Viagra ( Sildenafil )
68 Dapoxetine, an SSRI in phase III clinical trials with a rapid onset and short half-life, is being studied as an on-demand treatment for premature ejaculation.
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Disorders of Male Orgasm and Ejaculation
Alan W. Partin MD, PhD , in Campbell-Walsh-Wein Urology , 2021
Dapoxetine has received approval for the treatment of PE in more than 50 countries worldwide. Dapoxetine has not received marketing approval by the US Food and Drug Administration (FDA). It is a rapid-acting and short half-life SSRI with a pharmacokinetic profile supporting a role as an on-demand treatment for PE ( Pryor et al., 2006 ). No drug-drug interactions associated with dapoxetine, including phosphodiesterase inhibitor drugs, have been reported. In RCTs, dapoxetine 30 mg or 60 mg taken 1 to 2 hours before intercourse is more effective than placebo from the first dose, resulting in2.5 and 3.0-fold increases in IELT, increased ejaculatory control, decreased distress, and increased satisfaction. Dapoxetine was comparably effective in men with L-PE and A-PE ( Porst et al., 2010 ) and was similarly effective and well tolerated in men with PE and comorbid ED treated with PDE5I drugs ( McMahon et al., 2013 ). Treatment-related side effects were uncommon and dose dependent and included nausea, diarrhea, headache, and dizziness ( McMahon et al., 2011 ). They were responsible for study discontinuation in 4% (30 mg) and 10% (60 mg) of subjects. The incidence of treatment-related side effects has been reported to be lower with on-demand dapoxetine compared with daily dosed SSRIs ( Verze et al., 2016 ). There was no indication of an increased risk of suicidal ideation or suicide attempts and little indication of withdrawal symptoms with abrupt dapoxetine cessation ( Levine, 2006 ). Postmarketing experience does, however, report that the discontinuation rate for dapoxetine was high (87% at 12 months) predominantly because of cost and the lack of spontaneity associated with on-demand administration ( Park et al., 2017 ). Jiann et al. reported that 45% of men were satisfied with their response to dapoxetine (30 mg) and that level of satisfaction was closely related to treatment response ( Jiann and Huang, 2015 ).
Derek G. Waller BSc (HONS), DM, MBBS (HONS), FRCP , Anthony P. Sampson MA, PhD, FHEA, FBPhS , in Medical Pharmacology and Therapeutics (Fifth Edition) , 2018
Premature ejaculation is orgasm with expulsion of semen following minimal penile stimulation. It usually is defined as ejaculation that occurs less than 1 minute after the onset of stimulation or vaginal penetration, and can produce significant psychological distress.
Ejaculation begins with emission of fluid from the ampullary vas deferens, seminal vesicles and prostate into the urethra under control of the sympathetic nervous system. Expulsion of the resulting semen from the urethra is due to a spinal reflex that produces rhythmic urethral contractions through pudendal nerve stimulation of the bulbospongiosus muscle.
Dapoxetine is a short-acting selective serotonin reuptake inhibitor (SSRI) that prolongs intravaginal latency time from less than a minute to an average of over 3 minutes. The mechanism of action is unclear but may involve increased serotonin in the brain stem, modulating pudendal nerve activity via descending pathways. Dapoxetine is taken ‘on demand’ 1–3 hours before sexual activity. The most common adverse effects are dizziness, headache and nausea.
Compendium: drugs used to treat erectile dysfunction and premature ejaculation
|Drugs used for erectile dysfunction|
|All drugs for erectile dysfunction should be used with caution in people with cardiovascular disease.|
|Phosphodiesterase type 5 inhibitors|
|All PDE5 inhibitors are given orally.|
|Avanafil||Rapid onset of action (15–30 min). Half-life: 6–17 h|
|Sildenafil||Taken between 30 min and 4 h before sexual activity; also used for primary pulmonary hypertension. Half-life: 2 h|
|Tadalafil||Long duration of action means tadalafil can be taken up to 12 h before sexual activity. Half-life: 17 h|
|Vardenafil||Usually taken about 1 h before sexual activity. Half-life: 4–5 h|
|Other drugs used for erectile dysfunction|
|Alprostadil||Prostaglandin E1 analogue. Care needed if partner is pregnant; can cause priapism. Given by intracavernosal injection, dermal cream or urethral application. Very short half-life (30 s)|
|Papaverine||Smooth muscle relaxant. Given by intracavernosal injection; not licensed for this indication in the United Kingdom. Half-life: 2 h|
|Phentolamine||An α1-adrenoceptor antagonist. Given with papaverine by intracavernosal injection (unlicensed indication). Half-life: 1.5 h|
|Drug for premature ejaculation|
|Dapoxetine||Selective serotonin reuptake inhibitor; may cause postural hypotension. Given orally 1–3 h before sexual activity. Half-life: 1.5 h|
Strategy and Drug Research
2.08.9 Changing Role of Contract Research Organizations
As well as biotechnology sector companies, potential licensees for projects at this stage from large pharmaceutical companies include some of the larger CROs. For instance, PPD has entered into a number of deals involving licensing opportunities at the late preclinical or phase I stage, which it then developed through clinical proof of principle to phase II or phase III, and sought a late stage development and/or marketing partner. Quintiles has set up a special division called PharmaBio specifically to pursue this strategy.
An example of a project which has been partially developed in this way includes dapoxetine for premature ejaculation. Dapoxetine is a selective serotonin reuptake inhibitor, structurally related to fluoxetine, which was initially being developed by Eli Lilly for the potential treatment of depression, for which it was in phase I trials; however, no development regarding this indication has been reported after 1995. PPD GenuPro, a subsidiary of PPD, which was established from a collaboration between Eli Lilly and PPD, gained the rights to develop dapoxetine in December 1999. Dapoxetine was evaluated in a phase II trial in the USA for the treatment of premature ejaculation. Results from the 155-patient trial indicated a significant increase in ejaculatory latency in dapoxetine recipients, relative to placebo. Dapoxetine moved into phase III development for the treatment of premature ejaculation in July 2003. In December 2000, ALZA Corporation, a wholly owned subsidiary of Johnson & Johnson, licensed exclusive rights to dapoxetine from GenuPro for genitourinary therapies, including premature ejaculation. Under the terms of the agreement, ALZA was to develop and commercialize dapoxetine and be responsible for manufacturing, clinical, regulatory, and sales and marketing costs resulting from the license. In exchange, GenuPro was to receive an undisclosed upfront payment. In addition to royalties on net sales, the terms of the agreement include milestone payments based on product approval and meeting certain sales levels. In December 2004, ALZA Corporation submitted a new drug application to the US Food and Drug Administration (FDA) for dapoxetine hydrochloride in the treatment of premature ejaculation. Very clearly, PPD used a series of license deals interspersed with financing of the development of a compound through some critical stages of pharmaceutical development, thereby adding value which it was to realise in the later of the license arrangements.
PharmaBio, Quintiles’ development group, offers innovative partnering solutions to pharmaceutical and biotech companies. For instance, it has participated in various investments, either directly or indirectly, into biotechnology sector companies (e.g., Innapharma Inc., a New Jersey company engaged in the development of a series of ‘small chain’ peptide-based products to treat central nervous system disorders, such as major depression). It also is active in product partnering, in which PharmaBio acquires product rights or products from pharmaceutical companies to help them develop and manage product portfolios, utilizing the parent company Quintiles’ development and commercialization capabilities. Finally, PharmaBio can also participate in various risk-sharing agreements for product development, in which a share in the end product value is returned for a financial contribution to product development.
These new ways in which CROs work emphasize the changing nature of the contract sector, and the desire of such companies to seek commercial advantage by offering a broader range of development alternatives which deflect the usual comparisons with competitors based solely on cost of service. These types of arrangements are currently only offered by the very largest CROs. With time, they may become more important as value drivers for the companies offering these services relative to the sector as a whole. These services may also be important differentiating factors for companies based in Europe, USA, and Japan when set against their competitors in India and China. As described above, offshoring is fast becoming a significant factor in contractual outsourcing and forcing the companies with higher cost bases to consider greater added value offerings.
SSRIs (Selective Serotonin Reuptake Inhibitors)
Name: Selective serotonin reuptake inhibitors (SSRIs)
Chemical Abstracts Service Registry Numbers: See representative chemicals
Chemical/Pharmaceutical/Other Class: Serotonin reuptake inhibitors; serotonin receptor upregulators
Representative Chemicals: Citalopram hydrobromide (CAS 59729-32-7) Celexa (Lundbeck), Dapoxetine (CAS 119356-77-3) (Priligy), Escitalopram oxalate (CAS 219861-08-2) Lexapro (Forest), Fluoxetine hydrochloride (CAS 59333-67-4) Prozac (Lilly), Fluvoxamine maleate (CAS 61718-82-9) Luvox (Solvay), Paroxetine hydrochloride (CAS 78246-49-8) Paxil (SmithKline–Beecham), Sertraline hydrochloride (CAS 79559-97-0) Zoloft (Pfizer). These are the six main selective serotonin reuptake inhibitors (SSRIs); others are under development and possibly in use in small populations or foreign countries.
Molecular Formula: Varies
Chemical Structure: Varies
Traditional Chinese Medicine, infertility, and sexuality dysfunction
Premature ejaculation and Traditional Chinese Medicine
PE for some men trying to conceive can be acquired meaning it has not happened before and for others it can be lifelong. The definition of PE is ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (LPE), or a clinically significant reduction in latency time, often to about 3 minutes or less (acquired PE). We know that it can have negative personal consequences for some men and others avoid sexual intimacy altogether. TCM offers solutions for PE with acupuncture and herbs. As always, it’s important to diagnose the underlying pattern. In one study it was concluded, “Our results confirm previous reports on the efficacy and safety of dapoxetine . Although less effective than dapoxetine (an SSRI for PE) acupuncture had a significant ejaculation-delaying effect.” In this study the following points were used: BL 30, Bl 52, ST 26, LI4, LIV3, Ren 3, and Yintang—twice a week for 20 minutes and the patients were followed up in a month  . Although SSRIs are used for PE, they are not recommended for fertility, says Dr. Philip Werthman, a Reproductive Urologist in Los Angeles. An option is to use herbs and acupuncture.
In another study the researchers showed that acupuncture can extend the ejaculation latency to a certain extent. On the basis of TCM theory, acupuncture can regulate the balance of Qi and blood by stimulating acupuncture points to improve human body function. Studies have shown that acupuncture points: tianshu (ST25), zusanli (ST36), and taichong (LIV3) can adjust neurotransmitter 5-HT levels and reduce nerve sensitivity  .
When it comes to PE (I like to call it early ejaculation) and fertility, chances are the limiting factor is the amount of pleasure with each experience. Some couples shy away from engaging in sex because of shame around this issue. For some men early masturbation style can lead to PE and the edging practice below can help to retrain them.
A Worldwide Yearly Survey of New Data in Adverse Drug Reactions
Keaton S. Smetana , . Sidhartha D. Ray , in Side Effects of Drugs Annual , 2018
Sildenafil oro-dispersable (ODF) film is a new formulation and was compared directly to film-coated sildenafil tablets (FCT) in a prospective, cross-over trial of 139 patients with erectile dysfunction (ED) [ 7c ].
Overall sexual satisfaction was improved in those taking the ODF formulation, and no additional adverse effects were observed. A systematic review including 29 studies of sildenafil in ED identified that overall sildenafil was well-tolerated [ 8R ]. Mild reactions occurring more than 2% of time included headache, flushing, visual alterations, congestion, back pain, myalgia, myalgia, nausea, dizziness, and rash. The ODT formulation was associated with similar overall drug exposure as ODF, irrespective of whether the ODF was consumed with water.
Herpes simplex encephalitis, albeit rare in immunocompetent individuals, is associated with significant mortality and morbidity. Sildenafil has potential to compromise the effectiveness of the blood–brain barrier secondary to its vasodilatory properties. As such, sildenafil has been studied to help increase penetration of certain drugs (e.g. chemotherapy) across the blood–brain barrier. In one case report, the authors describe herpes simplex encephalitis in a 62-year-old male taking sildenafil during a primary genital herpes simplex virus infection [ 9H ].
Treatment of premature ejaculation was evaluated in a prospective randomized, placebo-controlled trial comparing paroxetine, dapoxetine , sildenafil, or combination dapoxetine with sildenafil [ 10C ]. A total of 150 patients were included during 2015–2016. Those who received combination dapoxetine 30 mg with sildenafil 50 mg experienced improved premature ejaculation diagnostic tool, intravaginal ejaculatory latency time, and patient satisfaction scores. The most adverse effects in different groups were constipation (13.3% with placebo), sleep disturbances (30% with paroxetine), nausea (26.6% with dapoxetine), headache (26.6% with sildenafil), and headache and nausea (33.3% each with dapoxetine and sildenafil combination) [ 10C ].
Cerebral Venous Sinus Thrombosis
Cerebral venous sinus thrombosis (CVST) was associated with sildenafil use in two patient cases. The first was a 29-year-old man who presented with a 2 week history of bilateral visual deterioration, and severe headache [ 11c ]. He reported taking sildenafil for nearly 2 years two to three times daily without medical supervision and was not on any other medications. A fundus exam revealed stage two papilledema, the hypercoagulable work up was negative, and magnetic resonance imaging (MRI) revealed a filling defect in the right transverse sinus, sigmoid sinus, and jugular vein without infarcts. Cerebrospinal fluid revealed normal biochemistry and no abnormal cells, but had an opening pressure of 43 cm of H2O. The patient was treated with acetazolamide and bridged to warfarin with enoxaparin.
The second case was a 38-year-old man who reported to the emergency department (ED) with meningeal signs (headache, neck stiffness, photophobia) [ 12c ]. Six days prior he had undergone an elective inguinal hernia repair and received spinal anesthesia. His post-op course was complicated by a progressively worsening headache that had minimal response to caffeine. Initially a post-dural puncture headache was suspected, but the patient declined an epidural blood patch and was discharged. Three days after discharge the patient presented to the ED and was found to have a non-aneurysmal subarachnoid hemorrhage in the right sylvian fissure. A subsequent angiogram revealed thrombosis of the superior sagittal sinus, suggestive of CVST. The patient had initially failed to report taking sildenafil twice a week for the past 4 years for erectile dysfunction prior to the inguinal repair.
While the mechanism underlying PDE-5 induced CVST is unclear there are two proposed mechanisms that potentially overlap: (1) venous dilation results in venous stasis and insufficiency and (2) a biphasic platelet response to cyclic guanosine monophosphate (cGMP) activation of protein kinases exist (initially promoting aggregation then limiting thrombus formation over time) [ 12c ].
Hepatotoxicity with sildenafil is considered to be an extremely rare event. A recently published review highlighted five case reports of possible sildenafil-induced hepatotoxicity [ 13R ]. While the underlying mechanism of hepatotoxicity is unclear, some of the reported events involved consumption of herbal products used for sexual enhancements which may have been a contributing factor. The range of toxicity varied from asymptomatic elevations in liver enzymes to fulminant liver failure.
Visual disturbance is a known side effect of sildenafil occurring in about 3% of patients [ 14E ]. This adverse effect results from inhibition of retina-specific phosphodiesterase type 6. The implications of long-term sildenafil usage on the retina have not been well described. An experiment found that rats exposed to 10 mg/kg/day of sildenafil experienced toxic effects to the retina and optic nerve. In spite of the observed effects with sildenafil treatment, these effects diminished after sildenafil was discontinued. It is unclear what the effects are in humans at typical doses (0.5–1 mg/kg). Another case report described a 32-year-old African American woman who experienced bilateral, asymmetrical outer macular atrophy while receiving sildenafil chronically for pulmonary arterial hypertension (PAH) [ 15A ]. Her partial vision loss began 1 month after initiating sildenafil and was reported to continue for 5 years until discontinuing the medication. This was the first case report of such a finding associated with long-term sildenafil use for the treatment of PAH.
Sildenafil is being studied for the treatment of lymphatic malformations in children. A long-term follow-up study of 12 children with lymphatic malformations was undertaken to evaluate long-term clinical outcomes. The median duration of sildenafil treatment was 9 months and the average follow-up was 4 years. Ten patients reported positive therapeutic responses, and six required further interventions. The most common adverse effects experienced during the treatment period included flushing (20%) and prolonged ejections (50% of males) [ 16c ].
The synergistic anticancer activity of sildenafil was studied in conjunction with doxorubicin in a mouse model of breast cancer [ 17E ]. When added to 1 μM of doxorubicin in 4T1 breast cancer cells in vitro a 1.8-fold, 6.2-fold, and 21-fold statistically significant increase in cytotoxic effects were seen with increasing sildenafil doses (1, 30, and 100 μM, respectively). Compared to doxorubicin alone sildenafil plus doxorubicin resulted in a 4.7-fold statistically significant reduction in tumor size. The added anticancer effects are possibly due to smooth muscle relaxation in addition to alteration in vascular endothelial permeability [ 17E ].
A systematic review of sildenafil use during pregnancy was conducted to assess the incidence of adverse effects and impact on fetal development and obstetric complications [ 18R ]. A total of 16 studies including 165 pregnant women were included. Stillbirths and neonatal deaths were similar to sildenafil naïve individuals. No congenital defects were observed.
Medical Therapy of Delayed Ejaculation
Drug treatment of DE ejaculation has met with limited success. Many medications have been proposed as treatment strategies for delayed ejaculation, including cabergoline, amantadine, and even testosterone ( Abdel-Hamid et al., 2016 ). These drugs can facilitate ejaculation by either a central dopaminergic (cabergoline), anti-serotonergic (buproprion), or oxytocinergic (oxytocin) mechanism of action or a peripheral adrenergic mechanism of action (midodrine) ( Abdel-Hamid et al., 2016; Hsieh et al., 2012; Modell et al., 1997; Ishak et al., 2008 ). However, the evidence supporting pharmacological treatment of delayed ejaculation is relatively weak and limited to case reports, small case series and small trials ( Abdel-Hamid et al., 2016 ). Currently, no drugs have been approved by regulatory agencies for this purpose and most drugs that have been identified for potential use have limited efficacy, impart significant side effects, or are as yet considered experimental in nature ( McMahon, 2016 ).
Medical Therapy of Premature Ejaculation
Premature ejaculation (PE), is one of the most common male sexual disorders: According to the National Health and Social Life Survey, PE was reported to have a prevalence of 21% in men aged 18 to 59 in the United States ( Laumann et al., 1999 ). In addition to sexual dissatisfaction, severe premature ejaculation that prevents successful coitus will likely impact a couple’s ability to conceive naturally.
The exact etiology of PE is unknown and treatment is based on psychological, behavioral and pharmacological interventions. Behavioral and psychological therapy are often the first lines of treatment for patients presenting with PE. Psychotherapy includes both sexual therapy and relationship counseling, with the aim of addressing psychological and interpersonal issues that may be contributing to PE. Behavioral therapy involves physical techniques that have been developed to help men delay ejaculation. The “stop-start” technique involves the patient or his partner stimulating the penis until he feels the urge to ejaculate, then stopping until the sensation passes. Another behavioral therapy technique commonly employed involves the “squeeze” technique, where the patient squeezes the glans penis at the moment he feels the urge to ejaculate, until this sensation passes ( Melnik et al., 2011 ). Randomized controlled trials evaluating these behavioral modifications demonstrated that these techniques can improve insertion-to ejaculation time and sexual satisfaction compared to controls. However, these studies have found that the addition of pharmacological therapies combined with behavioral therapies were better than either intervention alone ( Cooper et al., 2015 ).
The serotoninergic system is felt to act as a suppressor of ejaculation at the level of the hypothalamus ( Porst, 2011 ) based on the anti-ejaculatory side effect of serotonin reuptake inhibitors (SSRIs) and other drugs that increase central activity of serotonin ( Foreman et al., 1989 ). One of the most commonly associated side effect of SSRIs are delayed ejaculation and absent or delayed orgasm ( Jannini et al., 2015 ), and these known side effects have been utilized in the off-label treatment of PE, in either on-demand doses or longer acting chronic courses.
Longer-acting SSRIs such as paroxetine, fluoxetine, and sertraline, as well as the tricyclic antidepressant clonidine, may be utilized in the treatment of men with medication-refractory PE. Paroxetine exerts the strongest delay in ejaculation ( Waldinger et al., 2004 ) when utilized in a daily dosing regimen. This regimen requires use 5–10 days prior to onset of effect, and an additional 2–3 weeks prior to full effect ( McMahon et al., 2004 ). Similar to dapoxetine, these other SSRIs have been found to be safe and effective treatment for delaying ejaculation ( Montague et al., 2004 ). Nausea, dry mouth, drowsiness and decreased libido are some common side effects of SSRI treatment, and long term use may be associated with weight gain and increased risk of developing Type 2 diabetes ( Fava et al., 2000 ). Lastly, while the risk for suicidal ideation or suicide attempts has not been found to be increased in non-depressed men on SSRIs for PE, there is a small increase in this risk in youths with depression on SSRIs ( Khan et al., 2003 ). Therefore, caution is recommended in prescribing SSRIs to young adolescents with PE aged 18 or less.
Topical anesthetics can be applied to the penis prior to beginning intercourse, and can be applied with a condom or without. Residual topical anesthetics can also cause vaginal numbness, so men should be counseled to either wash clean any residual active topical agent or wear a condom during intercourse. Lidocaine/prilocaine cream (2.5 g) applied for 20 to 30 min prior to intercourse has been shown to increase latency time ( Montague et al., 2004 ), with minimal side effects.
Immunotherapy Targeting Male Factor
Anti-sperm antibody (ASAB)-mediated male infertility is a rare cause of infertility, reported in 6–11% of infertility cases ( McLachlan, 2002 ). However, when present, it a potentially treatable cause. ASABs are felt to be formed in the epididymis, often in the presence of downstream obstruction (eg., vasectomy), infection/inflammation, or trauma. The IgG isotype is felt to be the most common, and important, of the isotypes seen. It appears that these Ab exert their effect in a variety of ways. Most think that they cause agglutination (sperm sticking together), thus inhibiting progressive forward motility, as well as clumping of the sperm in the cervical mucus. Others have reported reduced sperm viability due to cytotoxic ASABs, although this has been difficult to ascertain in vivo. Finally, impairment of the sperm-egg interaction has been demonstrated, with altered binding of the sperm to the zona pellucida. This has been demonstrated in conventional IVF. While there was also a theory of post-fertilization effects of ASABs, this has been disproven, as ICSI has been shown to be an effective treatment for ASABs, with no adverse effects on the fertilization rate or embryo development.
Diagnosis of ASABs is somewhat difficult, as they have been demonstrated in some fertile men. There are 2 methods for detection, direct and indirect. Direct methods identify ASABs on the sperm using anti-IgG antibodies. Indirect methods detect ASABs in body fluids (cervical fluid, blood, semen). The 2 most popular methods for direct testing are the immunobead test (IBT) and the mixed agglutination reaction (MAR). The strengths of the IBT are that the type of Ig, the percentage of sperm with beads attached and their location (head, mid-piece, tail) can be quantified. Reagent cost, time and non-specific binding are difficulties. Location of binding is important as well, as tail tip binding is of much less clinical significance than head or body binding. The MAR test methods uses latex beads or red blood cells labeled with human IgG A, M or G which are co-incubated with viable sperm following which anti-human Ig is added to cause agglutination with the sperm. Indirect testing is typically performed on the fluid in question using serologic tests to detect and quantify specific Ig isotypes.
The management of ASABs was previously difficult, as many treatments were empiric and anecdotal. However, with the advent of ICSI, most clinicians utilize this to overcome significant ASABs. There are situations; however, when couples are not open to IVF and wish to try medical therapy. There are 2 concepts used in the medical treatment of ASABs, either removal of the ASABs or suppression of their formation. The first method, removal, is rarely successful. ASABs bind to sperm prior to ejaculation; thus, attempts to wash them off are typically unsuccessful (they are bound by a nearly unbreakable covalent bond). Studies have explored prevention of ASAB formation through the use of immunosuppressive therapy. Most of these treatments utilize glucocorticoids, such as prednisone, in doses high enough to suppress the immune system, and are taken either cyclically or for several months. Unfortunately, the high rate of adverse events, particularly aseptic necrosis of the hip (reported in 1:150 cases), has limited the use of this treatment. One randomized study examined the use of immunosuppressive therapy with and without IUI and found the cumulative pregnancy rate with IUI to be 39% vs only 4% with timed intercourse. There were minimal side effects in this trial which used 40 mg of prednisone/day for 2 weeks, followed by 20 mg/day for 2 weeks ( Robinson et al., 1995 ). While this report was promising, none of the couples had attempted IUI previously, thus bringing the impact of the steroid treatment into question. Thus, the utilization of ICSI has become the standard treatment for immunologic-mediated male infertility.
The role of cerebral 5-HT in the control of the ejaculatory response has received particular attention. Selective 5-HT reuptake inhibitors (SSRIs) are widely prescribed as antidepressants and have long been associated with sexual side effects including delayed ejaculation. On this basis, new therapeutical approach of premature ejaculation was developed and eventually led to the registration of the first agent ( dapoxetine ) in this indication. The blockade of 5-HT transporters by SSRIs results in increased 5-HT extracellular levels and, consequently, in enhanced 5-HTergic neurotransmission in the CNS. The increased 5-HT tone is suggested to be the mechanism by which SSRIs lengthens ejaculation latency ( Giuliano and Clement, 2012 ). The mode of action of brain 5-HT in the control of ejaculation has been extensively studied in laboratory animals. An opposite action of 5-HT on sexual behavior and more particularly ejaculatory behavior was reported in male rats depending on the site where 5-HT is microinjected ( Hull et al., 2004 ). Delivery of 5-HT into 5-HTergic projection areas (forebrain, medial preoptic area) delayed or inhibited ejaculation whereas delivery into sites containing 5-HTergic neuron cell bodies (raphe nuclei) facilitated ejaculatory behavior. As aforementioned, a comprehensive view of the role of 5-HT is complicated by the variety of receptor subtypes expressed in the CNS. Ligands of 5-HT1A, 5-HT1B, and 5-HT2C receptors have been tested in different animal paradigms ( Giuliano and Clement, 2012 ; Hull et al., 2004 ). Stimulation of 5-HT1A receptors enhanced ejaculatory behavior in the male rat. This receptor subtype is a somatodendritic autoreceptor (i.e. expressed on cell bodies of 5-HT neurons) which activation turns down firing of 5-HT neurons and, as a consequence, decreases 5-HT release. Then, pro-ejaculatory action of 5-HT1A agonists may be explained by reduction of the 5-HTergic inhibitory tone on CNS ejaculatory mechanism. Stimulation of 5-HT1B receptors resulted in inhibition of ejaculation in the male rat. Although, because these receptor subtypes can be presynaptic autoreceptors or postsynaptic heteroreceptors, the exact modality of 5-HT1B involvement is still unclear. Finally, it was reported that stimulation of 5-HT2A/C receptors inhibited ejaculatory behavior in the male rat.
Synthetic Methods VI – Enzymatic and Semi-Enzymatic
V. Gotor , . E. Busto , in Comprehensive Chirality , 2012
184.108.40.206.3 Hydrolysis of amides
The enzymatic hydrolysis of amides is a very powerful approach for the production of high value-added compounds such as pharmaceuticals, amino acids, or biologically relevant compounds. Traditionally, aminoacylases, aminopeptidases, and lactamases have been used for the production of optically active amides, but lipases and esterases have also shown their potential in the stereoselective cleavage of amide bonds in recent years. 18
Aminocylases (EC 3.5.1.n) are the most used class of enzymes for the enantioselective cleavage of amides. They are able to accept a broad range of acyl groups such as (acetyl, chloroacetyl, formyl, and others), although they require a free α -carboxyl group. For instance, the preparation of optically active 3-amino-3-phenylpropan-1-ol, an interesting building block for the preparation of the antidepressant Dapoxetine , has been performed by means of the Penicillin G acylase (PGase)-catalyzed hydrolysis of racemic 3-[ N-(phenylacetyl)amino]3-phenyl-1-propanol ( Scheme 23 ). 40 Both enantiopure (S)-amide and (R)-amino alcohol were recovered with excellent isolated yields.
Scheme 23 . Enzymatic hydrolysis of β-amido alcohols.
Recently, Grundmann and Fessner studied the PGA-mediated kinetic resolution of N-acylated arylglycines, which are important intermediates in the synthesis of semisynthetic β-lactam antibiotics ( Scheme 24 ). 41 All the substrates were efficiently resolved by the protein, with a clear correlation between the enantioselectivity and the steric bulk of the aryl substituent. Thus, higher enantioselectivities were attained for derivatives with bulkier substituents. However, for most of the substrates the addition of 5% MeOH as a cosolvent led to higher E values.
Scheme 24 . PGase-catalyzed resolution of N-arylglycines.
Aminopeptidases (EC 3.4.11.n) are enzymes involved in the enzymatic digestion of proteins, also presenting interesting applications in the production of optically active β-amino acid amides ( Scheme 25 ). Heck et al. tested three different enzymatic sources, observing that the enzymes were especially useful for the hydrolysis of methyl and propyl β-amino acid amides, but also the bulkiest substrates were also efficiently resolved using d -aminopeptidase A from Ochrobactrum anthropi. 42
Scheme 25 . Kinetic resolution of aliphatic β-amino amides by β-aminopeptidases.
Lactamases (EC 220.127.116.11) are enzymes produced by gram-positive bacteria that are able to cleave the β-lactam ring. This group of enzymes is responsible for bacterial resistance to β-lactam antibiotics such as penicillins or cephalosporins. Whole cells containing lactamase enzymes have been successfully applied for the enantioselective hydrolysis of lactams, allowing the recovery of optically active amino acids and lactams. For instance, Evans and coworkers performed the kinetic resolution of 6-azabicyclo[3.2.0]hept-3-en-7-one using whole cells of Rhodococcus equi NCIB containing lactamase enzymes ( Scheme 26 ). 43 The remaining optically active (1R,5S)-lactam was isolated in an enantiopure form and a high yield, and then used as an adequate starting material for the production of the antifungal antibiotic cispentacin (FR 109615).
Scheme 26 . Lactamase-mediated hydrolysis of lactams.
Despite the fact that amidases, proteases, aminoacylases, and lactamases are the most useful enzymes for the enantioselective cleavage of amide bonds, different research groups have found that several lipases or esterases are able to cleave amide bonds. 18 However, these transformations should be attempted with highly purified enzymes since the presence of proteases as trace impurities could be responsible for the hydrolytic cleavage. In this context, Kanerva and coworkers recently found that CAL-A was able to catalyze the stereoselective cleavage of N-acylamino acids ( Scheme 27 ). 44 The authors performed protein fractionation in order to identify the catalytic protein, observing that a truncated form of Candida antarctica lipase type A (CAL-A) was responsible for the enantioselective cleavage of the amide bond. An explanation based on the more effective accommodation in this truncated form was proposed, although the presence of serine carboxypeptidase traces could also be responsible for the amidase activity.
Scheme 27 . CAL-A as a highly efficient catalyst for the hydrolysis of N-acyl-α-amino acids.
Although lipases are known to be generally inactive toward the cleavage of amide bonds, since the discovery of the promiscuous β-lactamase activity of hydrolases, many examples have appeared in the literature related to the lipase catalyzed hydrolysis, alcoholysis, and aminolysis of lactams. For instance, CAL-B has efficiently catalyzed with high selectivity (E>200) the hydrolysis of a wide panel of unsaturated alycyclic-fused β-lactams using an organic solvent as the reaction medium ( Scheme 28 ). 45
Scheme 28 . Lipase-catalyzed preparation of optically active lactams.
Sexual Disorders and Sexual Dysfunction
The essence of treatment for sexual disorders involves the treatment of preexisting illnesses (e.g., diabetes); discontinuation or substitution of offending medications; reduction of alcohol, smoking, or both; increase in exercise; improvement in diet; and addition of medications for psychiatric conditions (e.g., depression). Although many medications for the treatment of hypertension inhibit sexual function, the angiotensin II–receptor blockers (e.g., losartan), are not associated with sexual side effects and may actually help prevent or correct sexual problems (such as sexual dissatisfaction, low frequency of sex, ED). 52 Any hormone deficiency should be corrected (e.g., addition of testosterone for hypogonadism, thyroid hormone for hypothyroidism, estrogen/testosterone for postmenopausal females, or bromocriptine for elevated prolactin after neuroimaging of the pituitary). Many medical illnesses are associated with physiologic and psychological impairments that when treated improve sexual function; selected examples are shown in Table 24-9 . 5
Psychotropic Medication–Induced Sexual Dysfunction
Sexual dysfunction is a commonly reported side effect of selective serotonin reuptake inhibitors (SSRIs). According to some estimates, as many as 30% to 40% of SSRI users experience anorgasmia, 10% to 20% of patients experience decreased libido or ED, and 30% to 50% experience low desire. 5, 53 Strategies to treat SSRI-induced sexual dysfunction are presented in Table 24-10 . 53–62 Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) also cause sexual problems. Because of their sexual side effects, the SSRIs have been used with success to treat premature ejaculation and reduce compulsive sexual acts associated with Alzheimer’s disease, 63 paraphiliac behavior, 64 and sexual obsessions in obsessive–compulsive disorder (OCD) spectrum patients. 65
Typical antipsychotics (e.g., haloperidol and thioridazine) as well as atypical agents (e.g., risperidone and clozapine) are all associated with sexual dysfunction. Hyperprolactinemia may play a causal role. Most second-generation antipsychotics (e.g., olanzapine, quetiapine, aripiprazole, and ziprasidone) are associated with fewer sexual side effects. 66 Antipsychotics have also been used to dampen sexually inappropriate behaviors and paraphilias. 67
There is no Food and Drug Administration (FDA)-approved treatment for premature ejaculation. However, the SSRIs (e.g., fluoxetine, sertraline, and paroxetine), used continuously or intermittently (2 to 12 hours before sex), can cause delayed or retarded ejaculation, which can treat premature ejaculation. Low doses may be effective. Clomipramine (a TCA) may be more effective in delaying ejaculation than the SSRIs. 68 Dapoxetine , an SSRI in phase III clinical trials with a rapid onset and short half-life, is being studied as an on-demand treatment for premature ejaculation. 69 Topical anesthetic creams (such as lidocaine derivatives) appear to be successful in slowing ejaculation without inducing the systemic side effects of antidepressants; however, they can cause local skin irritation and penile numbing that sometimes leads to erectile problems. The most popular of these agents is EMLA cream, a combination of lidocaine and prilocaine. 70 When the premature ejaculation is secondary to ED, PDE-5 inhibitors should be used to treat ED first.
The mainstay of treatment for ED is the use of oral PDE-5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil), which can help men with a wide range of conditions; they are easy to use, and have few adverse effects ( Table 24-11 ). 19, 61, 71, 72 The PDE-5 inhibitors are effective in the treatment of antidepressant-induced ED and retarded ejaculation. Of note, the PDE-5 inhibitors are metabolized by P450 3A4 and 2C9 isoenzyme systems. Patients who take potent inhibitors (including grapefruit juice, cimetidine, ketoconazole, erythromycin, and ritonavir) of these P450 isoenzyme systems, should have a lower starting dose of a PDE-5 inhibitor. Statins may also help improve the efficacy of PDE-5 inhibitors.
Other oral agents are used to treat ED. Yohimbine (Yocon), an α2-adrenergic inhibitor, has been available for many years and it may be useful in the treatment of psychogenic ED; however, its efficacy is uncertain. Phentolamine (Vasomax) is an α-blocker (not yet FDA-approved), that may produce erections by dilation of blood vessels. Apomorphine (Uprima) is a centrally acting D1/D2 dopamine receptor agonist administered sublingually (not yet FDA-approved). Although efficacious in the stimulation of erections, the drug is limited by its side effects, especially nausea and vomiting. 19 Centrally acting melanocortin receptor agonists (in development as an intranasal preparation) appear to be effective, but side effects (flushing, nausea) may limit their utility. 73 The amino acid l -arginine (an NO precursor) appears promising in men.
Second-line treatments for ED include use of intrapenile injection therapy, intraurethral suppository therapy, and vacuum-assisted devices ( Table 24-12 ). The third-line treatment for ED is surgical implantation of an inflatable or malleable rod or penile prosthesis. Endarterectomy may correct ED in certain patients with underlying vascular disease. 74
Female Sexual Dysfunction
The only approved medical–surgical intervention for the treatment of female sexual dysfunction is EROS-CTD, a clitoral suction device, which is used to increase vasocongestion and engorge the clitoris for better sexual arousal and orgasm. Numerous drug trials are being done using medications approved for male sexual dysfunction (PDE-5 inhibitors), hormone-based therapies, and novel agents. In general, PDE-5 inhibitors are not effective in improving female sexual function, but they may benefit some women who exhibit greatly diminished genital vasocongestion. 75 PDE-5 inhibitors also appear to be effective for women with SSRI-induced sexual dysfunction.
Testosterone (in a variety of forms), in combination with estrogen (Estratest), has been shown to improve libido, sexual arousal, and the frequency of sexual fantasies in surgically and naturally postmenopausal women. 76 However, it requires a relatively high dose, and because long-term estrogen use (including combination with progestin) is associated with risks, it is not routinely recommended. Recently, transdermal testosterone was shown to improve sexual function in postmenopausal women not taking estrogen, but long-term safety data are not available. 77 Tibolone, a steroid hormone with estrogenic, androgenic, and progestogenic metabolites, has been shown to increase vaginal lubrication, arousability, and sexual desire, but not the frequency of sexual intercourse or orgasm. It is also associated with an increased risk of stroke in women with osteoporosis over age 60 years. 78, 79
Bupropion (a dopamine and noradrenergic agonist) may increase arousability and sexual response in women. As in men, trials of yohimbine, apomorphine, and melanocortin agonists are ongoing. l -Arginine may also enhance female sexual function. 44
Pharmacologic therapy for paraphilias is aimed at suppression of compulsive sexual behavior. The antiandrogen drugs, cyproterone (CPA) and medroxyprogesterone acetate (MPA, Depo-Provera), which act by competitive inhibition of androgen receptors, are used to reduce aberrant sexual tendencies by decreasing androgen levels (not yet FDA-approved). Treatment with leuprolide (approved for prostate cancer) and triptorelin (not yet FDA-approved), synthetic gonadotropin-releasing hormone analogues, decrease testosterone to chemically castrating levels (after an initial transient increase) and may completely abolish deviant sexual tendencies. The SSRIs and clomipramine may lower aberrant sexual urges by decreasing the compulsivity/impulsivity of the act and by decreasing aggressive behaviors. Antipsychotics have also been used to treat paraphilias. 80, 81
Gender Identity Disorder
The major treatment for gender identity disorder is sex-reassignment surgery. Hormone therapy may be necessary to suppress original sex characteristics (i.e., with luteinizing hormone–releasing hormone (LHRH) agonists, CPA, estrogens, and testosterone).