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A Review on Phosphodiesterase-5 Inhibitors as a Topical Therapy for Erectile Dysfunction (2022)
Mohammadsadegh Hamzehnejadi, PharmD,Marziye Ranjbar Tavakoli, PharmD, Ardavan Abiri, PharmD, Ali Ghasempour, PharmD, Mohammad Amin Langarizadeh, PharmD, and Hamid Forootanfar, PhD
ABSTRACT
Introduction: Due to the prevalence of erectile dysfunction and impotence among men in recent years, several pharmacotherapies have been considered for such problems. Systemic drug therapies in the treatment of erectile dysfunction have significant issues, including drug interactions and contraindications in a wide range of diseases, which makes researchers seek to design drugs and dosage forms with fewer side effects, interactions, and contraindications with maintained efficacy.
Objectives: 5-Phosphodiesterase inhibitors (5-PDEIs or PDE5Is), previously used systemically to treat erectile malfunction, are now appropriate candidates for topical application with considerable potency and fewer complications.
Methods: We sought to investigate the recent findings on the current subject in order to provide a comprehensive overview of the issue using an extensive literature search to pinpoint the latest scientific reports on this subject.
Results: In the present review, the function of 5-Phosphodiesterase inhibitors as topical formulations was evaluated with details including formulation type, adsorption, and comparative efficacy in all recent studies as an acceptable alternative therapy to systemic drugs.
Conclusions: Due to the fact that the influential factors in erectile dysfunction interact with many diseases and delinquent treatments, the use of topical therapeutic agents can be promising in mild to moderate cases. The utilization of 5-PDEIs through novel topical and transdermal drug delivery techniques plays a vital role in improving this effectiveness.
INTRODUCTION
By definition, ED is the consistent or recurrent inability to get a sufficient erection and adequate penile hardness for sexual intercourse, causing vacuity in sexual pleasure.1,2 The issue of ED has consistently been underestimated despite the great importance in the quality of life of patients and their partners and its high prevalence. One reason is that patients refuse to report such problems to their personal physicians.2 In the absence of treatment, the person usually loses self-confidence, and in addition to psychosocial issues, the overall quality of life of the patients and their partners also decreases.3 At this point, it is the physician's responsibility to examine the person regularly for sexual health, especially his erectile function. Examinations should include medical, sexual, psychological, and social records, as well as laboratory tests and physical examinations. Knowledge of culture, ethnicity and ethical and religious considerations can also be effective in prognosis, diagnosis, and treatment.4 Such studies lead to the early diagnosis of this disease, which in itself can be an indicator and criterion for the occurrence of several life-threatening diseases because the connection between ED and a specific range of morbidities has been proven.2 Continuous monitoring of people with heart disease, hypertension, hyperlipidemia, diabetes, hypogonadism, hypothyroidism or hyperthyroidism, hyperprolactinemia, and other risk factors that we will address below is essential to prevent ED.2,4 Depending on the patient's condition and the severity of the ED symptoms, different treatment protocols (from traditional medicine to surgery) can be used. Reasons such as invasive treatment, drug interactions, treatment inefficiency, multiple contraindications, annoying side effects, and patient's personal preferences have made topical treatments a desirable choice in resolving this problem.5,6 Several compounds such as alprostadil,7 minoxidil,8 testosterone,9 papaverine,10, and PDE5 inhibitors, including sildenafil and tadalafil, have been evaluated for topical treatment of erectile dysfunction. These compounds with different formulations (classic or modern) have been studied in various studies. Classic formulations used to treat erectile dysfunction include sildenafil gel,11 tadalafil gel,12 sildenafil cream,13 and tadalafil cream.14 There is no study related to the treatment of erectile dysfunction using topical ointment of phosphodiesterase 5 inhibitors. Also, studies examining topical avanafil and vardenafil therapy (with both conventional and modern formulations) are very limited and have good potential for future research. Modern formulations of PDEIs used for inclusive drug delivery also include nano-emulsions, transfersomes, bilosomes, centrosomes, nano-ethosomes, liposomes optimized multilayer vesicles (MLVs), and nano-sized colloidal systems such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). Still, in general, by examining the structure and anatomy of the penis, scrutiny of pathways affecting erection, detection of factors affecting transdermal absorption, and physicochemical properties of the drug and its carrier, it is possible to achieve the best formulation with the maximum therapeutic effect Table 1. summarizes the phosphodiesterase 5 inhibitors formulations used to treat erectile dysfunction with their efficacy, classification, and complete description of the formulation. (Table 1).
*Prevalence and Epidemiology
*Function and Physiology
*Risk Factors and Pathophysiology
*Pharmacology
*Management and Therapies
*Topical Applications of PDEIs
RESULTS AND DISCUSSION
Phosphodiesterase-5 Inhibitors (PDE5Is)
-Dose Adjustment
-Systemic Interactions and Contraindications
Topical PDE5Is and Erectile Dysfunction (ED)
-Sildenafil
-Tadalafil
-Vardenafil
-Avanafil
CONCLUSION
In recent decades, with the advancement of technology and human science, human has been able to find a solution to many of the rare and immedicable diseases that have spread in societies. Unaware that many diseases that humans are struggling with have specific and proven symptoms and causes, but for some reason, they have not been considered seriously despite their high prevalence in the population. Erectile dysfunction (ED) is among underestimated issues in human welfare. The expansion of this disease is undeniable and probably has an intimate connection with today's lifestyles of humans. Men may also refuse to visit a physician and try to treat the condition due to a lack of self-confidence, lack of knowledge about the disease and its causes and symptoms and possible treatment approaches, lack of trust in the doctor, embarrassment and timidity, lack of confidence in modern therapies, and relying on traditional methods and self-medication. Also, under no circumstances can this disease be described as a superficial disease because ED is bilaterally associated with several dangerous diseases such as cardiovascular disease and diabetes. Its rapid diagnosis and treatment can be a salvation and remarkably improve the patient's quality of life. As a first-line treatment for ED in many guidelines, PDE5Is are often taken orally and have systemic absorption. Apart from some significant contraindications and interactions with drugs like ritonavir, saquinavir, and erythromycin through CYP3A4 enzymes, following this method of administration, many people develop various complications, and therefore, treatment may not be continued.
On the other hand, patients often have backgrounds such as cardiovascular disease, and meaningful drug interactions, such as nitrate interactions with PDEIs, may limit treatment. PDEIs are also contraindicated in many of the conditions and diseases mentioned earlier. In such cases, topical use of these drugs will be promising if they have sufficient absorption and effectiveness because there will no longer be the issue of systemic absorption, so interactions and contraindications will be minimized. Among the benefits of transdermal use of PDEIs are as follow77:
*Lack of problems with gastrointestinal absorption due to gastrointestinal pH, enzymatic activity, and drug-food interaction
*Avoiding the first-pass effect
*Non-invasive nature of this dosage, higher acceptability for the
patients, and raised compliance
*Ease of removal from the skin and minimal side effects due to
diminished oscillations in drug concentrations
*Affordability and cost-effectiveness of this dosage form
*Providing the minimum dose to create a sufficient effect compared
to oral administration
*Localized effect besides the negligible side effects
Unfortunately, studies in this area have been limited to sildenafil and tadalafil, and other PDE5Is have not been well studied and evaluated. Further research into new phosphodiesterases, as well as their topical use with other drugs used for ED, including prostaglandins, could be promising in the future to treat this global problem.
Mohammadsadegh Hamzehnejadi, PharmD,Marziye Ranjbar Tavakoli, PharmD, Ardavan Abiri, PharmD, Ali Ghasempour, PharmD, Mohammad Amin Langarizadeh, PharmD, and Hamid Forootanfar, PhD
ABSTRACT
Introduction: Due to the prevalence of erectile dysfunction and impotence among men in recent years, several pharmacotherapies have been considered for such problems. Systemic drug therapies in the treatment of erectile dysfunction have significant issues, including drug interactions and contraindications in a wide range of diseases, which makes researchers seek to design drugs and dosage forms with fewer side effects, interactions, and contraindications with maintained efficacy.
Objectives: 5-Phosphodiesterase inhibitors (5-PDEIs or PDE5Is), previously used systemically to treat erectile malfunction, are now appropriate candidates for topical application with considerable potency and fewer complications.
Methods: We sought to investigate the recent findings on the current subject in order to provide a comprehensive overview of the issue using an extensive literature search to pinpoint the latest scientific reports on this subject.
Results: In the present review, the function of 5-Phosphodiesterase inhibitors as topical formulations was evaluated with details including formulation type, adsorption, and comparative efficacy in all recent studies as an acceptable alternative therapy to systemic drugs.
Conclusions: Due to the fact that the influential factors in erectile dysfunction interact with many diseases and delinquent treatments, the use of topical therapeutic agents can be promising in mild to moderate cases. The utilization of 5-PDEIs through novel topical and transdermal drug delivery techniques plays a vital role in improving this effectiveness.
INTRODUCTION
By definition, ED is the consistent or recurrent inability to get a sufficient erection and adequate penile hardness for sexual intercourse, causing vacuity in sexual pleasure.1,2 The issue of ED has consistently been underestimated despite the great importance in the quality of life of patients and their partners and its high prevalence. One reason is that patients refuse to report such problems to their personal physicians.2 In the absence of treatment, the person usually loses self-confidence, and in addition to psychosocial issues, the overall quality of life of the patients and their partners also decreases.3 At this point, it is the physician's responsibility to examine the person regularly for sexual health, especially his erectile function. Examinations should include medical, sexual, psychological, and social records, as well as laboratory tests and physical examinations. Knowledge of culture, ethnicity and ethical and religious considerations can also be effective in prognosis, diagnosis, and treatment.4 Such studies lead to the early diagnosis of this disease, which in itself can be an indicator and criterion for the occurrence of several life-threatening diseases because the connection between ED and a specific range of morbidities has been proven.2 Continuous monitoring of people with heart disease, hypertension, hyperlipidemia, diabetes, hypogonadism, hypothyroidism or hyperthyroidism, hyperprolactinemia, and other risk factors that we will address below is essential to prevent ED.2,4 Depending on the patient's condition and the severity of the ED symptoms, different treatment protocols (from traditional medicine to surgery) can be used. Reasons such as invasive treatment, drug interactions, treatment inefficiency, multiple contraindications, annoying side effects, and patient's personal preferences have made topical treatments a desirable choice in resolving this problem.5,6 Several compounds such as alprostadil,7 minoxidil,8 testosterone,9 papaverine,10, and PDE5 inhibitors, including sildenafil and tadalafil, have been evaluated for topical treatment of erectile dysfunction. These compounds with different formulations (classic or modern) have been studied in various studies. Classic formulations used to treat erectile dysfunction include sildenafil gel,11 tadalafil gel,12 sildenafil cream,13 and tadalafil cream.14 There is no study related to the treatment of erectile dysfunction using topical ointment of phosphodiesterase 5 inhibitors. Also, studies examining topical avanafil and vardenafil therapy (with both conventional and modern formulations) are very limited and have good potential for future research. Modern formulations of PDEIs used for inclusive drug delivery also include nano-emulsions, transfersomes, bilosomes, centrosomes, nano-ethosomes, liposomes optimized multilayer vesicles (MLVs), and nano-sized colloidal systems such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). Still, in general, by examining the structure and anatomy of the penis, scrutiny of pathways affecting erection, detection of factors affecting transdermal absorption, and physicochemical properties of the drug and its carrier, it is possible to achieve the best formulation with the maximum therapeutic effect Table 1. summarizes the phosphodiesterase 5 inhibitors formulations used to treat erectile dysfunction with their efficacy, classification, and complete description of the formulation. (Table 1).
*Prevalence and Epidemiology
*Function and Physiology
*Risk Factors and Pathophysiology
*Pharmacology
*Management and Therapies
*Topical Applications of PDEIs
RESULTS AND DISCUSSION
Phosphodiesterase-5 Inhibitors (PDE5Is)
-Dose Adjustment
-Systemic Interactions and Contraindications
Topical PDE5Is and Erectile Dysfunction (ED)
-Sildenafil
-Tadalafil
-Vardenafil
-Avanafil
CONCLUSION
In recent decades, with the advancement of technology and human science, human has been able to find a solution to many of the rare and immedicable diseases that have spread in societies. Unaware that many diseases that humans are struggling with have specific and proven symptoms and causes, but for some reason, they have not been considered seriously despite their high prevalence in the population. Erectile dysfunction (ED) is among underestimated issues in human welfare. The expansion of this disease is undeniable and probably has an intimate connection with today's lifestyles of humans. Men may also refuse to visit a physician and try to treat the condition due to a lack of self-confidence, lack of knowledge about the disease and its causes and symptoms and possible treatment approaches, lack of trust in the doctor, embarrassment and timidity, lack of confidence in modern therapies, and relying on traditional methods and self-medication. Also, under no circumstances can this disease be described as a superficial disease because ED is bilaterally associated with several dangerous diseases such as cardiovascular disease and diabetes. Its rapid diagnosis and treatment can be a salvation and remarkably improve the patient's quality of life. As a first-line treatment for ED in many guidelines, PDE5Is are often taken orally and have systemic absorption. Apart from some significant contraindications and interactions with drugs like ritonavir, saquinavir, and erythromycin through CYP3A4 enzymes, following this method of administration, many people develop various complications, and therefore, treatment may not be continued.
On the other hand, patients often have backgrounds such as cardiovascular disease, and meaningful drug interactions, such as nitrate interactions with PDEIs, may limit treatment. PDEIs are also contraindicated in many of the conditions and diseases mentioned earlier. In such cases, topical use of these drugs will be promising if they have sufficient absorption and effectiveness because there will no longer be the issue of systemic absorption, so interactions and contraindications will be minimized. Among the benefits of transdermal use of PDEIs are as follow77:
*Lack of problems with gastrointestinal absorption due to gastrointestinal pH, enzymatic activity, and drug-food interaction
*Avoiding the first-pass effect
*Non-invasive nature of this dosage, higher acceptability for the
patients, and raised compliance
*Ease of removal from the skin and minimal side effects due to
diminished oscillations in drug concentrations
*Affordability and cost-effectiveness of this dosage form
*Providing the minimum dose to create a sufficient effect compared
to oral administration
*Localized effect besides the negligible side effects
Unfortunately, studies in this area have been limited to sildenafil and tadalafil, and other PDE5Is have not been well studied and evaluated. Further research into new phosphodiesterases, as well as their topical use with other drugs used for ED, including prostaglandins, could be promising in the future to treat this global problem.
