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Effectiveness of Textile Materials in Gynaecology and Obstetrics

Lupine Publishers| Journal of Reproductive

Abstract

The article reviews some significant advances in the use of textile materials in obstetrics and gynaecological procedures. Some developments in texture suture materials have been highlighted. Despite millennia of experience with wound closure biomaterials, no study or surgeon has yet identified the perfect suture for all situations. In recent years, a new class of suture material-barbed suture-has been introduced into the surgeon's armamentarium. Focus has been directed on barbed suture to better understand the role of this newer material in obstetrics and gynaecology. Cellulose nonwoven modified with chitosan nano particles has been developed and its physical-chemical, morphological and physical-mechanical aspects characterized in order to explore their possible use in medicine as gynaecological tampons. Tampons have been developed using viscose fibres coated by chitosan dissolve in acetic or lactic acids both inhibit the growth of micro organisms and adjust the pH. Such a tampon proved better than existing ones and thereby proves beneficial for pregnant women.

Keywords: Suture material; Suture characteristics; Barbed sutures; Medical tampons; Viscose; Chitosan; Wound closure

Introduction

The relationship between wound closure biomaterials and surgery dates back as far as 4000 years, when linen was used as a suture material. The list of materials used to close wounds has included wires of gold, silver, iron, and steel; dried gut; silk; animal hair; tree bark and other plant fibers; and, more recently, a wide selection of synthetic compositions. Despite millennia of experience with wound closure biomaterials, no study or surgeon has yet identified the perfect suture for all situations. Natural polymers like cellulose, starch and chitosan find use in pharmacy and medicine due to their desired properties like biocompatibility, lack of toxicity and allergenic action [1,2]. Prepared from natural polymers are materials that mimic the extracellular matrix; they reveal a soft and strong but also elastic structure which provides mechanical stability to tissue and organs [3,4].

The availability and low price is the economic assets of natural polymers. Environment protection issues, now strongly pronounced by the European Union, also speak for the use of natural polymers, which are seen as environmentally-friendly. In general, natural polymers enjoy a growing interest. They are primarily used in modern medical devices contributing to advanced healing procedures. Chitosan counts as a polymer and is in abundance in nature, revealing beneficial biomedical properties like antibacterial activity against Escherichia coli and Staphylococcus aureus, which is primarily responsible for septic shock [5-7]. During the recent years, cellulosic fibres have been used in the development of medical textile products as proved by the literature available [8,9]. Owing to their active surface area, strength and molecular structure, cellulosic fibres exhibit enormous possibilities in the design of bioactive, biocompatible, and advanced materials [10]. One such area of application could be cellulose tampons which are used by women and have biodegradable and antimicrobial properties. It protects from physiological and pathological vaginal discharge, which could otherwise increase the vaginal pH beyond the desirable limit of 3.6-4.5 [11].

Developments in Suture Materials

A perfect suture would have the following properties:

a. Adequate strength for the time and forces needed for the wounded tissue to heal
b. Minimal tissue reactivity
c. Comfortable handling characteristics
d. Unfavourable for bacterial growth and easily sterilized
e. Nonelectrolytic, noncapillary, nonallergenic, and noncarcinogenic

This review discusses the wound healing process and the biomechanical properties of currently available suture materials to better understand how to choose suture material in obstetrics and gynaecology. Inflammatory tissue reactions due to the presence of suture material will persist as long as the foreign body remains within the tissue. Determining the balance between the added strength the suture provides to the tissues while they heal versus the negative effects of inflammation is central to choosing the proper suture. Irrespective of the knot configuration and material, the weakest spot in a surgical suture is the knot and the second weakest point is the portion immediately adjacent to the knot, with reductions in tensile strength reported from 35% to 95% depending on the study and suture material used. Applying our current understanding of the wound healing process and the biomechanical properties of the variety of available suture materials, obstetricians and gynaecologists should choose suture material based on scientific principles rather than anecdote and tradition.

Stages in Wound Healing

The following stages are involved in wound healing and inflammatory responses

A. Inflammation [12-16]
B. Proliferation [17]
C. Maturation an remodelling [12,13]

Suture Characteristics that Assist Surgeons

The following are the different categories of suture classification that are considered to best assist surgeons in choosing the proper suture material for their surgeries. These are:

i. Suture size [18].
ii. Tensile strength [19-21].
iii. Absorbable versus nonabsorbable [22-27].
iv. Multifilament versus monofilament [28-31]
v. Stiffness and flexibility [32,33].
vi. Smooth versus barbed [34-42].
vii. Barbed suture [43].

Practical Aspects to be considered in Suture Materials

A perfect suture has adequate strength for the time and forces needed for the wounded tissue to heal; minimal tissue reactivity; comfortable handling characteristics; is unfavourable to bacterial growth and easily sterilized; and is nonelectrolytic, noncapillary, nonallergenic, and noncarcinogenic.

a) Inflammatory tissue reactions due to the presence of suture material persist as long as the foreign body remains within the tissue. The degree of tissue reaction depends largely on the chemical nature and physical characteristics of the suture material.
b) Suture classifications that best assist surgeons in choosing the proper suture material for surgery include suture size, tensile strength, absorbability, structure, flexibility, and surface texture.
c) The perfect suture material should retain adequate strength throughout the healing process and disappear afterward with minimal associated inflammatory reaction.
d) Irrespective of the knot configuration and material, the weakest spot in a surgical suture is the knot and the second weakest point is the portion immediately adjacent to the knot, with reductions in tensile strength reported from 35% to 95% depending on the study and suture material used.
e) Bidirectional barbed sutures may offer multiple advantages: they eliminate the need for a knot, which effectively reduces wound tissue reactions; there is a more uniform distribution of wound tension across the suture line, yielding more consistent wound opposition; and the secure anchoring of barbed suture at 1 mm intervals may provide a reduction in gaps and thereby create a more "watertight" seal. On the downside, currently available barbed sutures are produced in a limited variety of materials and sizes.

Reflecting the age-old dictum, "It's always important to never say always and never," there is no one best suture or suture material for all surgical procedures. Although sutures have been reflecting the age-old dictum, "It's always important to never say always and never," there is no one best suture or suture material for all surgical procedures. Although sutures have been complications, surgeons must constantly review not only their technique, but the adjuvant materials they use in their craft. This review focused on absorbable suture materials for use in basic obstetric and gynaecologic procedures. It is meant to be neither comprehensive nor definitive. Rather, it is intended to introduce newer technologies and reinforce old concepts. Applying our current understanding of the wound healing process and the biomechanical properties of the variety of available suture materials, obstetricians and gynaecologists should choose suture material based on scientific principles rather than anecdote and tradition. Tissue characteristics, tensile strength, reactivity, absorption rates, and handling properties should be taken into account when selecting a wound closure suture. The currently available suture materials and their relative general characteristics have been listed [44].

With these considerations in mind, in most obstetric and gynaecologic procedures (excluding suspension procedures and oncologic procedures in which either adjuvant chemotherapy and/ or radiation therapy is anticipated), there is little role for either nonabsorbable sutures or collagen gut sutures [45]. The newer synthetic absorbable sutures consistently display both theoretical and clinically proven advantages for wound healing over their older, naturally derived cousins. The introduction of bidirectional barbed sutures has the potential to dramatically alter the wound closure landscape by both equalizing the distribution of disruptive forces across the suture line and eliminating the need for surgical knots.

Use of Barbed Sutures

Sutures and surgery have been tied together since the first operations were performed. Throughout the history of surgery, the variety of materials used to close wounds has included wires of gold, silver, iron, and steel; dried gut; silk; animal hairs; tree bark and other plant fibers; and, more recently, a wide selection of synthetic compositions. Despite the multitude of different procedures performed with a host of different wound closure biomaterials, no study or surgeon has yet identified the perfect suture for all situations. In recent years, a new class of suture material-barbed suture-has been introduced into the surgeon's armamentarium. Currently, there are 2 commercially available barbed suture products: the Quill™ SRS bidirectional barbed suture product line (Angiotech Pharmaceuticals, Inc., Vancouver, BC, Canada) and the V-Loc™ Absorbable Wound Closure Device product line (Covidien, Mansfield, MA). These synthetic sutures eschew the traditional, smooth, knot requiring characteristic of sutures in favour of barbs that serve to anchor the sutures to tissue without knots. This review focuses specifically on barbed suture to better understand the role of this newer material in obstetrics and gynaecology. Given the paucity of published data on the V-Loc sutures, the review will mostly focus on Quill bidirectional barbed sutures.

Key Considerations

In the author's opinion, there are few scientific data to support the current use of either plain or chromic gut sutures in any surgical procedure. A recent study of porcine gastrointestinal closure burst- strength pressures in wounds closed with barbed suture were no different than repairs performed with traditional knotted, smooth suture lines. When considerations for blood loss and hemostatis are added, the need for faster, more secure suture lines becomes readily apparent. To this end, barbed suture materials are an ideal solution. As with myomectomy closures, hysterotomy closures during caesarean delivery are facilitated by the use of barbed suture. The barbed sutures more easily draw the tissue edges together and the 1-mm spacing between the barbs seems to yield better hemostasis.

Important Practical Aspects

I. A new class of suture material-barbed suture-has been introduced; these synthetic sutures eschew the traditional, smooth, knot requiring characteristic of sutures in favour of barbs that serve to anchor the sutures to tissue without knots.
II. The 6 categories of suture classification believed to best assist surgeons in choosing the proper suture material for their surgeries are suture size, tensile strength, absorbability, filament construction, stiffness and flexibility, and surface characteristics (smooth or barbed).
III. A knot-secured, smooth suture creates an uneven distribution of tension across the wound. Although the closed appearance of a wound may be that of equal tension distribution, there is unequal tension burdens placed on the knots. This tension gradient across the wound may subtly interfere with uniform healing and remodelling.
IV. Although the data are limited and almost exclusively based on studies with bidirectional suture, barbed suture lines appear to be at least as strong if not stronger than traditional, knotted, smooth suture lines.
V. To choose the best suture material for an obstetrics- gynaecology procedure, surgeons should take into account all the variables present, such as a tissue's collagen structure, blood supply, disruptive forces, and potential for infection. When these characteristics are considered, the physical characteristics of barbed sutures make these materials an attractive option.

Comparison between Smooth and Barbed Sutures

In 1956, Dr. J. H. Alcamo was granted the first.com patent for a unidirectional barbed suture, although the concept dates back to 1951 when the idea of using barbed sutures was presented for tendon repairs [46,47]. The first.com Food and Drug Administration (FDA) approval for barbed suture material was issued in 2004 to Quill Medical, Inc., for its Quill bidirectional barbed polydioxanone suture [48]. In March 2009, the FDA approved the V-Loc 180 barbed suture from Covidien. Whether bidirectional or unidirectional barbed suture is better is unknown, although there are reported complications of unidirectional barbed sutures migrating or extruding [49,50].

This problem is thought to have been due to the lack of counterbalancing forces on the suture line. Barbed sutures are available in a variety of both absorbable and nonabsorbable monofilament materials. Specifically, currently available bidirectional and unidirectional barbed suture materials include PDO, polyglyconate, poliglecaprone 25, glycomer 631, nylon, and polypropylene. Bidirectional barbed sutures are manufactured from monofilament fibers via a micromachining technique that cuts barbs into the suture around the circumference in a helical pattern. The barbs are separated from one another by a distance of 0.88 to 0.98 mm and are divided into 2 groups that face each other in opposing directions from the suture midpoint (Figure 1) [51].

Figure 1:

Needles are swaged onto both ends of the suture length. Owing to its decreased effective diameter as a result of the process of creating barbs, barbed suture is typically rated equivalent to 1 USP suture size greater than its conventional equivalent. For example, a 2-0 barbed suture equals a 3-0 smooth suture. Unidirectional barbed sutures are similarly manufactured from monofilament fibers, but needles are swaged onto only 1 end whereas the other end maintains a welded closed loop to facilitate initial suture anchoring (Figure 2). Unlike bidirectional barbed suture, unidirectional barbed suture is rated equal in strength to its USP smooth suture counterpart. However, this strength rating difference between the 2 barbed varieties is the result of labeling differences rather than an actual material benefit.

Figure 2:

Importance of suture knots

It is difficult for many surgeons to think about suture material without an accompanying knot. Nonetheless, the surgical knot used with a length of smooth sutures is a significant necessary evil that is accepted as the only irrefutable means to anchor suture material within a wound. A knot-secured, smooth suture inevitably creates an uneven distribution of tension across the wound. Although the closed appearance of a wound may be that of equal tension distribution, there is unequal tension burdens placed on the knots rather than on the length of the suture line. This tension gradient across the wound may subtly interfere with uniform healing and remodelling. The weakest spot in any surgical suture line is the knot. The second weakest point is the portion immediately adjacent to the knot, with reductions in tensile strength reported from 35% to 95% depending on the study and suture material used [52,53].

When functional biomechanics are considered, this finding should not be surprising considering both the effects of slippage of suture material through the knot and the unavoidable suture elongation that occurs as a knot is formed and tightened. Given the excessive relative wound tension on the knot and the innate concerns for suture failure due to knot slippage, there is a predilection toward overcoming these concerns with excessively tight knots. However, surgical knots, when tied too tightly, can cause localized tissue necrosis, reduced fibroblast proliferation, and excessive tissue overlap, all of which lead to reduced strength in the healed wound [54]. A surgical knot represents the highest amount and density of foreign body material in any given suture line. The volume of a knot is directly related to the total amount of surrounding inflammatory reaction [55]. If minimizing the inflammatory reaction in a wound is important for optimized wound healing, then minimizing knot sizes or eliminating knots altogether should be beneficial as long as the tensile strength of the suture line is not compromised. Finally, with minimally invasive laparoscopic surgeries, the ability to quickly and properly tie surgical knots has presented a new challenge. In cases where knot tying is difficult, the use of knotless, barbed suture can securely re-approximate tissues with less time, cost, and aggravation [56,57].

Although the skills necessary to properly perform intra- or extracorporeal knot tying for laparoscopic surgery can be achieved with practice and patience, this task is a difficult skill that most surgeons still need to master to properly perform closed procedures. In addition, laparoscopic knot tying is more mentally and physically stressful on surgeons and, more importantly, laparoscopically tied knots are often weaker than those tied by hand or robotically [58-62].

Barbed Sutures in Practical Use

The choice and use of sutures in obstetrics and gynaecology (ob- gyn) is based more on anecdote and experience than data. Though many of the suture materials routinely used in myomectomies, hysterectomies, and caesarean deliveries have endured the test of time, this should preclude neither the application of scientific review nor the quest for improvement. In addition to understanding the physical properties and characteristics of the variety of available sutures, surgeons need to consider the tissue and physiologic milieu into which suture will be placed before choosing the material to use. For example, in general, the suture-holding strength of most soft tissues depends on the amount of fibrous tissue they contain. Thus, skin and fascia hold sutures well whereas brain and spinal cord tissue do not. Further along this line, healthier tissues tend to support sutures better than inflamed, edematous tissues.

To choose the best suture material for an ob-gyn procedure, surgeons should take into account all the variables present, such as a tissue's collagen structure, blood supply, disruptive forces, and potential for infection. When these characteristics are considered, the physical characteristics of barbed sutures make these materials an attractive option. The first use of barbed sutures in gynaecologic surgery was reported by Greenberg and Einarsson in 2008 [56]. Since that report, numerous print and video publications have followed. Inprocedures such as laparoscopic myomectomy and hysterectomy, the use of barbed sutures has become commonplace. Myomectomy re-approximation of the myometrium after removal of myomas requires a suture material that adequately addresses the need for a prolonged wound disruptive-force reduction, hemostasis, and minimal tissue reactivity.

Traditionally, this suture has been either a polyglycolic acid suture or polydioxanone. However, as noted earlier, braided sutures cause more tissue abrasion and inflammation than monofilaments, and the transition from open to closed procedures has introduced the difficulty of laparoscopic suturing. When considerations for blood loss and hemostatis are added, the need for faster, more secure suture lines becomes readily apparent. To this end, barbed suture materials are an ideal solution. Their synthetic, monofilament configurations should minimize local inflammation, and their absorption profiles and tissue pull-through strengths are well within the parameters needed for reduction of disruptive forces. Further, because barbed sutures allow for only minimal tissue recoiling, closing spaces such as myomas defects is easier with each subsequent suture pass exposed to less tension than the previous bite. Finally, without the need for knot tying, wound closure times and blood loss are significantly reduced [63-65].

Barbed sutures are used in obstetric and gynaecologic procedures in following areas

a) Hysterectomy [66-71].
b) Sacrocolpopexy [72-74].
c) Caesarean delivery [75-79].

Barbed suture is a relatively new but exciting addition to the variety of suture materials. As experience grows with barbed sutures, more applications for its use will likely arise [80]. Obstetric and gynaecologic surgeons who are interested in choosing the best materials for their operations should benefit from better understanding the underlying principles of wound healing and suture material biomechanics, and may discover many advantages to the use of barbed suture.

Chitosan Modified Cellulosic Nonwoven Material

It also displays activity against the fungi Candidiaalbicans, which often produces vaginal candidiasis [81,82], and antiviral action, for example against the human papilloma virus (HPV), which is the cause of cervical carcinoma [83-85]. Thanks to its ability of controlled slow- release, chitosan is often used as carrier of active substances. Various sterilization methods can be employed for chitosan without upsetting its structure and physical-chemical properties [86]. Its beneficial properties ensure chitosan is widely used in pharmacy and medicine as a safe, non-toxic polymer originating from nature [86,87]. Both natural and synthetic polymers like PLA, poly (DL-lactideco-glycolide) and PP are often modified with chitosan [88-91]. The process is intended to prepare new materials with beneficial biological, physical-chemical and mechanical properties [91-93]. The modified composite materials obtained open wide avenues of application and contribute to the introduction of new healing techniques. The incorporation of chitosan into the cellulose matrix yields devices with high biological activity and good mechanical strength.

The medical devices have potential use in gynaecology as medical materials with beneficial biological and mechanical properties. Basic cellulose material with built-in chitosan nanoparticles provides optimal and controlled diffusion of chitosan to the mucous membrane of the vagina and ovarium. Tampons holding antimicrobial chitosan particles may also find use as post-operation dressings and in the healing of diseases and infections due to high antimicrobial activity; alternatively they may be employed for carrying active substances. This is crucial because infections and gynaecological ailments are problems women are mostly plagued with. More than 40 microorganisms are the reason for infections in the region of female sexual organs. The copolymer system proposed also permits to minimalise irritation due to the adjustment of chitosan concentration as the active agent. It is also hoped that the more developed surface of the biopolymer material shall provide better contact with the vagina and neck of the uterus, thus enhancing the antimicrobial effect. The use of modern biopolymer medical devices opens new ways in medicine.

Assessment of the impact of chitosan nanoparticles added to a cellulose matrix upon biological activity and toxicity was the aim of the research conducted. Structural examinations and estimation of chemical purity, as well as antibacterial and useful properties were made. Prepared was a system to control the medical device in respect of microorganism growth and fulfilment of quality requirements of medical devices [94,95]. This article presents preliminary studies on the assessment of the effect of modification of cellulose nonwoven with nanoparticles of chitosan upon biological activity, toxicology and mechanical properties. The addition of nano chitosan was supposed to influence antimicrobial properties; however it was necessary to verify the correlation between the concentration of chitosan and the activity. A very important purpose was to examine how the addition of chitosan would influence the mechanical properties and chemical purity. It is necessary to guarantee optimum activities and the safety of human life and health simultaneously. Therefore according to the standards and scientific literature available, research methods were selected and used to assess cellulose nonwovens for their possible use in medicine as gynaecological tampons. Cellulose fibres used in the preparation of the nonwovens have good properties, both physical- mechanical and physical chemical, including chemical purity.

The addition of chitosan in the amount of 0.25 and 0.5% to the nonwoven caused an inhibition of the growth of E. coli, while such an effect was not observed with S. Aureus. Nonwoven with a 1.4% content of chitosan completely stopped the growth of bacteria E. coli and S. Aureus. The initial material revealed antifungal activity against C. Albicans on at the level of 91.7%; the addition of 0.5% of chitosan entirely inhibited the growth of microorganisms. Antifungal activity of the nonwoven with 0.25% of chitosan against C. albicans was slightly below 100%. Based on the results of physical-mechanical testing, it was found that the nonwoven with 0.5% of chitosan has the best mechanical and useful properties [96]. Assessment of the chemical purity of the materials tested points, at best, to useful properties in the case of nonwoven with 0.5% of chitosan. The structure of the fibres examined after extraction simulating normal use was not disturbed, which may evidence safe use of the hygiene material manufactured. Summarizing the results of the examinations, it may be concluded that the initial cellulose fibres are a good raw material for use in the preparation of innovative medical devices.

Use of Chithsan Based Viscose Material

An increase in pH may cause a reduction in the natural defence of the vagina. This suggests conduciveness for development of bacteria and hence prone to development of bacteria [11-12,9798]. A number of techniques and formulations have been evolved in order to manage the problem of increased pH value of the vagina, than the normal [13,99]. But these have been unsatisfactory from the practical point of view considering the usage and acceptability. Therefore, the development of materials for prevention and treatment of gynaecological infections still represent a significant challenge. Chitosan is the next most abundant polysaccharide found on earth, in comparison with cellulose. It is a biopolymer that is polycationic and covers a broad spectrum of medical properties activity, such as antibacterial, antifungal, and haemostatic properties [100]. Chitosan possesses many desirable characteristics with regard to vaginal infections. It is effective against vaginal candidiasis, toxic shock syndrome, treatment of ovarian cancer, and ensures safe pregnancy and proves conducive in avoiding premature child birth.

Chitosan is found highly suitable for adsorption onto cellulose fibres and thereby impart antimicrobial activity. The functionalization of viscose cellulose using chitosan has been investigated. The objective is to assess the potential use of such a material for the development of new tampons, which apart from maintaining/creating the desired physiological pH value would also possess antibacterial and antimycotic properties. The tampons do not exhibit negative effects, such as inflammation risks, and infections from yeasts, and on repeated use, help to sustain the required moisture in the vagina.

Conclusion

Textile materials have made their entry into many areas of medical textiles, of which gynaecology and obstetrics is one such. Textile sutures are one well explored area. In the choice of a wound closure suture tissue characteristics, tensile strength, reactivity, absorption rates, and handling properties should be considered. The wound healing process and the biomechanical properties of currently available suture materials have been reviewed to better understand how to choose suture material in obstetrics and gynaecology. Despite the multitude of different procedures performed with a host of different wound closure biomaterials, no study or surgeon has yet identified the perfect suture for all situations. In recent years, a new class of suture material-barbed suture-has been introduced into the surgeon's armamentarium. The barbed suture has been studied to better understand the role of this newer material in obstetrics and gynaecology. The impact of the addition of chitosan nanoparticles upon the biological activity and toxicity of the materials prepared.

Methodology was prepared for the examination of the gynaecological devices in the range of their useful properties, notably the mechanical strength, surface density and absorption. Aqueous extracts were examined after an extraction process that simulated standard use of the medical device, and after a surplus extraction. The content of water-soluble-, surfactant- and reductive substances was estimated as well as the contents of heavy metals like cadmium, lead, zinc and mercury by the ASA method. Morphology examination permitted to assess the impact of the extraction processes on the fibre structure. Antibacterial activity against Escherichia coli and Staphylococcus aureus, and antifungal activity against Candida albicans was measured. Altogether examinations were made to assess whether the cellulosic nonwoven modified with chitosan nanoparticles meets the demands of medical devices and lends itself to the manufacture of tampons. The suitability of chitosan-acetic acid treated tampons for gynaecological use has been evaluated. The use of such tampons could prove beneficial for pregnant women, as in vitro trials have confirmed resistance of the tampons against Streptococcus Agalactiae bacteria, which pose serious problems for pregnant women and their infants.

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Selective Androgen Receptor Modulators (SARMs): A Mini-Review

Lupine publishers| Journal of reproductive

Abstract

Selective Androgen Receptor Modulators (SARMs) were discovered in the late 1990’s.They may have an application in treatments of various diseases, including muscle wasting, cancer cachexia, breast cancer, osteoporosis, andropause and sarcopenia. In this minireview the development, pharmacodynamics, and the phase 1 and 2 trial results of the SARMs are discussed with a special emphasis on the illicit use of the SARMs.

Introduction

The androgen receptor (AR) is a member of the steroid hormone receptor family that plays important roles in the physiology and pathology of diverse tissues.AR ligands,which include circulating testosterone and locally synthesized dihydrotestosterone bind to activate the AR to elicit their effects.Ubiquitous expression of the AR metabolism and cross reactivity with other receptors limit broad therapeutic utilisation of steroidal androgens.However,the discovery of selective androgen receptor modulators (SARMs) provide an opportunity to promote the benificial effects with greatly unwanted side effects. In the last two decades SARMs have been proposed as treatments of choice for various diseases, including muscle wasting, breast cancer and osteoporosis. In addition, they may have an application in andropause, sarcopenia, cancer cachexia and as selective anabolic steroids in performing body building sports [1-6]. In this mini-review the development, pharmacodynamics and the phase 1 an2 trial results of the SARMs are discussed,with a special emphasis on the illicit use of the SARMs.

Development of SARMs

Synthesized steroidal androgens due to their ability to mimic the actions of their endogenous counterparts have been used ckinically as valuable therapeutic agents to target a variety of male and female disorders resulting from androgen deficiency. The principle clinical indication of androgens is as replacement therapy for hypogonadal men [1,2]. Other documented clinical uses of androgens include delayed puberty in boys, anemias, primary osteoporosis, heriditary angioneurotic edema, endometriosis, estrogen receptor-positive breast cancer and muscular diseases, as Duchenne’s muscular dystrophy [3-6].
Since the discovery of the therapeutic benefits of testosterone in the 1930’s a variety of androgen preparations have been introduced and tested clinically.
Unfortunately, all current available androgen preparations have severe limitations [2,6]. Unmodified testosterone is impractical for oral administration due to its low systematic bioavalability [7]. Testosterone esters (e.g., testosterone propionate and testosterone enanthate) are presently the most widely used testosterone preparations, usually administered by intramuscular injection in oil-vehicles [8,9]. A prolonged duration of action is achieved with these esters. However,they produce highly variable testosterone levels. 17-alpha alkylated testosterones (e.g., methylteststerone and oxandrolone) can be given orally. Nevertheless,they often cause unacceptable hepatotoxicity and are less efficacious; hence they are not recommended for long-term androgen therapy [9-11].
At the end of the 1990’s studies with affinity ligands for the androgen receptor started. The discovery of these nonsteoidal androgens offered an opportunity for the development of a new generation of selective androgen receptor modulators (SARMs) superior to current androgens. Theoretically, SARMs are advantegeous over their steroidal counterparts in that they can obtain better receptor selectivity and allow greater flexibility in structural modification. Thus SARMs can potentially avoid the undesirable side effects caused by cross-reactivity and achieve superior pharmacokinetic properties [12].

Pharmacodynamics of SARMs

Structural modifications of the acryl propionamide analogues bicalutamide and hydroxyflutamide led to the discovery of the first generation SARMs. The compounds S1 and S4 in this series bind AR with high affinity and demonstrate tissue selectivity in the Herzberger assay,that utilizes a castrated rat model [13-20]. Both S1 and S4 prevented castration induced atrophy of the levator ani muscle and acted as weak agonists in the prostate. At a dose of 3mg/kg/day, S4 partially restored the prostate weight to <20% of intact weight, but fully restored the levator ani weight, skeletal muscle strength, bone mineral density, bone strength and lean body mass and suppressed LH(luteinizing hormone) and FSH( follicle stimulating hormone) [20,21].
S4 also prevented ovariectomy-induced bone loss in a female rat model of osteoporosis [22]. The ability of SARMs to promote both muscle strength and bone mechanical strength constitutes a unique advantage over other therapies for osteoporosis, that only increase bone density. S1 and S4 are partial agonists thus in intact male rats [20,21]. S1 and S4 compete with endogenous androgens and act as antogonists in prostate, such SARMs with antagonistic or low intrinsic activity in prostate might be useful in the treatment of benign prostate hyperplasia (BPH) or prostate cancer. The suppressive effects of this class of SARMS on gonadotrofin secretion in rats suggests a potential application for male contraception [21]. The ether linkage and B-ring para-position substitution are critical for agonist activity of the acryl propionamide SARMs [19]. Based on crystal structures, compounds with ether linkage appear to adapt a more compact confirmation than bicalutamide due to formation of an intramolecular H-bond, allowing the B-ring to avoid steric conflict with the side chain of W741 in AR and potentially explaining the agonist activity [23].
The hydantoin derivatives developed by the BMS group have an A-ring structure that is similar to that of bicalutamide. The cyanonitro group of these molecules interact with Q711 and R752 [24- 26]. The benzene ring or the naphtidyl group,together with the hydantoin ring overlaps the steroid plane, while the hydantoin rings forms a H-bond with N705.BMS-564929 binds AR with high affinity and high specificity. BMS-564929 demonstrated anabolic activity in the levator ani muscle and a high degree of tissue selectivity as indicated by a substantially higher ED50 (Effective Dose for 50% of the population receiving the drug) for the prostate. Hydantoin derivatives are potent suppressors of LH. BMS=564929 is orally available in humans with a half-life of 8-14 hours. The prolonged half-life of these ligands in rats may explain the lower dose needed to achieve pharmacological effects. Differences regarding in vivo activities of SARMs, that share similar binding affinity and in vitro activity,may be related to the differences in pharmacokinetics and drug exposure [27].
Hanada et al. [28] Pharmaceutical Co. reported a series of tetrahydroquinolinone derivatives as AR agonists for bone. Although these compounds displayed high AR affinity and strong agonist activity in prostate and levator ani,they demonstrated little selectivity between androgenic and anabolic tissues [27]. Significant in vivo pharmacological activity was only observed at high subcutaneous doses [27,28]. Ligand Pharmaceuticals developed LGD 2226 and LGD 2941, that are bicyclic 6 anilino quinolinone derivatives, showing anabolic activity on the levator ani muscle as well as on bone mass and strength, while having little effect on prostate size in a preclinical rodent model [29-31]. LGD 2226 was also shown to maintain male reproductive behavior in the castrated rodent model [30].
Scientists at Johnson and Johnson replaced the propionamide linker with cyclic elements such as the pyrazoles, benzimidazoles, indoles and cyclic propionanilide mimetics [31]. Merck scientists have developed a number of 4-azosteroidal derivatives and butanamides [32]. All the above mentioned SARMs belong to the so called “first generation SARMs”. The mechanisms that contribute to the tissue specific transcriptional activation and selectivity of biologic effects of the SARMs remain poorly understood.Three general hypotheses have been proposed, although these hypotheses are not mutually exclusive.
a) The coactivator hypothesis assumes that the repertoire of coregulator proteins that associate with the SARM-bound AR differs from that with testosterone-bound AR leading to transcriptional activation of a differentially regulated set of genes.
b) The conformational hypothesis states that functional differences in ligand classes (agonist, antagonists and SARMs) are reflected into conformationally distinct states with distinct thermodynamic partitioning. Ligand binding induces specific conformational changes in the ligand binding domain, which could modulate surface topology and subsequent proteinprotein interactions between the AR and other coregulators involved in genomic transcriptional activation or cytosolic proteins involved in non-genomic signalling. Differences in ligand-specific receptor conformation and protein-protein interactions could result in tissue-specific gene regulation, due to potential changes in interactions with the AR effectors, coregulators or transcriptional factors.
c) The third hypothesis states that the tissue selectivity of SARMs could also be related to differences in their tissue distribution,potential interactions with 5-alpha reductase or CYP19 aromatase or tissue specific expression of coregulators [33]. Testosterone actions in some androgenic tissues are amplified by its conversion to 5-alpha dihydro testosterone [34]. Nonsteroidal SARMS do not serve as a substrate for 5-alpha reductase. Tissue selectivity of SARMs might be related to tissue specific expression of coregulatory proteins. Similarly, some differences of the action of SARM of testosterone could be related to the inability of nonsteroidal SARMs to undergo aromatization.

Preclinical and early clinical trials with SARMs

A large number of candidate SARMs have undergone preclinical proof of concept and toxicology studies and have made it iinto phase 1 and phase2 clinical trials [29,35]. These compounds are being positioned for early efficacy trials for osteoporosis,frailty,cancer cachexia and aging-associated fundamental limitations. The use of SARMS for the treatment of androgen defiency in men has been proposed. However, the relative advantages of SARMs over testosterone for this indication are not readily apparant. Many biological features of testosterone, especially its effects on libido and behavior, bone and plasma lipids require its aromatization to estrogen. Because the currently SARMs are neither aromatized nor 5-alpha reduced, these compuonds would face an uphill regulatory bar for FDA approval, as they would be required to show efficacy and safety in many more domains of androgen action, than has been required of testosterone formulations.
While the FDA regulatory pathway for the approval of drugs for osteoporosis has been well delineated, because of precedence set by previously approved drugs, the pathway for approval of function promoting anabolic therapies has not been clearly established. Efforts are underway to generate a consensus around indications, efficacy outcomes in pivotal trials, and minimal clinically important differences in key effective outcomes These efforts should facilitate efficacy trials of candidate molecules. There are 2 types of administering SARMs: orally or in injectable dosages. Well known SARMs are LGD-4033, Ostarine (MK-2866), S4(Andarine), RAD 140, Cardarine(GW 501516) and SR9009. The last two preparations are usually grouped with SARMs, but are not the same and are used as endurance supplements.SARMs have been prohibited by the World Anti-Doping Agency (WADA) since 2008. SARMs have the potential to be misused for performance enhancement in sport due to their anabolic properties, as well as their ability to stimulate androgen receptors in muscle and bone. THey are currently prohibited atall times-in the category of “other anabolic agents” under section S1,2 of the WADA Prohibited List [36] Full clinical FDA approval for human consumption as prescription drugs has not yet been accomplished for any of the SARMs until now.

Ligandrol (LGD-4033)

Ligandrol is a SARM discovered by Ligand Pharmaceuticals and currently under licensed development by Viking THerapeutics [37]. There has been a lot of research into the efficacy of SARMs, but very little published research to date on LGD-4033. Ligandrol has exhibited desirable in vivo efficacy on skeletal muscle and bone measurements in animal models of disease. There is only one published study on the effects of LGD-4033 in humans, as well as phase B1 clinical trial results. A 2010 phase1 clinical trial was the first study in humans of LGD-4033 and evaluated the safety, tolerability and oharmacokinetic profiles of the molecule in a single escalating dose, double-blind, placebo-controlled study in 48 healthy volunteers [38].
In 2013, Bhasia et al. [36] conducted a rigorous 3-week pacebocontrolled study of 76 healthy men (21-50 years),that looked at the safety and tolerability of LGD-4033. During this study participants were randomized to placebo,0,1.0,3 or 1mg LGD-4033 for 21 days. The study evaluated the safety, tolerability, pharmacokinetics and the effects of ascending doses of LGD-4033 on lean body mass, muscle strength, stair climbing power and sex hormones [39]. The sample size was still small and the study was not based on considerations of effect sizes, as the study’s primary aim was to establish safety and tolerability, rather than efficacy. Similarly, the 3-week study duration was not designed to demonstrate maximal effects on muscle mass and strength. Therefore larger and longer studies are needed to access the efficacy of LGD-4033. Furthermore the study was supported by Ligand Pharmaceuticals, who developed LGD-4033.
Ligandrol showed a dose-dependent suppression of total testosterone from baseline to 21 days, rather than an increase. Ligandrol did not result in fat loss in this study. It promoted muscle growth, but the evidence is very early weak evidence at this stage. There was an increase in lean body mass, that was doserelated. The mechanisms by which androgens increase muscle mass remain incompletely understood. However, the increase in strength measured by stair climbing speed and power also showed improvement, but not enough to be statistically significant. With a larger sample size and or longer study, it is possible that this effect may be demonstrated. LGD-4033 displayed an immediate effect on hormones in the body from the time it was taken. The research showed gains in lean muscle mass within the 21 days of the study. Adverse effects were not noted. LGD-4033 displayed a prolonged elimination half- life of 24-36 hours. Upon discontinuation of LGD- 4033 the hormone levels returned to baseline by day 56 [39]. There is just not enough research to show the efficacy of Ligandrol at this stage,despite it was safe and well tolerated at all doses administered.

Ostarine (MK-2866,Enobosarm)

Merck presented the results of a phase2 clinical trial evaluating Ostarine (MK-2866),an investigational SARM in patients with cancer induced muscle loss,also known as cancer cachexia at the Endocrine Society Annual Meeting in Washington in 2009 [40]. In this study 159 cancer patients with non-small cell lung cancer, colorectal cancer, non-Hodgkins lymphoma, chronic lymphocytic leukemia or breast cancer were randomized. Participants received placebo,1mg or 3mg Ostarine daily for 16 weeks. Average weight loss prior to entry was 8,8 percent and patients were allowed to receive standard chemotherapy during the trial. The drop-out rate during the trial was 33%.
Ostarine treatment led to statistically significant increases in lean body mass (LBM) and improvement in muscle performance measured by stair climbing in patients with cancer cachexia compared to baseline in both the Ostarine 1mg and 3mg cohorts. In the study Ostarine met the primary endpoint of LBM mesured by DEXA(dual energy x-ray absorptiometry) scan, by demonstrating significant increases in LBM compared to baseline in both the Ostarine 1mg and 3mg treatment was o,1kg(p=0,874 compared to baseline, 1,5kg(p=0,001) and 1,3 kg(p=0,0045) at the end of the 16 week trial.
The study also met the secondary endpoint of muscle function as measured by a 12 step stair climbing test measuring speed and calculating power with each Ostarine treatment arm demonstrating a statistically significant average decrease in time to completion and average percentage increase in power exerted.The change from baseline in stair climb power in the placebo,1mg,and 3mg treatment groups was 0,23 Watts (p=0,66,compared to baseline)8,4Watts (p=0,002) and 10,1 Watts (p=0,001),respectively. A critical appraisal results in the same critics,as depicted for the Ligandrol results. Ostarine is also known as Enobosarm and S-22 SARM by various licensing contracts in the body building world.
Ostarine had already shown significant improvement in the ability of healthy,elderly men and women to climb stairs in a phase2A study in 2007.Elderly men and women improved climbing stairs in speed and power,accompanied by significant increases in LBM and decreases in fat mass after only 86 days [41]. Enobasarm (GTx-024,Ostarine and S-22) is the most well characterized clinically and has consistently demonstrated increases in LBM and better physical function across several populations, along with a lower hazard ratio for survival in cancer patients. Enobosarm was eveluated in the POWER 1(Prevention and Treatment of Muscle Wasting in Patients with Cancer)and in the POWER 2 trial. These are the first phase 3 trials for a SARM. Full results from these studies will soon be published and will guide the development of future anabolic trials [42].

Andarine (S4)

Andarine(S4) was studied in 120 ovariectomized rats for 120 days. The study found that treatment with S4 (Andarine) was benificial to maintain cortical bone content and whole body and trabecular bone mineral density (BMD) measured by DEXA scan. The S4 treatment also decreased body fat and increased body strength in these animals. It was further disclosed by this study that S4 had the ability to reduce the incidence of fractures via minimizing the incidence of falls, through increased muscle strength and through direct effects on bone,as compared to current therapies that are primarily antiresorptive in nature. The study also found that dosages of S4 were effective to increase LBM and reduce body fat in intact and ovariectomized rats. It was also revealed that Andarine provides the unique potential to prevent bone resorption, increase skeletal muscle mass and strength positions and promotes bone anabolism, that makes it a possible new alternative for the treatment of osteoporosis [43]. To date there are no clinical human studies of Andarine in osteoporosis.Andarine has a half-life of 4-6 hours and is prized for weight loss and building and repair of muscle as a muscle boosting supplement in the fitness community.

RAD 140 (Teslolone)

RAD 140 is a SARM that stimulates muscle weight increases at a lower dose than that required to stimulate prostate weight. It results in the expected lowering of lipids (LDL,HDL,triglycerides),without elevation of liver enzyne transaminase levels.RAD 140 has excellent pharmacokinetic properties and is a potent anabolic [44]. RAD 140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action,including the AR-mediated repression of estrogen receptor1 (ESR1).It inhibits the growth of multiple AR/ ER+ breast cancer PDX (patient –derived xenograft) models as a single agent,and in combination with palbociclib.These preclinical data present support for further investigation of RAD 140 in AR/ ER+ breast cancer patients [45].
RAD 140 is a SARM that stimulates muscle weight increases at a lower dose than that required to stimulate prostate weight. It results in the expected lowering of lipids (LDL,HDL,triglycerides),without elevation of liver enzyne transaminase levels.RAD 140 has excellent pharmacokinetic properties and is a potent anabolic [44]. RAD 140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action,including the AR-mediated repression of estrogen receptor1 (ESR1).It inhibits the growth of multiple AR/ ER+ breast cancer PDX (patient –derived xenograft) models as a single agent,and in combination with palbociclib.These preclinical data present support for further investigation of RAD 140 in AR/ ER+ breast cancer patients [45].
In the fitness community Testolone is seen as one of the latest additions to the line of SARMs. Testolone is developed by Radius Health Company. The increase in LBM and fat loss are highly appreciated, as its androgenic-anabolic ratio of 90:1, compared to testosterone. Recommended dosages of Testolone vary from 20- 30 mg once daily and it is used in cycles of 12-14 weeks duration. Because Testolone does not interact with the aromatase enzyme and is not liver toxic, no adverse effects are claimed. The half-life of Testolone is estimated 12-18 hours.

Cardarine(GW 501516) and SR 9009 (Stenab0olic)

These two preparations are usually grouped with the SARMs in the fitness community, but are not the same. Cardarine is used as an enhancing running endurance supplement. Cardarine is not a SARM, but a peroxisome proliferative activated receptor-omega agonist (PPAR-omega), that increases PPAR-omega, and regulates muscle metabolism and reprograms muscle fibre types to enhance running training endurance. While training alone increases the exhaustive running performance Cardarine treatment enhances running endurance and the proportion of succinate dehydrogenase(SDH)- positive muscle fibres in both trained and untrained mice. It appeared while training increases energy availability by promoting protein catabolism and gluconeogenesis, Cardarine enhances specific consumption of fatty acids and reduces glucose utilisation [47]. In the fitness community Carderine is regarded as”king of the gym”. Half-life is between 16-24 hours and it should be taken at 10 mg once a day or twice daily. It is claimed to be useful in conjunction with anabolics and stimulants of any kind without adverse reactions in 12-14 week cycles.
SR 9009 (Stenabolic) is a REV-ERB (revised-viral nuclear erythroblastosis receptors) agonist, that can modulate the expressions of circadian core clock proteins and therefore help to modulate the circadian rythm. Modulation of the REV-ERB activity by synthetic agonists e.g., SR 9009 SR 9011 alters the expression of genes involved in lipid and glucose metabolism and, therefore plays an important role in maintaining the energy homeotasis. Effects of SR9009 and SR9011 in animal studies are increased basal oxygen consumption, decreased lipogenesis, cholesterol and bileacid synthesis in the liver, increased mitochondrial content, glucose and fatty oxidation in the skeletal muscle and decreased lipid storage in the white adipose tissue. The observed increase in energy expenditure and decrease in fat mass make the REV-ERB agonists promising drug candidates for the treatment of several metabolic disorders.They are also attractive for performance enhancement by athletes. Such use can be classified as doping [48].
SR9009 (Stenabolic) has been developed by Scripps Research by the team of Prof. Thomas Burris. Stenabolic is taken orally as a metabolism enhancer in the fitness community. It is believed to have results similar to Cardarine, but with considerable more extra benefits. It is recommended as a very good addition to any steroid (Anavar or Trembolone) or SARMs cycle, especially when used together with Cardarine. The half-life is short, 30-60 minutes,so the dose should be spaced through the day e.g.,10 mg 4-6 times daily. Again no adverse effects are reported.

Illicit use of SARMs

Recently, the FDA issued a consumer warning letter against supplement-like bodybuilding products,that contain SARMs. The FDA warning came on the heels of warning letters sent to three companies, that market products containing the ingredients. FDA had this to say about the offending products distributed by Infantry Labs LLC,Iron Mag Labs and Panther Sports Nutrition: “ Although the products identified in the warning letters are marketed and labeled as dietary supplements, they are not dietary supplements. The products are unapproved drugs, that have not been reviewed by the FDA for safety and effectiveness” [49]. FDA told consumers among the dangers associated with SARMs are liver toxicity and the potential to increase the risk of heart attack and stroke.But the agency said the long- term effects of these substances are unknown. However, these FDA health risk statements can not be supported by the few small clinical human phase 1 and2 SARMs studies performed and the ongoing POWER trials. Furthermore, the FDA did not mention that Ostarine and Ligandrol have previously been investigated as new drugs, which makes them ineligible for use as dietary supplements.
Nevertheless, as clinical research of SARMs is slow, we are now in the wonderful situation the real world clinical SARMs experience is now represented by the fitness and body building world. It is estimated that ther are between 2 and 4 million young people in the U.S. alone, who have used performance-enhancing drugs sometime in their life. There are thousands of internet sites offering SARMs in and outside the U.S [50]. So the magnitude of the problem is completely unknown,if there is any problem at all. In general,these young people are very concerned about their health and “looks” and have the good right of their own responsability.
A recent JAMA publication found that the chemical analysis of 44 products sold via the internet as SARMs revealed, that only 52% contained SARMs and another 39% contained another unapproved drug. In addition, 25% of products contained substances not listed on the label, 9 percent did not contain an active substance and 59% contained substance amounts,that differed from the label [50]. Although these figures must be frightening,there is no registered SARMs epidemic at the U.S. emergency rooms. At present the biggest problems are the “loopholes” in the FDA regulation of dietary supplements.

Conclusion

The SARMs were discovered in the late 1990’s. Clinical development is slow. Few human phase 1 and 2 clinical studies are available Results of the phase 3 POWER trials,studying SARMs in wasting, are awaiting and will guide the development of future anabolic trials. Until now no SARM has received FDA approval. Due to “loopholes” in the FDA regulations the SARMs are widespread used as dietary supplements in the fitness community and body building world. This results in the wonderful situation the clinical experience with SARMs is represented by illicit SARMs use and not by clinical science


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