Developer institutions:
SI «Institute of Urology of the National Academy of Medical Sciences of Ukraine»
Shupyk National Medical Academy of Postgraduate Education
Authors:
Gorpinchenko Igor Ivanovich, Doctor of Medical Sciences, Professor, Head of the Department of Sexology and Andrology, SI «Institute of Urology of the National Academy of Medical Sciences of Ukraine».
Gurzhenko Yuriy Mykolayovych Doctor of Medical Sciences, Professor, Chief Researcher of the Department of Sexology and Andrology, SI «Institute of Urology of the National Academy of Medical Sciences of Ukraine».
Spiridonenko Volodymyr Volodymyrovych, Candidate of Medical Sciences, Associate Professor, Senior Researcher of the Department of Sexology and Andrology, SI «Institute of Urology of the National Academy of Medical Sciences of Ukraine».
Reviewer:
Luchitsky V.I., Doctor of Medical Sciences, Professor, Head of the Department of Andrology, SI «Institute of Endocrinology of the National Academy of Medical Sciences of Ukraine».
Annotation
Data on various types of infertility in men and the possibility of infertility correction with a comprehensive non-hormonal herbal therapy are given in the recommendations to "Adrius® – a modern remedy for improving the male reproductive system". Data on clinical and pharmacological aspects of each of the components of Adrius, indications and methods of application are given as well.
Practical recommendations are intended for urologists, andrologists, sexologists, family physicians, interns and students.
SUMMARY
Adrius® – a modern remedy for improving the male reproductive system.
Gurzhenko Y., Spyrydonenko V.
State Institution «Institute of Urology of National Academy of Medical Sciences of Ukraine»
The article presents the research digest dedicated to pharmacological effects of Adrius components: Tribulus terrestris extract, extract of roots and leaves of Withania somnifera, extract of velvet bean pods (Mucuna pruriens), Asparagus racemosus root extract, apilak (Royal jelly) and yohimbine hydrochloride (Yohimbine HCl USP). The effects of the abovementioned ingredients provide a positive effect of Adrius as stimulation of libido, sexual and germinal function in men.
Keywords: sexual function, libido, spermatogenesis, tribulus terrestris, withania somnifera, mucuna pruriens, asparagus racemosus, royal jelly, yohimbine.
The problem of male infertility remains relevant today, and the methods of treatment are increasingly shifting towards extracorporeal technologies [1, 2]. Recently, a sharp increase in the number of infertile couples is reported around the world. The percentage of male infertility factor averages 45 to 50% [3]. In turn, the requirements for the quality of ejaculate have already decreased significantly, due to the widespread use of various reproductive technologies. The structure of male infertility has remained virtually unchanged for decades. About 40% of causes are verified as possible (varicocele, immunological factor, testicular tumours), 30% are cases of idiopathic infertility, 10% are hypogonadism and various secondary causes [4]. The means of achieving the desired goal of childbirth in certain periods of history and different cultures were extremely diverse. Sometimes they were absurd, but the oral method of taking remedies is the oldest. However, such way of introduction has been moved a side by in vitro reproductive technologies, but it still remains a world-renowned method.
Effective means to improve sexual and reproductive function have interested society throughout human history. In different times and regions of our planet medicine used different means (organic and inorganic), so the success was also different. In the nonsurgical treatment of male infertility the most important role play remedies that have demonstrated their effectiveness in the context of evidence-based medicine, with clear meta-analyse data obtained from a large population of men [5]. Currently, despite the many synthetic drugs, the need for natural remedies is as high as ever. Therefore, the pharmaceutical proposals in this field are trying to meet this demand of society.
Pathological conditions of different parts of the genital system are closely related. Fertility disorders may be accompanied with decreased libido and erectile function. Thus, market requirements for a universal herbal remedy continue and will always be relevant.
Selection of plant components, which should increase fertility, requires compliance with a number of conditions: the presence of probable therapeutic effects, confirmed by research data; the lack of negative impact and cumulative effects between components; the presence of potentiation effect of one ingredient to another; no side effects; search for quality raw materials and many other factors.
One of the most effective treatment systems in human history is phytomedicine, which has its own individual approach to improving sexuality, male sexuality and fertility. Adrius is a typical representative of the above remedies, containing plants with extensive experience in folk medicine,
Each capsule of Adrius contains:
Although each of the above ingredients can cause the activation of various body functions, their combination allows to stimulate all parts of the sexual sphere: libido, erectile function, androgenic status and spermatogenesis. Each of the composites has a scientific effectiveness basis in the world literature. The pharmacokinetic and pharmacognostic characteristics are confirmed by reliable clinical studies.
The effectiveness of each component of Adrius is given below separately.
Tribulus terrestris extract has been used for 2.5 thousand years to treat various diseases of the internal organs (diuretic, anti-inflammatory agent) and genital system (stimulant), both in men and women. Its positive effects are described in ancient works of Ayurveda, Siddha, Unani and used by traditional medicine in China, India, the Mediterranean region to treat headaches, nervous and sexual disorders, liver, kidney, urinary and cardiovascular systems. As a traditional representative of Ayurveda, Tribulus terrestris extract is referred to as "Gokshura" and is recommended as a diuretic, an anti-inflammatory agent or a sexual tonic. Current studies on Tribulus terrestris raw materials prove diuretics, biostimulants, urolithic, immunomodulatory, antiglycemic, antitoxic, hypolipidemic, cardio, psychotonic, hepatoprotective, anti-inflammatory, antispasmodic, antitumor, antibacterial, antiviral effects of Tribulus terrestris. Pharmacological studies of active substances (saponins) are dictated by increasing demand for Tribulus terrestris raw materials in the form of medicinal products and food supplements [6, 7].
In the clinical practice of Ukraine, 10 years ago the use of Tribulus terrestris was intended to men's health problems only (improving testosterone metabolism). They have a positive assessment of clinicians [8-11]. Tribulus terrestris is more widely used in sports medicine as a food supplement that improves energy and protein metabolism in muscles, and athletes testosterone metabolism as well [12].
Analysis of medical resources on the Internet (Medline, etc.) indicates a large number of studies on the use of Tribulus terrestris as a remedy enhancing libido and erectile function, removing kidney stones and treating arthralgias, male and female infertility and premature ejaculation, etc. [13-16].
Extensive clinical experience has been gained in China, where Tribulus terrestris is used as a tonic, antihypertensive, urolithic agent, and as a treatment for eye diseases, oedema, bloating, abnormal discharge, male and female fertility disorders. In one of the oldest Chinese medical treatises "Shern-Nong Pharmacopoeia" Tribulus terrestris is mentioned as an effective treatment for toxic and metabolic liver diseases, mastitis, flatulence, conjunctivitis, headache, vitiligo and others. [17].
In the folk medicine of Central Asian cultures, Tribulus terrestris is used for the treatment of various pathological conditions. Avicenna described their diuretic and urolithic effects in his works. He recommended to use Tribulus terrestris for the treatment of tumors, ulcers, headaches, conjunctivitis, and as tonics and laxatives as well. In this region of Asia, the powder of dried Tribulus terrestris fruits was smoked for syphilis, gonorrhea and other sexually transmitted diseases.
Scientific research of USSR scientists has found cardiotonic, diuretic, local anti-inflammatory, antiviral and fungicidal effects of Tribulus terrestris. The bactericidal effectiveness of Tribulus terrestris is allowed to recommend them as an extract for the treatment of psoriasis, mastopathy, xanthoma, xanthelasma, viral and allergic skin diseases [18]. Tribulus terrestris therapy was prescribed for dyslipidemia and carbohydrate metabolism disorders (metabolic syndrome) to reduce headache, tinnitus and to lower blood pressure in atherosclerosis, and to normalize sleep as well [19].
In Bulgaria, Tribulus terrestris is widely used as a stimulant of sexual and erectile function in men. In women, Tribulus terrestris is prescribed for inflammatory diseases of the genital organs in order to correct the hormone levels in menstrual disorders, and to improve training results in athletes. The experience of Bulgarian scientists is one of the most scientifically substantiated in the context of the influence of furostanol composition saponins in spermatogenesis pathology and hormone function disorders of the female reproductive system.
In Ukraine and the CIS countries, the experience of using Tribulus terrestris until the first decade of the XXI century is limited. The first Tribulus terrestris drug introduced into medical practice, was a drug made by a Bulgarian manufacturer. The USSR phytotherapeutic guide contains information on the use of Tribulus terrestris raw material in folk medicine for the treatment of urolithiasis and genitourinary system diseases. Over the past 15 years, more than 10 scientific papers have been published by the researches of the Department of Sexology and Andrology of the Institute of Urology of the National Academy of Medical Sciences of Ukraine. In the Arabian countries, Tribulus terrestris is used as an anti-inflammatory agent, sexual stimulant, hepatoprotector, etc. In Iran, Tribulus terrestris raw material is used to eliminate inflammatory conditions of various localizations, and to treat skin diseases and to increase libido in men, if necessary. There are data on their anticancer effects on some forms of skin and liver cancer. In Turkey, Tribulus terrestris is used to reduce high blood pressure and to normalize plasma cholesterol profiles, and to increase libido and fertility.
Phytochemical studies of Tribulus terrestris have found the presence of saponins, flavonoids, glycosides, alkaloids and tannins [20]. The pharmacognostic properties of the Ayurvedic remedy Tribulus terrestris ("Gokshura") are characteristic of Tribulus terrestris Linn., Although some remedies use Pedalium murex Linn fruits. According to researchers, these fruits do not have such a unique furostanol set of saponins [19]. In general, the presence of furostanol and spirostanol saponins, tigogenin, neotigogenin, gitogenin, neohytogenin, hecogenin, neohecogenin, diosgenin, chlorogenin, ruscogenin, sapogenin and other substances was determined in Tribulus terrestris. Furostanol glycosides (protodioscin and protogracillin) take the first place. Protodioscin is dominant, and the content of spirostanol glycosides has no pronounced effect [21, 22]. The amount of basic flavonoids is 1.5 times higher than all other fractions (such as caffeol, quercetin, rutin, kaempferol, etc.) [23, 24, 25, 26]. Recent studies indicate the several new saponins of the furostanol series, capable of stimulating the synthesis of sex hormones and libido [27].
In the last 5 years of research, 16 steroidal saponins, 7 of which are previously unknown (so-called terrestrins), have been found in Tribulus terrestris raw materials. The latest technologies of 1D and 2D NMR spectroscopy, mass-spectrometry and biochemical methods have defined the structure of Tribulus terrestris as follows: 26-O-β-D-glucopyranosyl- (25R)-furost-4-ene-3 and β-2α, 22α, 26-tetrol-12-one (terrestrinin C), 26-O-β-D-glucopyranosyl-nosil-(25R)-furost-4-ene-22α, 26-diol-3,12-dione (terrestrinin D), 26Po-β-D-glucopyranosyl-(25S)-furost-4-ene-22α, 26-diol-3,6,12-Trione (terrestrinin E), 26-B-β-D-glucopyranosyl-(25R)-5α-furostan-3β, 22α, 26-triol-12-one (terrestrinin F), 26-O-β-D-glucopyranosyl-(25R) furost-4-en-12β, 22α, 26-triol-3vin (terrestrinin G), 26-O-β-D-glucopyranosyl (1 → 6)-β-D-glucopyranosyl-(25R)-furost-4-ene-22α, 26-diol-3,12-dione (terrestrinin Н) and 24-O-β-D-glucopyranosyl-(25S)-5α-spirostan-3β, 24β-diol-12-one-3-O-β-D-glucopyranosyl-(1 → 4)-β-D-galactopyranoside terrestris).
In addition, terestrobizamide, tribulosterin, Np-coumarolthyramine, terestroamide, hegogenin, aurantoamide, xanthosine, β-sitosterol, sigmasterol [23], β-algalomani, carman algalomanagan have been found in Tribulus terrestris raw materials.
This chemical composition of Tribulus terrestris forms its positive effect on various parts of homeostasis in humans [30].
It should be noted that along with the traditional ideas about the therapeutic effect of Tribulus terrestris on the body, every year there are scientific data on its new pharmacological properties. Thus, in Ukraine, when using Tribulus terrestris to improve libido, erectile and reproductive functions, we virtually ignore the pronounced diuretic and litholytic effects, which were found in ancient times. This also applies to antitumor effects of some Tribulus species, which are mentioned by some recent studies [31].
The diuretic effect of Tribulus terrestris may be due to the high concentrations of essential oils, sodium ions, potassium, chlorides and nitrates in its fruits and seeds. The litholytic effect of Tribulus terrestris is also due to the reduction of myofibrils of the upper urinary tract and activation of renal function, which is proved by the results of experimental trials [32] and clinical data [33].
Subsequent Tribulus terrestris studies have proven the development of a dose-dependent antilithogenic effect by increasing the formation of uroprotein promoter of antiprecipitation of lithogenic agents, with decreasing concentrations of lithogenic substances (fibrin, calcium salts, phosphates) in the experimental model of a foreign body on the mucous membrane of the urinary tract. Other researchers emphasise that the use of Tribulus terrestris helps to reduce leukocyturia and serum urea levels [35], and is also characterized by the presence of antioxidant effect, namely: reducing the severity of lesions of tubular epithelial cells (NRK 52E) with calcium oxalate concretions; with inhibition of the formation of foci of lithogenesis in litho promoters experiments (sodium glycolate and ethylene glycol) [36]; the ability to inhibit the promoter of oxalate metabolism of glycol oxidase, due to non-competitive (quercetin) and competitive (kaempferol) inhibitors [37].
The eroticizing effect of Tribulus terrestris is determined by two pharmacological aspects: indirect – by activating sex hormones (indirect stimulation of luteinizing hormone synthesis with increasing testicular testosterone), and direct – by increasing the erectile component (increased nitric oxide levels in the endothelium of corpora cavernosa on the background of stimulation of penile neurotrophy by active testosterone fractions) [38]. The results of experimental studies regarding improved erection in mammals taking Tribulus terrestris indicate a leading mechanism in the form of increased relaxation of cavernous tissue in response to increased release of nitric oxide by vascular endothelium [39, 40]. Under the influence of Tribulus terrestris, activation of NO/NOS cascade in the penile endothelium with subsequent conformation of intracellular guanylate cyclase, which regulates the contraction of smooth muscle in cavernous tissue through cGMP-dependent protein kinase mechanisms, is proved by a number of scientific studies [41, 42].
Of all the active substances of Tribulus terrestris, furostanol saponin protodioscin which is a promoter of the conversion of endogenous testosterone to dihydrotestosterone is the most studied [16, 43, 44]. The clinical manifestations are the activation of muscle growth, increased libido and bone marrow red cell function with a improvement in oxygen transport in certain body systems. In addition to the anabolic effect, the activation of testosterone metabolism with clinically significant increase in libido and erectile function is take place [45, 46, 47]. This is proved by stimulation of extragenital sources of testosterone with the development of androgen-substituting effect and activation of sexual desire in castrated male rats [10, 48-51].
Clinical use of Tribulus terrestris in elderly men has increased testosterone levels and improved erectile function (with stable LH) [52].
Also, there were interesting data on the presence of androgen-protective activity in cases of testicular tissue exposure to a number of toxic substances: cadmium salts [53], hydroperoxides (inhibition of lipid peroxidation and activation of antioxidant system with activation of Leydig cell function) [54]; opioid toxins [55].
Tribulus terrestris causes improved reproductive function in fish [56], mammals [57, 58, 13.] and humans [59, 60], including the cases of oligozoospermia [61, 62].
Both monotherapy and its combination with other components is a successful practice of using Tribulus terrestris [63, 64].
The effects of Tribulus terrestris in primates, rats and rabbits are short-lived. Therefore, the further study of the mechanisms of activation of spermatogenesis and erectile function in mono and combination therapy is required [65, 57].
There are scientific studies on the positive effects of Tribulus terrestris in people with symptoms of lower urinary tract on the background of benign prostatic hyperplasia [66].
In one study the immunomodulatory effect of Tribulus terrestris has been demonstrated [67] with emphasis of the dose-dependent effect of furostanol saponins on increasing the activity of phagocytosis (nonspecific immune response), increasing antibody titers and activation of delayed-type hypersensitivity response (specific immune response).
Significant effect of Tribulus terrestris on metabolic metabolism in the form of antilipidemic and antiglycemic [68] effects is a very important issue in the treatment of severe fertility disorders in men with diabetes [69], because such therapy increases antioxidant activity while reducing neoglucogenesis, 72, 73].
Hypertension is one of the components of metabolic syndrome (MS). Tribulus terrestris is able to have antihypertensive effect (potassium-sparing and diuretic effects) [74] with the possibility of cardioprotection by dilating coronary arteries, improving coronary circulation and blood clotting processes [75, 76, 77, 78, 79]. In combination with other Ayurvedic components of the Rasayana Ghana system, Tribulus terrestris promotes the development of anxiolytic and antidepressant effects due to high levels of harmin (a natural MAO inhibitor that increases dopamine levels in brain tissues) and β-carboline alkaloid. It is proved experimental data [80, 81].
Hepatoprotective (decreased transaminase activity of the liver and decreased levels of glutathione) [82], anti-inflammatory (inhibition of expression of cyclooxygenase-2, induced NO-synthetase in liposaccharide-induced cells RAW264.7; suppression of tumor necrosis factor TNF-α and interleukin IL-4) [83, 84, 85], antispasmodic [86], antitumor (antiangiogenic, proapoptotic) [87, 88, 89, 90, 91, 92], antiproliferative [93 ], antimicrobial [94, 95], antifungal [96], anthelmintic [97, 98] and other positive effects have been found.
Medicinal raw materials in the form of Withania somnifera root and leaf extract are derived from plants of nightshade family (Ashwagandha, Indian ginseng, poisonous gooseberry, winter cherry), which has several morphologically similar species of Withania. W. somnifera (ashwagandha) and W. coagulans (ashutosh booti) species are economically significant and cultivated for medical use [99]. According to Ayurveda, Ashwagandha is able to relieve stress, enhance memory and cognitive function, improve fertility in both women and men, increase libido, stimulate hormonal balance, stabilize androgenic status, delay aging and promote rejuvenation [100-102 ]. The root of the plant is rich in amino acids that are involved in the metabolism of sex hormones and improve neuronal trophism. Withania lipids have a positive effect on high blood pressure, and a beneficial effect on the sexual sphere and the cardiovascular system by creating a general effect of rejuvenation of cellular structures of the body. Bioactive peptides and nucleic acids of Withania raw materials stimulate biochemical processes, and play a protective role in stressful situations or infections. Ayurvedic practice recommends Withania for metabolic disorders, decreased body defenses, nervous and physical fatigue; in order to stimulate sexual activity; to normalize the condition after diseases, injuries and surgical intervention; in debilitated elderly and children with developmental delays; in circulatory disorders, anemia; to enhance cognitive functions and other pathological processes. Oral administration of Withania has also been shown to increase muscle strength, endurance, and performance [103].
Mucuna pruriens is an annual plant widely known as "velvet beans". It was widely used as food in southern China and eastern India. Since Vedic times (1500-1000 BC) Mucuna pruriens has been widely used as a powerful aphrodisiac and medicine for various nervous disorders [105]. Velvet beans have a special place in the treatment of parkinsonism [106].
Nowadays, Mucuna pruriens is one of the most popular legumes grown in Asia, America, Africa and the Pacific Islands. Mucuna species, belonging to Fabaceae family, includes about 150 species of annual and perennial legumes, including Mucuna pruriens, which is common in tropical and subtropical regions of the world. It is considered as a source of dietary protein due to the high concentration of protein (23-35%), which can be compared in value with soy [107, 108, 109].
Mucuna types, also known as "cowitch" and "cowhage" in English, have abundant nettling hairs on the pods. Mucunain contained in these hairs causes severe dermatitis upon contact with them [110]. In Mucuna pruriens with small silky hairs, this phenomenon is almost not expressed.
All parts of Mucuna plant have medicinal properties [111]. In vitro and in vivo studies have found active biological substances with a wide range of pharmacological effects, such as anti-inflammatory, antidiabetic, neuroprotective, antioxidant effects.
Mucuna pruriens is a unique plant with healing properties. Its fruits contain common phenolic compounds, oligosaccharides (raffinose, stachyose, verbacose), some alkaloids with antidiabetic action, and protease inhibitors [112]. Mucuna pruriens leaf extract exhibits antimicrobial and antioxidant activities.
The main phenolic compound in Mucuna fruit is L-DOPA (5%) [113]. The ripe seeds contain about 3.1-6.1% L-DOPA [114]. In addition to the effect of levodopa, Mucuna pruriens contains a small amount of serotonin (5-hydroxytryptophan), dimethyltryptamine, nicotine, bufotenine and other active substances, such as DMT-n-oxide, bufotenine, 5-MeO-DMT-n-oxide, and β-carboline. Taken together, all of these substances can potentially have psychedelic effects [115].
It has been experimentally established that dopamine and serotonin from Mucuna leaf extract are able to have anticataleptic and antiepileptic effects in white mice [116].
Mucuna-derived L-DOPA is able to cross the blood-brain barrier and be converted to dopamine, restoring impaired neurotransmission. This indicates its advantages over the synthetic analogue in patients with Parkinson's disease [117, 118, 119].
As mentioned above, Mucuna spp. extracts contain toxic compounds L-dopa and hallucinogenic tryptamines, and tannins and phenols, which contribute to the saturation effect [120]. Due to the high concentrations of L-DOPA (4-7%), velvet beans are a commercial source of the substance used in the treatment of parkinsonism. The toxicity of Mucuna raw materials is expressed in its low susceptibility to insect pests [121, 122], anthelmintic (pods) effect and the ability of plant to suppress competing plants (herbicidal effect) [123]. Despite their toxic properties, various species of Mucuna are cultivated as a small food crop. The green pods and ripe beans are eaten boiled. In Guatemala and Mexico, the beans are even used as a coffee substitute.
Mucuna extract is able to increase sexual desire and is usually used to obtain a pronounced effect only in combination with other drugs [124]. Mucuna pruriens enhances the natural secretion of testosterone and has an anabolic effect, accelerating muscle growth and reducing the percentage of adipose tissue.
Seed extracts and Mucuna pruriens leaf extracts are widely used in the East as an aphrodisiac for the treatment of male infertility and various nervous disorders [125]. The Rasayan system in Ayurveda traditionally uses M. pruriens to treat Parkinson's disease. It is believed that the main effect of M. pruriens is antiparkinsonian and neuroprotective effects, which may be due to the plant's ability to absorb free radicals, including reactive oxygen species, and to affect various parts of the nervous system. The aphrodisiac effect in Mucuna is manifested due to the presence of a number of substances that have a stimulating effect on the receptors of the nervous system. The therapeutic effects are due to a whole set of active substances (polyphenols, trypsin inhibitors, phytates, cyanogenic glycosides, oligosaccharides, saponins, lectins and alkaloids) in beans and other parts of the plant. Protein and polypeptide phenolic compounds that inhibit the activity of digestive and hydrolytic enzymes (amylase, trypsin, chymotrypsin and lipase) exhibit anticancer, antiviral, antimicrobial, anti-inflammatory, antihypertensive and antioxidant activities. Phytic acid (myoinositol-1,2,3,4,5,6-hexa (dihydrogen phosphate)), as the main component of plant seeds, may be involved in the regulation of spermatogenesis.
Cyanogenic glycosides are plant toxins, and their content in the fruits of M. pruriens is manifested by neuroprotective effects. Velvet beans have been found to contain high levels of PUFA, such as linoleic, palmitic, oleic and linolenic acids [126, 127]. Tissue metabolism of linoleic acid in the human body regulates the activity of hormone-like prostaglandins, which help to reduce smooth muscle and lower blood pressure.
The main phenolic component of M. pruriens beans is L-DOPA (5%) with tetrahydroisoquinoline (0.25%) [118, 128] and tryptamines in M. pruriens seed extracts [129]. The alkaloids mukunin, mukunadin, prurienin and prurieninin have been isolated from raw material extracts [130].
Muсuna seed alcoholic extracts have also been shown to have potential antioxidant activity in experimental models of stress-induced lipid peroxidation [129]. The latter is one of the most important pathogenetic mechanisms of nerve tissue damage and a number of authors believe that L-DOPA and its metabolites cause a prooxidant effect, contributing to oxidative DNA damage, adversely affecting the morphology of nervous tissue in neurodegenerative diseases, reducing the levels of renewed glutathione in the formation of reactive semihinones from L-dopa [131, 132]. H-propanol extract from M. pruriens seeds gives the highest effect in neuroprotective testing, which includes the growth and survival of DA neurons in cell culture in virto. Such extracts with a low concentration of L-dopa show significant neuroprotective activity. The latter suggests that high-dose M. pruriens seed extract could outweigh the effects of synthesized L-DOPA in the treatment of parkinsonism [133].
The antimicrobial properties of Mucuna pruriens leaf methanolic extracts are characterized by moderate activity against some bacteria under experimental conditions, demonstrating the prospect of further research [138].
Over the last 20 years of research, the antidiabetic effect of Mucuna pruriens seeds has been established. In particular, due to a combination of chromatographic and NMR methods, the presence of d-chiro-inositol and its two galacto-derivatives, O-α-d-galactopyranosyl (1 → 2) -d-chiro-inositol (FP1) and O-α-d-galactopyranosyl (1 → 6) -O-α-d-galactopyranosyl- (1 → 2) -D-chiroinositol (FP2), and bioactive substances that improve tissue metabolism in endocrine glands has been found in M. pruriens seeds [139]. It is believed that the presence of cyclitol (galactopyranosyl and d-chiroinositol) promotes the development of insulin-mimetic effect, which is a new signaling system to control glucose metabolism [140, 141]. According to a study, the use of M. pruriens seed extract caused a decrease in plasma glucose levels due to the content in this dosage of approximately 7 mg of d-chiroinositol and its galacto derivatives [142].
The important role of lipid peroxidation in the formation of pathological spermatogenesis is currently emphasized by all researchers. In the human body, the processes of lipid peroxidation are one of the most important regulatory systems of apoptosis and maintenance of general homeostasis. Free radicals having one or more unpaired electrons are formed in the process of both normal and disrupted cellular metabolism, and reactive oxygen species, reacting with free radicals, also become radicals. Antioxidants protect DNA and protein molecules of cellular structures of the body from damage by reactive oxygen species and products of lipid peroxidation. Antioxidant substances are phytochemical compounds (saponins, glycosides), phenolic compounds (phenolic acids, polyphenols, flavonoids), which have a wide range of properties, including antioxidant, antimutagenic and anticancer activity [143, 144]. They remove free radicals - peroxides, hydroperoxides and lipoperoxides, thus suppressing oxidative mechanisms. An in vitro study has found that the methanol extract of the whole plant M. pruriens, as a hydrogen donor, contains a large number of phenolic compounds, exhibits a high antioxidant activity and the ability to remove free radicals [145].
There are a large number of studies indicating the use of Mucuna pruriens for the treatment of psoriasis, dermatitis and eczema as processes associated with the suppression of the expression of certain proteins in keratinocytes of human skin that, in turn, is due to increased oxidative stress and aggressive oxygen forms. [146, 147].
Asparagus adscendens root extract, as a derivative of the known food product, is not common in medicinal composites [148].
Asparagus has long been known for its medicinal effects and ability to positively affect the patient's clinical condition. In folk medicine it is recommended for leukorrhea, diarrhea, dysentery, diabetes, senile pruritus, bronchial asthma, weakness, including genital, spermatorrhea and other diseases.
Asparagus adscendens and Asparagus racemosus are used in traditional Indian medicine to improve general health and stress-related immune disorders. The effects of methanolic and aqueous extracts of the tuberous roots of these plants were studied in rats in an experimental model of stress caused by swimming. The extracts were shown to have an inhibitory effect on proinflammatory cytokines (interleukin-1β, TNF-α), and on the production of nitric oxide stimulated with lipopolysaccharide in vitro in macrophage cells of RAW 264.7 mice. The obtained data indicate the ability of asparagus to reduce stress and the severity of inflammatory processes [149].
The dose-dependent effect of Asparagus adscendens root extract on anabolic, reproductive and sexual activity in male rats was a significant increase in body weight and testicles with enhancement of the corresponding functions, which became a scientific basis for the use of this plant[150].
Asparagus adscendens, having a certain proandrogenic potential, is a rich source of potential antidiabetic agents (saponins, flavonoids, triterpenes). One study has found that aqueous extract of A. adcendens induces a significant non-toxic increase in glucose-dependent insulinotropic factor in the BRIN-BD11 pancreatic β-cell clone line, with a marked increase in glucose uptake in adipocytes that opens up new possibilities for 3T3-L1 carbohydrate metabolism [151].
Asparagus is a traditional herbal remedy that is prescribed in the Asian world as an aphrodisiac and neurotonic. In a stress experiment in mice treated with A. adcendens extract (25, 50 and 100 mg/kg/day; intraperitoneally) for 14 days, the neuroprotective effects were characterized by increased monoamine levels, decreased corticosterone levels, accompanied by the development of antidepressant-like effect as a result of modulation of the monoaminergic system and regulation of the hypothalamic-pituitary-adrenal axis with reduction of oxidative stress [152].
Asparagus, as a food product, can also act as a substrate for the use of new technologies. Experimental study of a potentially new dual inhibitor derived from A. adcendens by molecular docking (a molecular modeling method, which allows to predict the most favourable orientation and conformation of the ligand at the receptor binding site for the formation of a stable complex). Asparagus has neuroprotective and neurotonic properties. The alkaloid Conypododiol derived from the chloroform fraction of the methanolic extract of A. adscendens has shown a significant inhibition of both acetylcholinesterase and butyrylcholinesterase, without showing signs of cytotoxicity to nephrothelia in LCMK-2 monkeys and hepatocytes in mice [153]. Himalayan asparagus (Asparagaceae) in traditional Asian medicine is an antitumor agent.
An experimental study of A. adscendens root raw materials on human carcinoma cell lines (breast - MCF7; liver - HEPG2, lung tissue - A549 and bladder - EJ138) has shown a pronounced cytotoxic efficacy due to sapogenins [154].
Royal jelly preparation, such as apiserum (France), apifortil (Germany), longivex (Canada), lacapnis (Bulgaria), epirginol, phytadone, melcalcin (Romania), are produced in many countries. It should be noted the well-known fact that fresh royal jelly is more effective than dried or canned. Apilac continues to be one of the most recognized and popular beekeeping products in various regions of our planet. Yohimbine (Quebrahin) is the main alkaloid of yohimbe tree (Pausinystalia johimbe Pierre ex Beille) of the Rubiaceae family, which grows in central Africa. In addition, it is found in the bark of South American plants "white quebracho" (Aspidosperma quebracho-blanco Schltr.) and "Rauwolfi serpentina Benth. Ex Kurz" (Apocynaceae family). Sum of alkaloids (Yohimbine hydrochloride, Yohimbine HCl USP) is used in medicine as a treatment for erectile dysfunction and libido stimulant. For more than 70 years, yohimbine has been used to treat sexual problems in men and women, acting as an aphrodisiac, with a moderate effect on erection [166].
The pharmacological action of yohimbine is due to the predominant effect on the central and peripheral receptors of the sympathetic nervous system with increasing its motor activity. The primary purpose of using yohimbe was to treat erectile dysfunction, increase libido and other sexual qualities, with increased antidepressant and tonic effects. In addition, an important effect of yohimbine is its ability to bind to β-adrenoceptors [167]. Indications for the use of this remedy are symptoms of psychogenic and neurogenic forms of erectile dysfunction, and the standard dosage is 5 mg 1-3 times/day. The course of treatment can last from 30 days to six months. Yohimbe bark extract has a positive effect on libido in men.
In a clinical study of patients with severe erectile dysfunction, administration of yohimbine at doses up to 40 mg/day caused complete recovery of erection in 14%, significant improvement in 20%, and no clinical effect in 65% of patients [168]. Patients with psychogenic forms of erectile dysfunction who took yohimbine showed positive results in 71% of patients [169].
Erectile dysfunction can be caused by the inability of the smooth muscles of the penis to relax and most prescribed drugs have a direct effect, facilitating this process (prostaglandins E, nitric oxide donors, 5-phosphodiesterase inhibitors, alpha-blockers) [170, 171].
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The erectile reflex includes autonomic and somatic efferent influences and is modulated by supraspinal reflexes that control erection. Dopamine, acetylcholine, nitric oxide (NO) and neuropeptides (oxytocin, adrenocorticotropic and melanocyte-stimulating hormones) have a stimulating effect; serotonin has both stimulating and inhibitory properties, and enkephalins are exclusively inhibitory agents for erection processes. Peripheral balance between contractile and relaxant factors controls the degree of contraction of the smooth muscles of the corpora cavernosa and determines the functional state of the penis. Metabolism of norepinephrine is carried out in the sinuses of the cavernous tissues and vessels of the penis by stimulating α1-adrenoceptors.
The use of selective α2-receptor antagonists such as yohimbine will enhance the release of norepinephrine, leading to the binding to α2-adrenoceptors on non-adrenergic, non-cholinergic nerves and the release of nitric oxide.
Cholinergic nerves inhibit the release of norepinephrine from the adrenergic nerve before connection with increased synthesis and release of nitric oxide, so the most effective strategy to reduce adrenergic activity and facilitate erection is to combine α1 and α2-adrenoceptor antagonists [172]. Nitric oxide is considered to be the most important factor for relaxing the vessels of the penis and the structures of the corpora cavernosa. The role of other mediators released from nerve tissue or endothelium has not been clearly established.
Although yohimbine has been on the pharmaceutical market longer than sildenafil, its clinical characteristics are limited. It is believed that as a monotherapy yohimbine is quite moderately effective in patients with erectile dysfunction. In short and long-term studies, it was found that yohimbine does not cause side effects in the range of medium therapeutic doses. Side effects (high blood pressure, anxiolytics, increased urination) occur with high doses of yohimbine. However, they are easily corrected by reducing the dose or discontinuing the remedy. There is growing evidence that the effectiveness of yohimbine in the treatment of erectile dysfunction may be increased when used in combination (with nitric oxide donors) [173].
It is believed that yohimbine demonstrates the highest therapeutic potential as a synergistic effect in combination with other compounds of natural and synthetic origin [174].
Among the side effects are increased agitation, and any manifestations of the sympathomimetic state. An interesting effect, described in the literature and clinical trials, is the possibility of using yohimbine in people with BPH and bladder atony, as well as in cases of concomitant manifestations of the so-called "male menopause".
In the world medical practice there is a huge variety of combinations of phytopreparations and the minimum number of medicinal plants that are prescribed as monotherapy. The use of combinations of known herbal remedies, as a rule, justifies itself with high efficiency and safety of drugs.
One of such combinations is Adrius®. Adrius® has a balanced composition of components that have a complex effect on various pathogenetic links in the development of infertility. Adrius® reduces lipid peroxidation, increases libido, normalises hormonal status, and reduces the negative effects of stress on male reproductive function.
It is recommended to take 1-2 capsules of Adrius® twice a day for 3 months. Adrius can be recommended for use in general medical practice in the complex treatment of male infertility.
The list of literature is in the editorial office.
