulin and its salts. Insulin is a pol eptide containing 51 amino-acid groups and is produced in the islets of Langerhans o f t e pancreas of numerous animals. Human insulin can be obtained by extraction from the pancreas, by modification of bovine or porcine insulin or by biotechnological processes involving bacteria or easts to produce recombinant human insulin. Insulin is a factor in the cellular u take o circulating glucose and other nutrients, as well as their storage as glycogen and at. Pure insulin is a whte, non-hygroscopic amorphous powder or s h y crystals, soluble in water. Its clinical use is in the treatment of diabetes. Insulin salts include insulin hydrochloride. YA P f' (3) Corticotropin (INN) (ACTH (adrenocorticotropic hormone), adrenocorticotropin). A polypepbde, soluble in water. It stimulates increased production of adrenocortical steroids. Giractlde (INN) is an analogue of corticotropin. (4) Lactogenic hormone (LTH, galactin, galacto ene hormone, luteotrophin, mammotrophin, prolactin). A olypeptide which can be crystal tsed. Activates milk secretion and influences the activlty o the corpus luteurn. ! H (*) If a name is used in the International Nonproprietary Names or the International Nonproprietary Names (Modified) for ~harmaceuticalsubstances ~ublishedbv the World Hcalth Organization. this name is mentibned F i t and marked (TNN) or respectively. - --- - - - m), - (5) Thyrotrophin (INN) (thyrotrophic hormone, TSH (thyroid-stimulatin hormone)). A glycoprotein which intervenes in the action of the thyroid gland on the lood and in the removal of iodine. It affects growth and secretion. t (6) Follicle-stimulating hormone (FSH). A glycoprotein, soluble in water. It activates sexud functions. (7) Luteinising hormone (LH, ICSH (interstitial-cell-stimulating hormone), luteinostimulin). A glycoprotein, soluble in water. It stimulates sexual functions by stimulating steroid secretion, ovulation and interstitial cell development. (8) Chorionic gonadotrophin (INN)(hCG (human chorionic gonadotrophin)). Formed in the placenta; it is a lycoprotein extracted from the urine of pregnant women. White crystals, relatively unstab e in aqueous solution. Stimulates follicle maturity. f (9) Serum gonadotrophin (INN) (equine chorionic gonadotropin (eCG)). It is a gonadstimulating gl coprotein produced in the placenta and endometrium of pregnant mares. Originally cal ed pregnant mare serum gonadotropin. ? (10) Oxytocin (INN (a-hypophamin). A polypeptide, soluble in water. Its chief action is on the contraction of e uterus and on milk ejection from the mammary gland. Also included are the analogues carbetocin (INN), demoxytocin (INN), etc. d (1 I) Vasopressins : argipressin (INN) and lypressin (INN), their derivatives and structural analogues. Vasopressins are olypeptides which raise blood pressure and cause an increase in water retention b the ki ey. Also included here are polypeptide analogues such as terlipressin (INN), esmopressln (INN),etc. i dh (12) Calcitonin (INN). (TCA (thyrocalcitonin)). A hypocalcaemic and hypophosphatemic polypeptide. (13) Glucagon (INN) (HGF (h er lycaemic-glycogenolytic factor)). A polypeptide which has the property of increasing e b ood-glucose concentration. ?E f (14) Thyroliberin (TRF, TRH). This polypeptide stimulates the secretion of thyrotropin. (15) Gonadorelin (INN)(gonadoliberin, gonadotrophin releasing hormone, LRF, GnRH). This polypeptide promotes the secretion of follicle-stimulating and lutein-stimulating hormones in the pituit land. Also included are the olypeptide analogues buserllin (INN), goserihn &S$,!ertirelin (INN), sermorelin etc. (dl, (16) Somatostatin MN) (SS, SRIH, SRIF). This polypeptide inhibits the release of growth hormone and TS! H fiom the pituitary gland and has a neurotropic action. (17) Atrial natriuretic hormone (ANH, ANF), a 01 eptide hormone secreted fiom the atria of the heart. When the cardiac atrium is stretc e y increased blood volume, secretion of ANH is stimulated. ANH in turn increases salt and water excretion and reduces blood pressure. RX (18) Endothelin, a pol eptide hormone secreted by endothelial cells throughout the vasculature. ~ l t h o u gendothelin is released into the blood circulation, it acts local1 in a paracrine fashion to constrict adjacent vascular smooth muscle and to increase glood pressure. (19) Inhibin and activin, hormones found in gonadal tissue. (20) Leptin, a polypeptide hormone roduced by adi ose tissue that is thought to act on receptors in the brain to regulate ody weight an fat deposition. Also included here is metreleptin (INN),the recombinant methionyl derivative of leptin, which has a similar activity and which is considered to be an analogue of leptin. ! (B) STEROIDAL HORMONES, THEIR DERIVATIVES AND STRUCTURAL ANALOGUES (1) Corticosteroid hormones, secreted in the cortical zone of the adrenal glands, play an important role in the functioning of the body's metabolism. They are also known as adrenal cortical hormones or corticoids, and are generally divided into two groups, depending upon their physiolo ical action : (i) glucocort&oids, which regulate protein and carbohydrate metabolism and t i ) mineralocorticoids, whch cause the retent~onof sodium and water by the body and hasten the excretion of potassium. The properties of mineralocorticoids are utilised in the treatment of kidney deficiencies and of Addison's disease. These include the following corticosteroid hormones, derivatives and analogues : (a) Cortisone (INN). A glucocorticoid which regulates protein and carbohydrate metabolism and also has a local anti-inflammatory effect. @) Hydrocortisone (INN) (cortisol). A glucocorticoid with effects similar to those of cortisone. (c) Prednisone (INN)(dehydrocortisone). Glucocorticoid. A derivative of cortisone. (d) Prednisolone (INN) (dehydrohydrocortisone). Glucocorticoid. hydrocortisone. A derivative of (e) Aldosterone (INN). A nineralocorticoid. (Q Cortodoxone (INN). Some derivatives are modified so as to suppress their cortical hormone effect in favour of their anti-inflammatory effect, which is regarded as being a hormonal effect. These are principally derivatives of cortisone (INN), h drocortisone (INN), predqisone (INN) and predmsolone (INN), which are used as anti-in ammatory and anhrheumatlsm agents. X (2) Halogenated derivatives of corticosteroid hormones are steroids in which the hydrogen atom generally at the 6- or 9-position on the gonane ring is substituted by a chlorine or fluorine atom (e-g., dexamethasone (INN)) and which greatly enhance the glucocorticoid and anti-inflarnmato effect of the corticoids fiom which they are derived. These derivatives are often er modified and marketed in the form of esters, acetonides (e.g., fluocinolone acetonide (INN)), etc. & (3) Oestro ens and progestogens. These are two major groups of sex hormones secreted by the ma e and female genital or8ans. They may also be obtained by synthesis. These hormones are also called progestins and gestagens. k Oestrogens are female sex hormones produced by the ovaries, testes, adrenal glands, placenta and other steroid- roducing tissues. They are characterised by their ability to roduce oestrus in the fema fe mammal. Oestrogens are responsible for the development of Female sex characteristics and are used in the treatment of meno ause or in the pre aration of contraceptive drugs. They include the following oestrogens, Livatives and ana ogues : P (a) Estrone (INN). A principal oestrogen in humans. (b) Estradiol (INN). An important natural oestrogen. (c) Estriol (INN). A natural oestrogen. (d) Ethinyl estradiol (INN). An important synthetic oestrogen which is orally active and used as a main oestrogenic component in combination oral contraceptives. (e) Mestranol (INN). Ether derivative of ethiny1 estradiol. Used as an oral contraceptive. Progesto ens are a class of steroids named for their progestational effects, which are essential or the initiation and continuation of pregnancy. These female sex hormones prepare the uterus for pregnancy and for the maintenance of pregnancy. Because they sup ress ovulation, many progestins are used as components of contraceptive drugs. They inc ude : f f' (a) Progesterone (INN). The primary pro estin in humans and an intermediate in the biosynthetic pathwa s of oestrogens, an ogens and corticosteroids. It is produced by the corpur luteurn &er release of the ovum and in the adrenal gland, the placenta and the testes. L (b) Pregnandiol. Naturally occurring progestin with a much weaker biological activity than that of progesterone. (4) Other steroidal hormones. Androgens are a major group of sex hormones not included above, which are produced mainly by the testes and, to a lesser extent, by the ovaries, adrenal glands and placenta. Androgens are responsible for the development of male sex characteristics. Androgens influence metabolism, i.e., have an anabolic effect. Testosterone (INN) is one of the most important androgens. This part also includes synthetic steroids used to inhibit or counteract the effects of hormones, such as anti-oestrogens, anti-androgens, and anti- ro estogens (antiprogestins, antiestagens). Steroidal antiprogestins are progestin antagonists w ic have found man uses in the treatment of some diseases. Examples of this group mclude onapristone (INN)an aglepristone (INN). \-g B The most important of these steroids in international trade are listed below. The products are cited in alphabetical order, accordin to their short names, followed b an indication of their main hormonal function. If severa names exist, the name used is ti! at of the International ublished by the World Health Nonproprietary Names for harrnaceutical reparations ( Organization or that of tfe Internationa Non ropriet Mohfied (INNM). The Rules for Nomenclature of chemical names given are in accordance Steroids. r List of steroids used rimarily for their hormone unction P Short name Chemical name Adrenosterone androst-4-ene-3,11,17-trione Aldosterone (INN) 1 1P,2 1-dihydroxy-3,20-dioxopregn4-en18-a1 Allylestrenol (INN) 17a-allyloestr-4-en-17~-ol (No short name) Main hormonal function Androgen Corticosteroid Progestogen Androgen intermediate 5a-androstane-3,17-dione Androstanolone (INN) Androgen 17P-hydroxy-5a-androstan-3-one Androstenediols androst-5-ene-3P, 1 7P-diol androst-5-ene-3P,17a-diol Anabolic intermediate (No short name) Androgen intermediate androst-4-ene-3,17-dione Androsterone Androgen 3 a-hydroxy-5a-androstan-17-one Betamethasone (INN) 9a-fluoro-11 p, l7a,21 -trihydroxy-16~-methylpregna-l,4-diene-3,2O-dione Bolasterone (INN) 17P-hydroxy-7a,17a-dimethylmdrost-4-en-3 -one Chlormadinone (INN) 6-chloro- 17a-hydroxypregna-4,6-diene-3,20-dione Corticosteroid Anabolic Progestogen Short name Chemical name Main hormonal function Chloroprednisone (INN) 6a-chloro- 17a,21-dihydroxypregna-1,4-di-3 11,20-trione Corticosteroid Clocortolone (INN) 9a-chloro-6a-fluoro-11J3,21-dihydroxy-1&a-methylpregna-1,4diene-3,20-dione Corticosteroid Clostebol (INN) 4-chloro- l7P-hydroxyandrost-4-en-3 -one Anabolic Corticosterone 11J3 ,2 1-dihydroxypregn-4-ene-3,2Mone Corticosteroid Cortisol - see Hydrocortisone Cortisone (INN) 17a,21-dihydroxypregn-4-ene-3,11,20-lrione Corticosteroid Corticosteroid Deoxycorticosterone - see Desoxycortone Desoxycortone (INN) 2 1-hydroxypregn-4-ene-3,2O-dione Corticosteroid Dexamethasone (INN) 9a-fluoro-11p, 17a,21-trihydroxy-16a-methylpregna-l,4-diene3,20-dione Corticosteroid Dihydroandrosterooe 5a-androstane-3a,17P-diol Dydrogesterone (INN) 9p, 1 Oa-pregna-4,6-diene-3,20-dione Androgen intermediate Progestogen Equilenin 3 -hydroxyoestra-1,3,5(10),6,8-pentaen-17-one Oestrogen Equilin 3-hydroxyoestra-1,3,5(10),7-tetraen-17-one Oestrogen Short name Chemical name Main hormonal function Estradiol (INN) oestra-1,3,5(10)-triene-3,17~o1 Oestrogen Estriol (INNM) Oestrogen oestra-1,3,5(10)-triene-3,16a,17P-trio1 Estrone (INN) Oestrogen 3-hydroxyoestra-1,3,5(10)-trien-17-one Ethinylestradiol (INN) 1701-ethynyloestra-l,3,5(10)-triene-3,17p-diol Ethisterone (INN) 17a-ethynyl-l7~-hydroxyandrost4-en-3-one Ethylestrenol (INN) 17a-ethyloestr-+en-1 7P-01 Etynodiol (INN) Oestrogen Progestogen Anabolic Progestogen 17a-ethynyloestr-4-ene-3P, 17P-diol Fludrocortisone (INN) 9a-fluoro- 1 1P,17a,2 1-trihydroxypregn-4-ene-3,20-dione Corticosteroid Flumetasone (INN) 6a,9a-difluoro-l l ~,17a,21-trihydroxy-16a-methylpregna-l,4diene- 3,20-&one Corticosteroid Fluocinolone (INNM) 6a,9a-difluoro-1 lP,16a,17a,2 1-tetrahydroxy-pregna-1,4-diene3,20-dione Corticosteroid Fluocortolone (INN) 6a-fluoro- 11P,2 1-dihydroxy-l6a-methylpregnal,4-diene-3,20dione Corticosteroid Fluorometholone (INN) Corticosteroid 9a-fluoro-l lp, 17a-dihydroxy-6a-methylpregnal,4-diene-3,20-dione Corticosteroid Short name Chemical name Main hormonal function Fluoxymesterone (DIN) 9a-fluoro-l l J3,17~-dihydroxy-17a-methylandrost-4-en-3-one Androgen Fluprednidene 0 9a-fluoro- 11p,l7a,2 1-trihydroxy-16methylenepregna-1,4-diene3,20-dione Corticosteroid Fluprednisolone (INN) 6a-fluoro-l l P,17a,21-trihydroxypregna-l,4-diene-3,20-dione Corticosteroid Flurandrenolone 6a-fluoro-11P, 16a,17a,21-tetrahy&oxypregn*-ene-3,20-dione Corticosteroid Formocortal (INN) 3-(2-ch1oroethoxy)-9a-fluoro-6-fomyl-l l P,2ldihydroxy-l6a, 17isopropylidenedioxypregna-3,5-dien-20one 21-acetate Corticosteroid Gestonorone (INNM) 17~-ethyl-l7a-hydroxyoestr-4-ene-3,20-dione Progestogen Hydrocortisone (INN) 1 I p, l7a,21-trihydroxypregn-4-ene-3,20-dione Corticosteroid Hydroxyprogesterone(INN) 17a-bydroxypregn-4-ene-3,20-dione Progestogen Lynestrenol (INN) 17a-ethynyloestr-4-en-17P-01 Progestogen Medroxyprogesterone(INN) 17a-hy&oxy-6a-methylpregn-4-ene-3,20-done Progestogen Megestrol (INN) 17a-hydroxy-6-methylpregna-4,6-diene-3,20-dione Progestogen Mestanolone (INN) 17~-hydroxy-l7a-methyl-5a-androstan-3-one Anabolic Mesterolone (INN) 17P-hydroxy-1a-methyl-5a-androstan-3-one Androgen Short name Chemical name Main hormonal function Mestranol (INN) 17a-ethy~1yl-3-methoxyoestra-1,3,5(10)-trien-l7~-ol Oestrogen Metandienone (INN) Anabolic 17~-hydroxy-l7a-methylandrosta-l,4-dien-3-one Metenolone (INN) l7a-hydroxy-1-methyl-5a-androst-1 -en-3-one Anabolic Methandriol (INN) 17a-methylandrost-5-ene-3p, 17P-diol Anabolic Corticosteroid Corticosteroid Methylnortestosterone 1 7P-hydroxy- 17a-methyloestr-4-en-3-one Progestogen Oestrogen Methylprednisolone (INN) 11J3,17a,21-trihydroxy-6a-methylpregna1,4-diene-3,20-done Corticosteroid Methyltestosterone (INN) 17P-hydroxy- 17a-methylandrostd-en-3 -one Androgen Nandrolone (INN) 17~-hydroxyoestr-4-en-3-one Anabolic Norethandrolone (INN) 17a-ethyl-l7P-hydroxyoestr4-en-3-one Anabolic Norethisterone (INN) 17a-ethynyl-l7~-hydroxyoestr4-en-3-one Progestogen Noretynodrel (INN) 17a-ethynyl-17P-hydroxyoestr-5(10)-en-3-one Progestogen Short name Chemical name Norgestrel (INN) 13~-ethyl-l7a-ethyny1-17~-hydroxygon-4-en-3-one Main hormonal function Progestogen Normethandrone - see Methylnortestosterone Nortestosterone - see Nandrolone Oxabolone (INNM) 4,17P-dihydroxyoestr-4en-3-e Anabolic Oxymesterone (NN) 4,17P-dihydroxy-l7a-rnethylandrost4en-3-one Anabolic Oxymetholone (INN) 17~-hydroxy-2-hydroxymethylene-17a-methyl-5a-androstan-3-one Anabolic Parsmethasone (INN) 6a-fluoro-1 1 p,l7a,21 -trihydroxy-16a-rnethylpregna-1 ,4-diene3,20-dione Prasterone (INN) 3p-hydroxyandrost-5-en17-one Corticosteroid Androgen Prednisolone (INN) 1 1p, 17a,21-trihydroxypregna-l,4-diene-3,20-dione Corticosteroid Prednisone (INN) 17a,21 -dihydroxypregna-1,4-diene-3,11,20-trione Corticosteroid Prednylidene (INN) 1 1p,17a,21 -trihydroxy-16-met.hylenepregna-l,4-diene-3,20-dione Corticosteroid Pregnenolone (INN) 3p-hydroxypregn-5-en-20-one Corticosteroid Progesterone (INN) pregn4-ene-3,20-&one Stanolone - see Androstanolone Progestogen Short name Chemical name Main hormonal function Testosterone (INN) 17P-hydroxyandrost-4-en-3-one Androgen Tiomesterone (INN) 1 a,7a-di(acety1thio)-17j3-hydroxy-17a-methylan&ost-4-m-3-one Anabolic Triamcinolone (INN) 9a-fluoro-1 1P,16a, 17a,21 -tetrahydroxypregna-1,4-diene-3,20dione Corticosteroid (C) PROSTAGLANDINS, THROMBOXANES AND LEUKOTRIENES,THEIR DERIVATIVES AND STRUCTURAL ANALOGUES These products are derivatives of arachidonic acid. (1) Prostaglandins. The most important arachidonic acid derivatives are prostaglandins, endogenous substances operating in minute doses as hormones and containing the fundamental structure of rostanoic acid. Prostaglandins influence the regulation of blood circulation, kidney !!unction and the endrocnne system (e.g., by reducing the production of pro esterone by the corpus luteurn); they also stimulate the contraction of smooth muscles or llation of blood vessels, prevent latelet aggregation and regulate gastric secretions. These include the following prostag andins, derivatives and analogues : d P (a) Alprostadil (INN) (prostaglandin El). A primary rostaglandin crystallised fi-om biological extracts. It is used as a vasodilator. It also Enctions to stimulate the release of erythropoietin fkom the renal cortex and inhibits blood platelet aggregation. (b) Alfaprostol (INN). A synthetic prostaglandin analogue used in the treatment of infertility in mares. (c) Tilsuprost (INN).A prostaglandin analogue which has had an oxygen and a carbon atom replaced by a nitrogen and a sulphur atom with ring closure. This grou also includes other synthetic products such as prostalene (INN), dinoprost fiNN), etc., which retain the basic structure of natural products and have similar physiological activity. (2) Thromboxanes and leukotrienes. Thromboxanes and leukotrienes, like prostaglandins, are synthesised in cells from arachidonic acid; although their fhction is comparable to that of prostaglandins and their structure is very similar, the do not contain the fundamental structure of prostanoic acid. Thromboxanes are biosynt ietically derived from prostaglandins. They cause platelet ag egation and contraction of arteries, and are important re lators of the act~onsof sahlnued fatty acids. Leukotrienes received their name gcause of their origin in f,"d%ytes and their con'ugated triene structure. They are potent bronchoconstrictors and play an important role in ypersensitivity reactions. h B2.A vasoconstrictor, a bronchoconstrictor and an inducer of blood platelet aggregation. (a) Thromboxane (b) Leukotriene Cq. Found to be 100 to 1,000 times more potent than histamine or prostaglandins in their effects on pulmonary air passages. (D) OTHER HORMONES Classified here are other hormones whose structure differs from that of the hormones referred to above. An example is melatonin, which is found in the pineal land and can be considered to be a derivative of indol. Other hormones classified here are the fo lowing : (I) Catecholamine hormones, their derivatives and structural analogues. This group of hormones includes those found in the medullar zone of the adrenal glands. (a) Epinephrine (INN)(adrenaline or (-)-3,4-dihydroxy-a-[(methyIamino)methyl]benzyl alcohol) and racepinephrine (INN) ((&)-3,4-dihydroxy-a[(methylamino)methyl benzyl alcohol). The structure of both of these hormones corresponds to the c emical name 1- 3,4-dihydroxypheny1)-2-methylaminoethanol. E ine hrine is a light brown or nearly w ite crystalline powder, affected by light; it is s ight y soluble in water and organic solvents. It may be derived from the adrenal glands of horses, but: is obtained mostly by synthesis. A hypertension hormone, it stimulates the sympathetic nervous system, increases the number of corpuscles and the sugar content in blood; it also has a strong vasoconstrictive action. P P h (b) Nore inephrine (INN) (levarterenol, noradrenaline or (-)-2-amino-1-(3,4dihy~oxThenyl)ethanol). Norepinephrine occurs as white stals, soluble in water. Its physio ogical activity is intermedxate between that of adrena ine and of ephedrine. (2) Amino-Acid Derivatives. eficiency in the active form. The I (b) Liothyronine (INN) and rathyronine INN) (DL-3,5,3'-triiodothyronine) (3-[4-(4hydroxy-3-iodo henoxy)-3,5-diiodopheny lalanine). Tn~odothyronineis also extracted from the thyroi!' gland; its physiologcal activity is greater than that of thyroxine. EXCLUSIONS The heading excludes : (1) Products not having a hormonal effect, but having a hormone-like structure : (a) Androst-5-ene-3a,17a-diol,androst-5-ene-3a,l7j3-diol(heading 29.06) and their diacetates (heading 29.15). (b) Adrenalone (INN)(3',4'-dihydroxy-2-methylaminoacetophenone)(heading 29.22). (c) The following products which are classified in heading 29.22 : (i) 2-Amino-l-(3,4-dihydroxypheny1)butan1-01. (ii) Corbadrine (INN) (2-amino- 1-(3,4-dihydroxypheny1)propan- 1-01, 3,4-dihydroxynorephedrine,homoarterenol). (deoxyadrenaline, 1-(3,4-dihydroxypheny1)-2-methyldoethane, (iii) Deoxyepinephrine epinin). (iv) 3',4'-Dihydroxy-2-ethylaminoacetophenone(4-ethylarninoacetylcatechol). (v) l-(3,4-Dihydroxyphenyl)-2-methyIarninoprop-l-o(3,4-dihydroxyephedrine). (vi) (&)-N-Methyl inephxine ((*I1-(3,4-dihydroxypheny1)-2-dimethylaminoethanl, methadrene, (3-N-methY1adrenaline). (2) Products having a hormonal effect, but not having a hormone-like structure : (a) Dienestrol (INN) (3,4-bis(p-hydroxypheny1)hexa-2,4-diene) (heading 29.07). (b) Hexestrol (INN) (3,4-bis(p-hydroxypheny1)hexane) (heading 29.07). (c) Dietb lstilbestrol (INN) trans-3,4-bis(p-hydrox hen 1)hex-3-ene) heading 29.07), its dimeXyl ether (heading 2 .09), its dipropionateyf)bea&ng29.15) an its furoate (heading 29.32). (d) Clomifene (INN)(anti-oestrogen)(heading 29.22). (e) Tamoxifen (INN) (anti-oestrogen)(heading 29.22). (f) Flutamide (INN) (anti-androgen) (heading 29.24). (g) Endothelin antagonists, such as darusentan (INN) (heading 29.33), atrasentan (INN)(heading 29.34) and sitaxentan (INN) (heading 29.35). (3) Natural substances with hormonal effects, but which are not secreted in the bodies of humans or animals : (a) Zearalenone, an anabolic agent (heading 29.32). (b) Asperlicin, a cholecistoquinineantagonist (heading 29.33). (4) The fotlowing products sometimes considered to be hormones but which have no real hormone activity : (a) Cystine, cysteine (INN) and their hydrochlorides (heading 2930). (b) Methionine and its calcium salts (heading 29.30). (c) Neurotransmitters and neuromodulators, such as dopamine (headin 29.221, acetylcholine heading 29.23), serotonin (5-h@ox . tamine or 5-hydroxy- -(b-arninoethy1)indole) heading 29-33], histamine (herdlag 2% and related products, such as their receptor agonists and antagonists. S (d) Leukemia-inhibiting factor (human) growth factor emfilermin (INN) (heading 29.33) and fibroblast growth factor repifermin (INN) (heading 29.33). (e) NMDA (N-rnethyl-D-as artic acid) receptor antagonists, such as lanicemine (INN) (heading 29.33) and nebostinel (I& (heading 29.24). (0 Heparin (heading 30.01). (g) Modified immunological products (heading 30.02). (5) Plant-growth regulators (e.g., phytohormones), natural or synthetic, which are classified : (A) When unmixed and not put up for retail sale, according to their chemical composition, for instance : (a) a-Naphthylaceticacid and its sodium salt (heading 29.16). (b) 2,4-Dichlorophenoxyacetic acid (2,4-D), 2,4,5-T QSO) (2,4,5-trichlorophenoxyaceticacid) and 4-chloro-2-methyl-phenoxyacetic acid (MCPA) (heading 29.18). (c) P-Indolylacetic acid and its sodium salt (heading 29.33). (B) When put up in forms or packings for retail sale or as preparations or articles, in heading 38.08. (6) Antagonists of thromboxanes and leukotrienes, which are classified according to their structure (e.g., seratrodast (INN) (heading 29.18) and montelukast (INN) (heading 29.33)). (7) Antagonists of tumor necrosis factor, such as ataquimast (INN)(heading 29.33). (8) Immunological products of heading 30.02. (9) Medicaments of heading 30.03 or 30.04, in particular, ",Retard Insulin " (zinc-insulin, protamin-zinc insulin, globin-insulin, zinc-globin insulin, histone-insulin). Sub-chapter XI1 GLYCOSLDES AND VEGETABLE ALKALOIDS, NATURAL OR REPRODUCED BY SYNTHESIS, AND THEIR SALTS, ETHERS, ESTERS AND OTHER DERIVATIVES GENERAL In this Sub-chapter, the term "derivatives" refers to chemical com ounds which could be obtained fiom a starting compound of the heading concerned and w ich retain the essential characteristics of the parent compound, including its basic structure. i
1.- Except where the context otherwise requires, the headings of this Chapter apply only to : (a) Separate chemically defined organic compounds, whether or not containing impurities; (b) Mixtures of two or more isomers of the same organic compound (whether or not containing impurities), except mixtures of acyclic hydrocarbon isomers (other than stereoisomers), whether or not saturated (Chapter 27); (c) The products of headings 29.36 to 29.39 or the sugar ethers, sugar acetals and sugar esters, and their salts, of heading 29.40, or the products of heading 29.41, whether or not chemically defined; (d) The products mentioned in (a), (b) or (c) above dissolved in water; (e) The products mentioned in (a), (b) or (c) above dissolved in other solvents provided that the solution constitutes a normal and necessary method of putting up these products adopted solely for reasons of safety or for transport and that the solvent does not render the product particularly suitable for specific use rather than for general use; (f) The products mentioned in (a), (b), (c), (d) or (e) above with an added stabiliser (including an anti- caking agent) necessary for their preservation or transport; (g) The products mentioned in (a), (b), (c), (d), (e) or (f) above with an added anti-dusting agent or a colouring or odoriferous substance or an emetic added to facilitate their identification or for safety reasons, provided that the additions do not render the product particularly suitable for specific use rather than for general use; (h) The following products, diluted to standard strengths, for the production of azo dyes : diazonium salts, couplers used for these salts and diazotisable amines and their salts. 2.- This Chapter does not cover : (a) Goods of heading 15.04 or crude glycerol of heading 15.20; (b) Ethyl alcohol (heading 22.07 or 22.08); (c) Methane or propane (heading 27.11); (d) The compounds of carbon mentioned in Note 2 to Chapter 28; (e) Immunological products of heading 30.02; (f) Urea (heading 31.02 or 31.05); (g) Colouring matter of vegetable or animal origin (heading 32.03), synthetic organic colouring matter, synthetic organic products of a kind used as fluorescent brightening agents or as luminophores (heading 32.04) or dyes or other colouring matter put up in forms or packings for retail sale (heading 32.12); (h) Enzymes (heading 35.07); (ij) Metaldehyde, hexamethylenetetramine or similar substances, put up in forms (for example, tablets, sticks or similar forms) for use as fuels, or liquid or liquefied-gas fuels in containers of a kind used for filling or refilling cigarette or similar lighters and of a capacity not exceeding 300 cm3 (heading 36.06); (k) Products put up as charges for fire-extinguishers or put up in fire-extinguishing grenades, of heading 38.13; ink removers put up in packings for retail sale, of heading 38.24; or (l) Optical elements, for example, of ethylenediamine tartrate (heading 90.01). 3.- Goods which could be included in two or more of the headings of this Chapter are to be classified in that one of those headings which occurs last in numerical order. 4.- In headings 29.04 to 29.06, 29.08 to 29.11 and 29.13 to 29.20, any reference to halogenated, sulphonated, nitrated or nitrosated derivatives includes a reference to compound derivatives, such as sulphohalogenated, nitrohalogenated, nitrosulphonated or nitrosulphohalogenated derivatives. Nitro or nitroso groups are not to be taken as “nitrogen-functions” for the purposes of heading 29.29. For the purposes of headings 29.11, 29.12, 29.14, 29.18 and 29.22, “oxygen function”, the characteristic organic oxygen-containing group of those respective headings, is restricted to the oxygen-functions referred to in headings 29.05 to 29.20.