madman
Super Moderator
Ethnopharmacological relevance: The prevalence and distress caused by erectile dysfunction (ED) to both male and female partners are increasing at a steady rate. ED has now become the most treated sexual disorder for men among young and old age groups due to varying physical and psychological factors. The treatment with synthetic Phosphodiesterase-5 (PDE5) inhibitors is cost-effective but due to adverse effects such as priapism, loss of vision, heart attack, and syncope, the daily life patterns of these patients are distressed and hence the need for alternative medicaments or sources are of utmost importance. Therefore, the exploration of medicinal plants as PDE5 inhibitors will be worthwhile in tackling the problems as many plant extracts and fractions have been long used as aphrodisiacs and sexual stimulants which may be found to be active against the PDE5 enzyme.
Aim of the study: To provide a review of the different medicinal herbs traditionally used as natural aphrodisiacs, libido, or sexual enhancers which are proven for their PDE5 inhibitory effect.
Materials and methods: Ethnobotanical and scientific information was procured, reviewed, and compiled from a literature search of electronic databases and search engines.
Results: A total of 97 medicinal plants exhibiting PDE5 inhibitory effects are reviewed in this paper which is supported by preclinical experimental evidence. Among them, 77 plants have been selected according to their traditional and ethnobotanical uses as aphrodisiacs and the rest are screened according to their effectiveness against predisposing factors responsible for ED and sexual dysfunction such as diabetes and hypertension or due to the presence of phytochemicals having structural similarity towards the identified natural PDE5 inhibitors. In addition, sixteen alkaloids, sixty-one phenolics, and eight polycyclic aromatic hydrocarbons have been isolated or identified from active extracts or fractions that are exhibiting PDE5 inhibitory activity. Among them, isoflavones and biflavones are the major active constituents responsible for action, where the presence of the prenyl group for isoflavones; and the methoxy group at the C-5 position of flavones are considered essential for the inhibitory effect. However, the prenylated flavonol glycoside, Icariin, and Icariside II isolated from Epimedium brevicornum Maxim (horny goat weed) are the most effective inhibitor, to date from natural sources. Traditional medicines or formulations containing extracts of Ginkgo biloba L., Kaempferia parviflora Wall. ex Baker, Clerodendrum colebrookianum Walp., Eurycoma longifolia Jack, and Vitis vinifera L. are also found to be inhibitors of the PDE5 enzyme.
Conclusion: The review suggests and supports the rational use of traditional medicines that can be further studied for the development of potential PDE5 inhibitors. Many traditional medicines still used in various regions of Africa, Asia, and South America are poorly characterized and experimented with. Despite the availability of a vast majority of traditional formulations as aphrodisiacs or sexual stimulants, there exists a need for systemic evaluation of the efficacy as well as the mechanism of action of the herbal constituents for the identification of novel chemical moieties that can be further developed for maximum efficacy.
1. Introduction
1.1. History and significance of PDE5 inhibitors
Theophylline, a xanthine alkaloid has been long used as a phosphodiesterase (PDE) inhibitor without any knowledge of its biochemical action. But in 1958, the use of Theophylline as a selective PDE inhibitor was found and led to innumerable pharmacological investigations aside from its adverse effects (Truss et al., 1996). Cyclic adenosine monophosphate (cAMP) was identified as a second messenger signaling in biological processes and PDE was found responsible for its breakdown, thereby paving the way for PDE inhibition. However, both cAMP and cyclic guanosine monophosphate (cGMP) control the regulation of vascular and airway smooth muscles as well as the muscle tone of the myocardium (Card et al., 2004; Koitabashi et al., 2010; Truss et al., 1996).
The PDE enzymes are synthesized from respective membrane-bound or soluble adenylate or guanylate cyclases by their corresponding nucleoside triphosphates. The phosphodiesterase enzymes are a ubiquitous group of hydrolytic enzymes that cleave the 3′ -ribose-phosphate bond of cAMP and cGMP (Card et al., 2004). Due to the considerable variations of their isoenzymes and their role in the regulation of cyclic nucleotides, the identification of PDE inhibitors have been narrowed down to selective or partially selective inhibitors. The list of reported families of PDE isoenzymes, their substrates, and distribution are given in Table 1 (Keravis and Lugnier, 2012; Ückert and Oelke, 2011). However, only six PDE enzymes have been reported to show any pharmacological significance, they are PDE1, PDE2, PDE3, PDE4, PDE5, and PDE11.
PDE5 isoenzyme inhibitors have been targeted due to its wide range of biological effects as it activates guanyl cyclase (GC) and thereby increasing guanosine monophosphate (GMP) synthesis which in turn, activates certain proteins and results in different pharmacological actions like neuronal plasticity, gene transcription, smooth muscle relaxation, cardiac protection, and endothelial permeability. For 80 years, theophylline was used as a non-selective PDE5 inhibitor but many selective inhibitors have been made available in the past 15 years. Zaprinast was an unsuccessful drug candidate (Keravis and Lugnier, 2012) related to the first selective PDE5 inhibitor, Sildenafil marketed by Pfizer Inc. as Viagra ™ for the treatment of male erectile dysfunction (Jiann, 2016). After the identification of Sildenafil, more effective PDE5 inhibitors were developed such as Tadalafil (Cialis ™, Lilly-ICOS), Vardenafil (Levitra ™, Bayer-GSK), and Avanafil (Stendra, Vivus Inc.) (Yafi et al., 2018). The major significance of PDE5 inhibitors is their effectiveness against cardiovascular diseases, pulmonary hypertension, altitude sickness, and memory dysfunction (Lee and Kass, 2012; Ückert and Oelke, 2011); improve systolic heart function, cardiac geometry, left ventricle diastolic function, inhibition of breast tumor growth activity, lower urinary tract symptoms and treatment of benign prostatic hyperplasia (Barone et al., 2017; Corinaldesi et al., 2016; Jiann, 2016).
The control of penile erection through the relaxation of the corpus cavernosum by the vasodilation effect of nitric oxide (NO) is one of the major uses of PDE5 inhibitors against erectile dysfunction. The effectiveness of PDE5 inhibition therapy for erectile dysfunction is based on the International Index of Erectile Function (IIEF) which denotes 80–85% improvement in erections when performed on male patients having hypertension, postprandial prostatectomy, diabetes mellitus, organic, psychogenic, or mixed causes of ED (Maschi et al., 2008). But reports suggest that the use of PDE5 inhibitors was unable to restore normal sexual life in 40–50% of the patients where the outcome improved with repeated daily dosing which led to major side effects such as headache, dyspepsia, myalgia, back pain, flushing, cyanopsia, runny nose, angina pectoris, myocardial infarction, arrhythmias, hypertension, priapism, loss of hearing and non-arteritic anterior ischemic optic neuropathy (NAION) that are reported in post-marketing studies (Balhara et al., 2015; Bourin, 2018; Gurney et al., 2011; Moreira et al., 2000; Yafi et al., 2018). Such the FDA July 2005 recommended discontinuing any usage of PDE5 inhibitors but in October 2007, FDA requested to include the potential risks to be displayed on the labels for PDE5 inhibitors (Kouvelas et al., 2009). Furthermore, additional reports also, suggest the increased expression of PDE5 and PDE9 during aging and in the case of Alzheimer’s disease, indicating that memory-related disorders can also be treated through the use of PDE5 inhibitors (Puzzo et al., 2008). Despite the overall advancements in PDE5 research, there exists a need for new PDE5 inhibitors with less toxicity and adverse effects where the utilization of medicinal plants as a source for effective targets will be worthwhile as they have provided competent pharmacophores.
1.2. PDE5 inhibition and erectile dysfunction
1.3. Current status of PDE5 inhibitors for the treatment of ED
4. Conclusion
Despite major scientific advancements, the PDE5 inhibitors in the market such as Viagra® (sildenafil) and Cialis® (tadalafil), there exist severe adverse effects in the usage of these pleasure-inducing love drugs. The major side effects are priapism (painful erections lasting for more than 6 h), non-arteritic anterior ischemic optic neuropathy (NAION), headache, and dyspepsia. Therefore, the need for alternative treatment methods or medications with fewer side effects is essential for effective management of ED as PDE5 inhibition works through the negative feedback mechanism of cGMP which directly regulates the smooth muscles of the penis. The use of natural aphrodisiacs or sexual stimulants may prove effective in the current scenario as a majority of herbal ingredients are used for centuries before the discovery of modern medicine. Therefore, the utilization of herbal sources for the identification and discovery of effective PDE5 inhibitors may prove useful with far lower side effects than conventional drugs.
The screening and selection of medicinal herbs for PDE5 inhibition can occur through different methods such as (1) use of valued ethnobotanical herbs or ingredients that are effective as aphrodisiacs (2) selection of medicinal plants that are effective against the predisposing factors for ED (3) screening of medicinal plants containing phytochemicals similar to that of the identified PDE5 inhibitors. The screening through these methods has identified effective PDE5 inhibitors such as icariin from Epimedium brevicornum Maxim (horny goat weed), biflavones from Ginkgo biloba L., flavones from Kaempferia parviflora Wall. ex Baker, phenyl propanoids from Clerodendrum colebrookianum Walp., flavonols from Eurycoma longifolia Jack, and Vitis vinifera L. are also found to be inhibitors of the PDE5 enzyme. In addition, several studies have also identified the major substituent groups that are necessary for their inhibitory action
Although a handful of medicinal herbs have been used as aphrodisiacs or sex stimulants among various communities for managing infertility and ED, only a few among them are screened for the identification of effective PDE5 inhibitors. Therefore, proper and effective screening methods involving sufficient information regarding the mechanism of action, side effects, and toxicity studies through quality research is in need for the identification of promising drug candidates with PDE5 inhibitory activity.
Aim of the study: To provide a review of the different medicinal herbs traditionally used as natural aphrodisiacs, libido, or sexual enhancers which are proven for their PDE5 inhibitory effect.
Materials and methods: Ethnobotanical and scientific information was procured, reviewed, and compiled from a literature search of electronic databases and search engines.
Results: A total of 97 medicinal plants exhibiting PDE5 inhibitory effects are reviewed in this paper which is supported by preclinical experimental evidence. Among them, 77 plants have been selected according to their traditional and ethnobotanical uses as aphrodisiacs and the rest are screened according to their effectiveness against predisposing factors responsible for ED and sexual dysfunction such as diabetes and hypertension or due to the presence of phytochemicals having structural similarity towards the identified natural PDE5 inhibitors. In addition, sixteen alkaloids, sixty-one phenolics, and eight polycyclic aromatic hydrocarbons have been isolated or identified from active extracts or fractions that are exhibiting PDE5 inhibitory activity. Among them, isoflavones and biflavones are the major active constituents responsible for action, where the presence of the prenyl group for isoflavones; and the methoxy group at the C-5 position of flavones are considered essential for the inhibitory effect. However, the prenylated flavonol glycoside, Icariin, and Icariside II isolated from Epimedium brevicornum Maxim (horny goat weed) are the most effective inhibitor, to date from natural sources. Traditional medicines or formulations containing extracts of Ginkgo biloba L., Kaempferia parviflora Wall. ex Baker, Clerodendrum colebrookianum Walp., Eurycoma longifolia Jack, and Vitis vinifera L. are also found to be inhibitors of the PDE5 enzyme.
Conclusion: The review suggests and supports the rational use of traditional medicines that can be further studied for the development of potential PDE5 inhibitors. Many traditional medicines still used in various regions of Africa, Asia, and South America are poorly characterized and experimented with. Despite the availability of a vast majority of traditional formulations as aphrodisiacs or sexual stimulants, there exists a need for systemic evaluation of the efficacy as well as the mechanism of action of the herbal constituents for the identification of novel chemical moieties that can be further developed for maximum efficacy.
1. Introduction
1.1. History and significance of PDE5 inhibitors
Theophylline, a xanthine alkaloid has been long used as a phosphodiesterase (PDE) inhibitor without any knowledge of its biochemical action. But in 1958, the use of Theophylline as a selective PDE inhibitor was found and led to innumerable pharmacological investigations aside from its adverse effects (Truss et al., 1996). Cyclic adenosine monophosphate (cAMP) was identified as a second messenger signaling in biological processes and PDE was found responsible for its breakdown, thereby paving the way for PDE inhibition. However, both cAMP and cyclic guanosine monophosphate (cGMP) control the regulation of vascular and airway smooth muscles as well as the muscle tone of the myocardium (Card et al., 2004; Koitabashi et al., 2010; Truss et al., 1996).
The PDE enzymes are synthesized from respective membrane-bound or soluble adenylate or guanylate cyclases by their corresponding nucleoside triphosphates. The phosphodiesterase enzymes are a ubiquitous group of hydrolytic enzymes that cleave the 3′ -ribose-phosphate bond of cAMP and cGMP (Card et al., 2004). Due to the considerable variations of their isoenzymes and their role in the regulation of cyclic nucleotides, the identification of PDE inhibitors have been narrowed down to selective or partially selective inhibitors. The list of reported families of PDE isoenzymes, their substrates, and distribution are given in Table 1 (Keravis and Lugnier, 2012; Ückert and Oelke, 2011). However, only six PDE enzymes have been reported to show any pharmacological significance, they are PDE1, PDE2, PDE3, PDE4, PDE5, and PDE11.
PDE5 isoenzyme inhibitors have been targeted due to its wide range of biological effects as it activates guanyl cyclase (GC) and thereby increasing guanosine monophosphate (GMP) synthesis which in turn, activates certain proteins and results in different pharmacological actions like neuronal plasticity, gene transcription, smooth muscle relaxation, cardiac protection, and endothelial permeability. For 80 years, theophylline was used as a non-selective PDE5 inhibitor but many selective inhibitors have been made available in the past 15 years. Zaprinast was an unsuccessful drug candidate (Keravis and Lugnier, 2012) related to the first selective PDE5 inhibitor, Sildenafil marketed by Pfizer Inc. as Viagra ™ for the treatment of male erectile dysfunction (Jiann, 2016). After the identification of Sildenafil, more effective PDE5 inhibitors were developed such as Tadalafil (Cialis ™, Lilly-ICOS), Vardenafil (Levitra ™, Bayer-GSK), and Avanafil (Stendra, Vivus Inc.) (Yafi et al., 2018). The major significance of PDE5 inhibitors is their effectiveness against cardiovascular diseases, pulmonary hypertension, altitude sickness, and memory dysfunction (Lee and Kass, 2012; Ückert and Oelke, 2011); improve systolic heart function, cardiac geometry, left ventricle diastolic function, inhibition of breast tumor growth activity, lower urinary tract symptoms and treatment of benign prostatic hyperplasia (Barone et al., 2017; Corinaldesi et al., 2016; Jiann, 2016).
The control of penile erection through the relaxation of the corpus cavernosum by the vasodilation effect of nitric oxide (NO) is one of the major uses of PDE5 inhibitors against erectile dysfunction. The effectiveness of PDE5 inhibition therapy for erectile dysfunction is based on the International Index of Erectile Function (IIEF) which denotes 80–85% improvement in erections when performed on male patients having hypertension, postprandial prostatectomy, diabetes mellitus, organic, psychogenic, or mixed causes of ED (Maschi et al., 2008). But reports suggest that the use of PDE5 inhibitors was unable to restore normal sexual life in 40–50% of the patients where the outcome improved with repeated daily dosing which led to major side effects such as headache, dyspepsia, myalgia, back pain, flushing, cyanopsia, runny nose, angina pectoris, myocardial infarction, arrhythmias, hypertension, priapism, loss of hearing and non-arteritic anterior ischemic optic neuropathy (NAION) that are reported in post-marketing studies (Balhara et al., 2015; Bourin, 2018; Gurney et al., 2011; Moreira et al., 2000; Yafi et al., 2018). Such the FDA July 2005 recommended discontinuing any usage of PDE5 inhibitors but in October 2007, FDA requested to include the potential risks to be displayed on the labels for PDE5 inhibitors (Kouvelas et al., 2009). Furthermore, additional reports also, suggest the increased expression of PDE5 and PDE9 during aging and in the case of Alzheimer’s disease, indicating that memory-related disorders can also be treated through the use of PDE5 inhibitors (Puzzo et al., 2008). Despite the overall advancements in PDE5 research, there exists a need for new PDE5 inhibitors with less toxicity and adverse effects where the utilization of medicinal plants as a source for effective targets will be worthwhile as they have provided competent pharmacophores.
1.2. PDE5 inhibition and erectile dysfunction
1.3. Current status of PDE5 inhibitors for the treatment of ED
4. Conclusion
Despite major scientific advancements, the PDE5 inhibitors in the market such as Viagra® (sildenafil) and Cialis® (tadalafil), there exist severe adverse effects in the usage of these pleasure-inducing love drugs. The major side effects are priapism (painful erections lasting for more than 6 h), non-arteritic anterior ischemic optic neuropathy (NAION), headache, and dyspepsia. Therefore, the need for alternative treatment methods or medications with fewer side effects is essential for effective management of ED as PDE5 inhibition works through the negative feedback mechanism of cGMP which directly regulates the smooth muscles of the penis. The use of natural aphrodisiacs or sexual stimulants may prove effective in the current scenario as a majority of herbal ingredients are used for centuries before the discovery of modern medicine. Therefore, the utilization of herbal sources for the identification and discovery of effective PDE5 inhibitors may prove useful with far lower side effects than conventional drugs.
The screening and selection of medicinal herbs for PDE5 inhibition can occur through different methods such as (1) use of valued ethnobotanical herbs or ingredients that are effective as aphrodisiacs (2) selection of medicinal plants that are effective against the predisposing factors for ED (3) screening of medicinal plants containing phytochemicals similar to that of the identified PDE5 inhibitors. The screening through these methods has identified effective PDE5 inhibitors such as icariin from Epimedium brevicornum Maxim (horny goat weed), biflavones from Ginkgo biloba L., flavones from Kaempferia parviflora Wall. ex Baker, phenyl propanoids from Clerodendrum colebrookianum Walp., flavonols from Eurycoma longifolia Jack, and Vitis vinifera L. are also found to be inhibitors of the PDE5 enzyme. In addition, several studies have also identified the major substituent groups that are necessary for their inhibitory action
Although a handful of medicinal herbs have been used as aphrodisiacs or sex stimulants among various communities for managing infertility and ED, only a few among them are screened for the identification of effective PDE5 inhibitors. Therefore, proper and effective screening methods involving sufficient information regarding the mechanism of action, side effects, and toxicity studies through quality research is in need for the identification of promising drug candidates with PDE5 inhibitory activity.
