Trenbolone acetate

Last updated
Trenbolone acetate
Trenbolone acetate.svg
Clinical data
Trade names Finajet, Finaplix, others
Other namesRU-1697; Trenbolone 17β-acetate; 19-Nor-δ9,11-testosterone 17β-acetate; Estra-4,9,11-trien-17β-ol-3-one 17β-acetate
Routes of
administration
Intramuscular injection
Drug class Androgen; Anabolic steroid; Androgen ester; Progestogen
Pharmacokinetic data
Elimination half-life Intramuscular: 3 days [1]
Identifiers
  • [(8S,13S,14S,17S)-13-Methyl-3-oxo-2,6,7,8,14,15,16,17-octahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.030.380 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H24O3
Molar mass 312.409 g·mol−1
3D model (JSmol)
  • CC(=O)O[C@H]1CC[C@@H]2[C@@]1(C=CC3=C4CCC(=O)C=C4CC[C@@H]23)C
  • InChI=1S/C20H24O3/c1-12(21)23-19-8-7-18-17-5-3-13-11-14(22)4-6-15(13)16(17)9-10-20(18,19)2/h9-11,17-19H,3-8H2,1-2H3/t17-,18+,19+,20+/m1/s1
  • Key:CMRJPMODSSEAPL-FYQPLNBISA-N

Trenbolone acetate, sold under brand names such as Finajet and Finaplix among others, is an androgen and anabolic steroid (AAS) medication which is used in veterinary medicine, specifically to increase the profitability of livestock by promoting muscle growth in cattle. [2] [3] [4] [5] It is given by injection into muscle. [5] [2]

Contents

Side effects of trenbolone acetate include symptoms of masculinization like acne, increased body hair growth, scalp hair loss, voice changes, and increased sexual desire. [5] The drug is a synthetic androgen and anabolic steroid [6] and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). [5] [2] [7] It has strong anabolic effects and highly androgenic effects, as well as potent progestogenic effects, and weak glucocorticoid effects. [5] [2] [7] [8] [9] Trenbolone acetate is an androgen ester and a short-lasting prodrug of trenbolone in the body.

Trenbolone acetate was discovered in 1963 and was introduced for veterinary use in the early 1970s. [5] [10] [11] In addition to its veterinary use, trenbolone acetate is used to improve physique and performance, and is purchased from black market suppliers. [5] The drug is a controlled substance in many countries and so non-veterinary use is generally illicit. [5]

Uses

Veterinary uses

A single cartridge of Finaplix-H containing 10 implants. Each implant contains 10 small yellow pellets. (Image Adapted from Medi-Vet Animal Health, LLC (https://www.medi-vet.com/Finaplix-H-p/16301.html)). A single cartridge of Finaplix-H containing 10 implants. Each implant includes 10 small yellow pellets (one whole column in the above image) which contains 200mg of trenbolone acetate.jpg
A single cartridge of Finaplix-H containing 10 implants. Each implant contains 10 small yellow pellets. (Image Adapted from Medi-Vet Animal Health, LLC (https://www.medi-vet.com/Finaplix-H-p/16301.html)).

In the livestock industry, trenbolone acetate is more often called Finaplix. It was intentionally developed to promote androgen and gain muscle mass in cattle. Due to its properties, this allows livestock to grow as much muscle as possible before they are transported to a slaughterhouse.

Methyl cellulose and yellow dye are usually present in pellets given to livestock. A single dosage generally consists of 10 pellets, and a package of Finaplix usually consists of one cartridge, which contains 100 pellets (See Figure). This is usually given to the animal by means of a subcutaneous injection into the posterior location of the ear (See Figure) with the use of an implanter gun. Finaplix is consistently implanted until the animal is ready to be slaughtered. There is no withholding period. Due to the common practice of trenbolone acetate use in veterinary medicine, it is quite common to find traces of trenbolone metabolites in cattle worldwide. [10] [12]

Image showing the general area of the implantation of Finaplix-H pellets displayed on bovine ear. General area of the implantation of Finaplix- H pellets displayed on bovine ear.jpg
Image showing the general area of the implantation of Finaplix-H pellets displayed on bovine ear.

Non-medical uses

Bodybuilding

Trenbolone acetate was never approved for use in humans and therefore guidelines for human consumption do not exist. [5] However, athletes and bodybuilders have been using trenbolone acetate as a physique- and performance-enhancing drug for decades. There are a large number of benefits as a bodybuilder through using trenbolone acetate as an AAS. Unlike testosterone, trenbolone acetate does not cause any fluid retention while gaining muscle mass. [10] This allows bodybuilders to appear leaner, and this is why it is more commonly used whilst preparing for competitive events. Trenbolone acetate does not convert into an estrogenic metabolite, [10] and this results in a lack of estrogenic side effects. [5] Trenbolone enanthate is also a very commonly used AAS and lasts much longer than trenbolone acetate with intramuscular injection. [5]

Medical uses

Trenbolone acetate was never approved for use in humans and hence has no medical uses. [5] However, as an AAS, it would be expected to be effective for indications in which other AAS are useful such as the treatment of conditions like androgen deficiency, wasting syndromes and muscle atrophy, and certain types of anemia. [5] [13]

Trenbolone was produced for human use as a human grade product, but only once. The product came in 1.5ml ampoules consisting of 76.2 mg of Trenbolone hexahydrobenzylcarbonate and made by Negma Pharmaceuticals of France. [ citation needed ]

Side effects

Trenbolone acetate, like any other AAS, has many side effects. [7] [14] [15] The strong androgenic nature of trenbolone acetate facilitates its tendency to produce virilization [7] and this is why it is not recommended for women for physique- or performance-enhancing purposes. [5] The side effects of trenbolone acetate are similar to other AAS; however, the negative side effects that are specifically facilitated by trenbolone acetate are as follows.

Androgenic

Trenbolone acetate has androgenic activity. [16] [17] [18] Specific to the androgenic properties of trenbolone, common side effects of the AAS use include oily skin, acne, seborrhea, increased facial/body hair growth, and accelerated scalp hair loss. [5] [7] [19] These side effects strongly rely on an individual's genetics and may not always occur in every individual. Men susceptible to hair loss related illnesses, such as baldness have a higher chance of becoming permanently bald with the use of trenbolone acetate. [7] In women, voice deepening, hirsutism, clitoral enlargement, and virilization in general may occur. [5]

Hypogonadism

Trenbolone acetate contributes greatly to muscle mass and feed efficiency; however, administration of the AAS suppresses natural testosterone production; i.e., it has the potential to cause hypogonadism. [5] [14] [19] This is a common effect of all AAS; the only difference is the variation in how much they suppress in comparison to others.

Cardiovascular

Administration of any AAS can lead to cardiovascular issues. [20] Trenbolone acetate can have a negative and strong impact on cholesterol through suppressing both high-density lipoprotein (HDL) cholesterol and increasing low-density lipoprotein (LDL) cholesterol. [21] When compared to oral AAS, trenbolone acetate has a stronger negative effect on cholesterol levels. This negative effect is much more severe with the use of injectable AAS, particularly trenbolone acetate. [22]

"Tren cough"

The exact mechanisms underlying the cause of the tren cough are not known; however, trenbolone acetate's androgenic effect activates a variety of lipid-like active compounds which are called prostaglandins. [23] Many of these prostaglandins are inflammatory and vasoconstrictive. Prostaglandins are signalled through two varying pathways cyclooxygenase (COX) (Also known as: prostaglandin-endoperoxide synthase) and lipoxygenases (LOX) (also known as: EC 1.13.11.34, EC 1.13.11.33, etc.). [24] The bradykinin peptide is well known to promote a cough reaction associated with ACE inhibitor medications prescribed for hypertension. [25]

Estrogenic and progestogenic

No form of trenbolone, including trenbolone acetate, is estrogenic. [5] Excess fluid retention is not possible with the administration of this AAS as a result of its not being estrogenic as opposed to testosterone. [5] However, due to trenbolone's potent progestogenic activity, gynecomastia, which is characterized by development and swelling of breast tissue, [26] may still be possible.[ citation needed ] Stimulation of estrogenic mechanisms are enforced by progestogenic activity[ citation needed ] as trenbolone acetate and its compounds bind with high affinity to the progesterone receptor. [10] [18] It has been assumed that gynecomastia as a result of trenbolone use is due to a buildup of the hormone prolactin; [26] however, a variety of studies conclude that it is the progestogenic activity of trenbolone promoting this and not prolactin.[ citation needed ] Trenbolone also has a negative impact on blood pressure, but it does not appear to negatively affect most healthy adult men in this way.[ citation needed ]

Pharmacology

Pharmacodynamics

The administration of the trenbolone hormone promotes a direct anabolic effect on Androgen Receptor (AR) activity. AR activity facilitated by trenbolone contributes to an increase in IGF-1 and IGF-1R levels, which then enhances skeletal muscle protein accretion. Activation and proliferation of satellite cells then facilitate an increase in skeletal muscle growth. How the administration of the trenbolone hormone causes muscle growth.jpg
The administration of the trenbolone hormone promotes a direct anabolic effect on Androgen Receptor (AR) activity. AR activity facilitated by trenbolone contributes to an increase in IGF-1 and IGF-1R levels, which then enhances skeletal muscle protein accretion. Activation and proliferation of satellite cells then facilitate an increase in skeletal muscle growth.

Trenbolone acetate is a prodrug of trenbolone. [2] [5] Like other AAS, trenbolone is an agonist of the androgen receptor (AR) and hence has anabolic and androgenic activity as well as antigonadotropic activity. [5] [2] [8] [17] Trenbolone carries a rating for both anabolic potency and androgenic potency of 500, relative to a standard of nandrolone acetate (rating 100 for both). [5] [14] In addition to its anabolic and androgenic activity, trenbolone is an agonist of the progesterone receptor (PR), and in relation to this, has moderate to strong progestogenic activity. [5] [8] [17] Conversely, trenbolone acetate is not a substrate for aromatase and hence lacks estrogenic activity. [5] [2] [8] The compound also has weak glucocorticoid activity. [8] [9]

Similar to many other AAS, trenbolone acetate has the capability to produce insulin-like growth factor-1 (IGF-1). [28] [29] This naturally produced protein-based hormone affects every cell in the body of an organism and plays a large role in muscle recovery and rejuvenation. Extreme muscle growth and cell splitting compared is facilitated through trenbolone acetate administration when compared to other AAS. [28] The facilitation of IGF-1 plays a significant role in the functions and properties of the central nervous system, pulmonary system, muscle tissue, ligaments, cartilage, and tendons. [29]

Trenbolone acetate also has the ability to increase red blood cell count. With a larger amount of red blood cells, blood oxygenation is enhanced. This allows for enhanced muscular endurance and therefore promotes a faster rate of recovery. Trenbolone acetate is capable of inhibiting glucocorticoids such as cortisol.[ citation needed ] The properties of glucocorticoid are the opposite of androgens as muscle tissue depletion and fat gain is promoted. [30] Administration of trenbolone acetate aims at decreasing the production of glucocorticoid hormones. Trenbolone acetate’s contribution to feed efficiency, also known as nutrient efficiency is what makes it an attractive AAS used for agricultural purposes. Food is one of the most anabolic substances that any living organism can consume, and therefore with the administration of trenbolone acetate, every nutrient in the body becomes a lot more valuable. [31] This facilitates an organism's body that is exposed to the AAS to make better use of the nutrients already consumed. [10] [31]

Pharmacokinetics

The acetate ester of trenbolone acetate allows for slow release post injection. This ester gives trenbolone an activated elimination half-life of about 3 days. [1]

Chemistry

Trenbolone acetate, or trenbolone 17β-acetate, is a synthetic estrane steroid and a derivative of nandrolone (19-nortestosterone). [5] [32] [33] It is the C17β acetate ester of trenbolone, which itself is δ9,11-19-nortestosterone (δ9,11-19-NT) or estra-4,9,11-trien-17β-ol-3-one. [5] [32] [33] Other trenbolone esters include trenbolone enanthate, trenbolone hexahydrobenzylcarbonate, and trenbolone undecanoate. [5] [32] [33]

Structural properties of major anabolic steroid esters
Anabolic steroidStructureEsterRelative
mol. weight
Relative
AAS contentb
Durationc
PositionMoietyTypeLengtha
Boldenone undecylenate
Boldenone undecylenate.svg
C17β Undecylenic acid Straight-chain fatty acid111.580.63Long
Drostanolone propionate
Drostanolone propionate.svg
C17β Propanoic acid Straight-chain fatty acid31.180.84Short
Metenolone acetate
Metenolone acetate.svg
C17β Ethanoic acid Straight-chain fatty acid21.140.88Short
Metenolone enanthate
Metenolone enanthate.png
C17β Heptanoic acid Straight-chain fatty acid71.370.73Long
Nandrolone decanoate
Nandrolone decanoate.svg
C17β Decanoic acid Straight-chain fatty acid101.560.64Long
Nandrolone phenylpropionate
Nandrolone phenylpropionate.svg
C17β Phenylpropanoic acid Aromatic fatty acid– (~6–7)1.480.67Long
Trenbolone acetate
Trenbolone acetate.svg
C17β Ethanoic acid Straight-chain fatty acid21.160.87Short
Trenbolone enanthate d
Trenbolone enanthate.svg
C17β Heptanoic acid Straight-chain fatty acid71.410.71Long
Footnotes:a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative androgen/anabolic steroid content by weight (i.e., relative androgenic/anabolic potency). c = Duration by intramuscular or subcutaneous injection in oil solution. d = Never marketed. Sources: See individual articles.

Structure–activity relationships

Trenbolone acetate is a modified form of nandrolone. [16] The structure of trenbolone acetate is a 19-nor classification, which represents a structural change of the testosterone hormone. Trenbolone acetate lacks a carbon atom at the 19 position and carries a double bond at carbons 9 and 11. The position of these carbons slows its metabolism, which greatly increases its binding affinity to the AR, and inhibits it from undergoing aromatization into the corresponding estrogenic metabolite. Trenbolone acetate contains trenbolone modified with the addition of a carboxylic acid ester (acetic acid) at the 17β-hydroxyl group. [10] This facilitates the slow release of the AAS from the area of injection.

History

Trenbolone acetate was first synthesized in 1963 and approved by the livestock industry as a growth promoter for beef cattle in the early 1970s. [5] [10] [11] During this period of its first administration, trenbolone acetate was sold under the names Finajet and Finaject. The original manufacturer of trenbolone acetate discontinued during the late 1980s and administered the synthesis of subcutaneous pellets called Finaplix. These pellets aimed to increase muscle mass and lean tissue of cattle prior to slaughter to increase the profitability of livestock when measured in total pounds of meat sold. [10]

The drug appears to have been an early development project of Roussel Uclaf, a French pharmaceutical company, and by the early 1970s, it was being sold as an injectable. [18] There are a number of trenbolone esters but trenbolone acetate is the only one known to be produced in veterinary AAS manufacturers.

Trenbolone acetate became popular among bodybuilders and athletes during the early 1980s. During this period, the AAS was transported illegally from Europe in large quantities. Although trenbolone acetate was very popular for a short amount of time, the large amounts of supplies were discontinued in 1987. [10] This decision was based upon the public concern of sports doping and its negative effects on athletes. [5]

Society and culture

Generic names

Trenbolone acetate is the generic name of the drug and its USAN Tooltip United States Adopted Name, USP Tooltip United States Pharmacopeia, and BANM Tooltip British Approved Name. [3] [4] [32] [33]

Brand names

Trenbolone acetate is or has been sold alone for veterinary use under the brand names Component TH, Component TS, Finaject, Finajet, Finaplix-H, and Finaplix-S. [3] [4] [5] [32] [33] It is or has also been sold in combination with estradiol or estradiol benzoate for veterinary use under the brand names Revalor and Synovex. [3] [4] [5] [32] [33]

Distribution and regulation

Trenbolone acetate, specifically referred to as Finaplix in the livestock industry, is available to purchase in veterinary drug markets. [5] A typical cartridge usually comes in the form of 20 mg pellets. It generally comes in the form of implant pellets containing 20 mg of trenbolone acetate each. [32] Preparations containing trenbolone acetate remain rare since its decline in production after the 1980s. Using AAS for any other purpose, or without a doctor's prescription, is illegal in most countries. Major sporting and bodybuilding organizations ban the use of controlled AAS, and the possession or sale of drugs can lead to arrest and conviction of drug-trafficking in many countries, including the United States and Australia. However, in the United Kingdom, owning AAS for personal use as a bodybuilding supplement is not illegal, but selling the AAS without a valid medical license or reason is still against the law. [34] [35]

Doping in sports

Regardless of their legality, AAS are still banned by most sporting leagues in the country, who routinely conduct drug tests to find the users of any AAS. There are known cases of doping in sports with trenbolone acetate by professional athletes.

Related Research Articles

<span class="mw-page-title-main">Metenolone</span> Chemical compound

Metenolone, or methenolone, is an androgen and anabolic steroid (AAS) which is used in the form of esters such as metenolone acetate and metenolone enanthate. Metenolone esters are used mainly in the treatment of anemia due to bone marrow failure. Metenolone acetate is taken by mouth, while metenolone enanthate is given by injection into muscle.

<span class="mw-page-title-main">Nandrolone decanoate</span> Anabolic steroid

Nandrolone decanoate, sold under the brand name ROLON among others, is an androgen and anabolic steroid (AAS) medication which is used primarily in the treatment of anemias and wasting syndromes, as well as osteoporosis in menopausal women. It is given by injection into muscle or fat once every one to four weeks.

<span class="mw-page-title-main">Metandienone</span> Androgen and anabolic steroid

Metandienone, also known as methandienone or methandrostenolone and sold under the brand name Dianabol (D-Bol) among others, is an androgen and anabolic steroid (AAS) medication which is still quite often used because of its affordability and effectiveness for bulking cycles. It is also used non-medically for physique- and performance-enhancing purposes. It is often taken by mouth.

<span class="mw-page-title-main">Trenbolone</span> Anabolic steroid

Trenbolone is an androgen and anabolic steroid (AAS) of the nandrolone group which itself was never marketed. Trenbolone ester prodrugs, including trenbolone acetate and trenbolone hexahydrobenzylcarbonate, are or have been marketed for veterinary and clinical use. Trenbolone acetate is used in veterinary medicine in livestock to increase muscle growth and appetite, while trenbolone hexahydrobenzylcarbonate was formerly used clinically in humans but is now no longer marketed. In addition, although it is not approved for clinical or veterinary use, trenbolone enanthate is sometimes sold on the black market under the nickname Trenabol.

<span class="mw-page-title-main">Ethylestrenol</span> Chemical compound

Ethylestrenol, also known as ethyloestrenol or ethylnandrol and sold under the brand names Maxibolin and Orabolin among others, is an androgen and anabolic steroid (AAS) medication which has been used in the past for a variety of indications such as to promote weight gain and to treat anemia and osteoporosis but has been discontinued for use in humans. It is still available for veterinary use in Australia and New Zealand however. It is taken by mouth.

<span class="mw-page-title-main">Norethandrolone</span> Chemical compound

Norethandrolone, sold under the brand names Nilevar and Pronabol among others, is an androgen and anabolic steroid (AAS) medication which has been used to promote muscle growth and to treat severe burns, physical trauma, and aplastic anemia but has mostly been discontinued. It is still available for use in France however. It is taken by mouth.

<span class="mw-page-title-main">Mesterolone</span> Chemical compound

Mesterolone, sold under the brand name Proviron among others, is an androgen and anabolic steroid (AAS) medication which is used mainly in the treatment of low testosterone levels. It has also been used to treat male infertility, although this use is controversial. It is taken by mouth.

<span class="mw-page-title-main">Fluoxymesterone</span> Chemical compound

Fluoxymesterone, sold under the brand names Halotestin and Ultandren among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, breast cancer in women, and anemia. It is taken by mouth.

<span class="mw-page-title-main">Trestolone</span> Chemical compound

Trestolone, also known as 7α-methyl-19-nortestosterone (MENT), is an experimental androgen/anabolic steroid (AAS) and progestogen medication which has been under development for potential use as a form of hormonal birth control for men and in androgen replacement therapy for low testosterone levels in men but has never been marketed for medical use. It is given as an implant that is placed into fat. As trestolone acetate, an androgen ester and prodrug of trestolone, the medication can also be given by injection into muscle.

<span class="mw-page-title-main">Selective androgen receptor modulator</span> Class of pharmaceutical drugs

Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in specific tissues, promoting muscle and bone growth while having less effect on male reproductive tissues like the prostate gland.

<span class="mw-page-title-main">Metribolone</span> Chemical compound

Metribolone is a synthetic and orally active anabolic–androgenic steroid (AAS) and a 17α-alkylated nandrolone (19-nortestosterone) derivative which was never marketed for medical use but has been widely used in scientific research as a hot ligand in androgen receptor (AR) ligand binding assays (LBAs) and as a photoaffinity label for the AR. More precisely, metribolone is the 17α-methylated derivative of trenbolone. It was investigated briefly for the treatment of advanced breast cancer in women in the late 1960s and early 1970s, but was found to produce signs of severe hepatotoxicity at very low dosages, and its development was subsequently discontinued.

<span class="mw-page-title-main">Anabolic steroid</span> Steroidal androgen that is structurally related and has similar effects to testosterone

Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor. Anabolic steroids have a number of medical uses, but are also used by athletes to increase muscle size, strength, and performance.

<span class="mw-page-title-main">Trenbolone enanthate</span> Chemical compound

Trenbolone enanthate, known by the nickname Trenabol, is a synthetic and injected anabolic–androgenic steroid (AAS) and a derivative of nandrolone which was never marketed. It is the C17β enanthate ester and a long-acting prodrug of trenbolone. Trenbolone enanthate was never approved for medical or veterinary use but is used in scientific research and has been sold on the internet black market as a designer steroid for bodybuilders and athletes.

<span class="mw-page-title-main">Nandrolone phenylpropionate</span> Anabolic steroid

Nandrolone phenylpropionate (NPP), or nandrolone phenpropionate, sold under the brand name Durabolin among others, is an androgen and anabolic steroid (AAS) medication which has been used primarily in the treatment of breast cancer and osteoporosis in women. It is given by injection into muscle once every week. Although it was widely used in the past, the drug has mostly been discontinued and hence is now mostly no longer available.

<span class="mw-page-title-main">Steroidal antiandrogen</span> Class of compounds

A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.

<span class="mw-page-title-main">Dimethandrolone</span> Chemical compound

Dimethandrolone (DMA), also known by its developmental code name CDB-1321, is an experimental androgen/anabolic steroid (AAS) and progestogen medication which is under investigation for potential clinical use.

<span class="mw-page-title-main">Boldenone undecylenate</span> Chemical compound

Boldenone undecylenate, or boldenone undecenoate, sold under the brand names Equipoise and Parenabol among others, is an androgen and anabolic steroid (AAS) medication which is used in veterinary medicine, mainly in horses. It was formerly used in humans as well. It is given by injection into muscle.

<span class="mw-page-title-main">Dimethandrolone undecanoate</span> Chemical compound

Dimethandrolone undecanoate (DMAU), also known by its developmental code name CDB-4521, is an experimental androgen/anabolic steroid (AAS) and progestogen medication which is under development as a potential birth control pill for men. It is taken by mouth, but can also be given by injection into muscle.

<span class="mw-page-title-main">Structure–activity relationships of anabolic steroids</span>

The structure–activity relationships (SAR) of anabolic steroids (AAS) have been extensively studied.

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