Candidate Molecule for Premature Ejaculation, DA-8031: In Vivo and In Vitro Characterization of DA-8031

Jeon, Hyungjun; Kim, Hae-Sun; Lee, Chanho; Lee, Younggun; Choi, Seol-Min; Sohn, Yong-Sung; Shin, Chang-Yong; Kim, Jung-Hoon; Shim, Hongjin; Kang, Kyung-Koo; Ahn, Byoung Ok; Kim, Soon-Hoe

doi:10.1016/j.urology.2010.11.046

Cited by 18 publications

(18 citation statements)

References 21 publications

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“…Monoamine transporter binding and reuptake inhibition assay demonstrates high affinity and selectivity to the serotonin transporter and low selectivity and affinity to dopamine and norepinephrine transporters (47). In a platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner (48).…”

Section: New Therapeutic Targets and Emerging Drugsmentioning

confidence: 99%

“…DA-8031 significantly inhibited ejaculation after oral and intravenous administration in both para-chloroamphetamine and meta-chlorophenylpiperazine-mediated ejaculation rat models (47). In electrical stimulation of the sensory branch of pudendal nerve (SBPdn) and para-chloroamphetamine (PCA)-induced ejaculation models, Kang et al demonstrated that DA-8031 administration resulted in inhibition of the expulsion phase of ejaculation by bulbospongiosus muscle activity modulation and impairment of the emission phase by blocking the seminal vesicular pressure rise (49).…”

Section: New Therapeutic Targets and Emerging Drugsmentioning

confidence: 99%

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Emerging and investigational drugs for premature ejaculation

McMahon

2016

Transl. Androl. Urol.

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Over the past 20−30 years, the premature ejaculation (PE) treatment paradigm, previously limited to behavioural psychotherapy, has expanded to include drug treatment. Pharmacotherapy for PE predominantly targets the multiple neurotransmitters and receptors involved in the control of ejaculation which include serotonin, dopamine, oxytocin, norepinephrine, gamma amino-butyric acid (GABA) and nitric oxide (NO). The objective of this article is to review emerging PE interventions contemporary data on the treatment of PE was reviewed and critiqued using the principles of evidence-based medicine. Multiple well-controlled evidence-based studies have demonstrated the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) in delaying ejaculation, confirming their role as first-line agents for the medical treatment of lifelong and acquired PE. Daily dosing of SSRIs is likely to be associated with superior fold increases in IELT compared to on-demand SSRIs. On-demand SSRIs are less effective but may fulfill the treatment goals of many patients. Integrated pharmacotherapy and CBT may achieve superior treatment outcomes in some patients. PDE-5 inhibitors alone or in combination with SSRIs should be limited to men with acquired PE secondary to co-morbid ED. New on-demand rapid acting SSRIs, oxytocin receptor antagonists, or single agents that target multiple receptors may form the foundation of more effective future on-demand medication. Current evidence confirms the efficacy and safety of dapoxetine, off-label SSRI drugs, tramadol and topical anaesthetics drugs. Treatment with α1-adrenoceptor antagonists cannot be recommended until the results of large well-designed RCTs are published in major international peer-reviewed medical journals. As our understanding of the neurochemical control of ejaculation improves, new therapeutic targets and candidate molecules will be identified which may increase our pharmacotherapeutic armamentarium.

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Section: New Therapeutic Targets and Emerging Drugsmentioning

confidence: 99%

Section: New Therapeutic Targets and Emerging Drugsmentioning

confidence: 99%

Emerging and investigational drugs for premature ejaculation

McMahon

2016

Transl. Androl. Urol.

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“…Anxiety or conditioning toward rapid ejaculation was attributed to psychological causes, and either hyposensitivity of 5-hydroxytryptamine 2C (5-HT 2c ) receptors or hypersensitivity of the 5-HT 1a receptors was associated with the neurogenic etiology 6,7. Selective serotonin reuptake inhibitors (SSRIs) are capable of increasing the activity of serotonergic cells in the nucleus paragigantocellularis, thereby inhibiting the expulsion phase of ejaculation by modulating bulbospongiosus muscle activity and impairing the emission phase by blocking the rise in seminal vesicular pressure 8,9…”

Section: Introductionmentioning

confidence: 99%

“…From preclinical studies, DA-8031 was shown to have a high selectivity and specificity for serotonin transporters compared with other monoamine transporters and to increase ejaculation latency time without altering the post-ejaculatory interval 15,16. Furthermore, DA-8031 had a low affinity to other receptors, and thus it could contribute to fewer adverse effects 8. Regarding the pharmacokinetics of DA-8031, <1% of DA-8031 was excreted in urine, feces, or bile in its unchanged chemical structure, and bioavailability was greater in the high-dose groups in the preclinical study (investigator’s brochure, unpublished data on file).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects

Shin

Lee

et al. 2017

DDDT

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ObjectiveDA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects.MethodsA dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated.ResultsAfter a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized Cmax and AUC0–t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.ConclusionIn conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20–80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.

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“…Dapoxetine has some minor "on demand" efficacy but clearly is not a breakthrough medicine in the treatment of PE [11]. Another SSRI, with a comparable profile as dapoxetine, DA-8031 is in development for PE, but efficacy data have not yet been elucidated [12,13]. Several other approaches for treatment of PE are used or are in development, including local anesthetics (e.g., lidocaine) used as cream, gel, or spray, and are moderately effective in delaying ejaculation [10].…”

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confidence: 99%

Introductory Chapter: Sexual Dysfunction - Introduction and Perspective

Olivier¹

2017

Sexual Dysfunction

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Psychiatric Association [1] gives the following classifications of sexual dysfunctions: delayed ejaculation, erectile disorder, female orgasmic disorder, female sexual interest/arousal disorder, genito-pelvic pain/penetration disorder, male hypoactive sexual desire disorder, premature (early) ejaculation, substance-/medication-induced sexual dysfunction, other specified sexual dysfunction, and unspecified sexual dysfunction. It is evident that sexual dysfunctions constitute a heterogeneous group of disorders. They are characterized by clinically significant disturbances to respond sexually or experience sexual pleasure. Determining the character of the sexual dysfunction is a complex issue, which needs extensive clinical and psychological/ psychiatric expertise in order to come to a correct clinical judgment and includes partner and relationship factors, individual vulnerability, psychiatric comorbidity, stressors, and cultural, religious, and medical factors.Sexual functioning involves a complex interaction of biological, sociocultural, and psychological factors, which makes a clear diagnosis sometimes rather difficult. In any case, problems should be ruled out that are caused by interfering factors, like drugs, medicines, a medical condition (e.g., pelvic nerve damage) or external factors like partner violence, or other severe stressors.

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Candidate Molecule for Premature Ejaculation, DA-8031: In Vivo and In Vitro Characterization of DA-8031

Cited by 18 publications

References 21 publications

Emerging and investigational drugs for premature ejaculation

Emerging and investigational drugs for premature ejaculation

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects

Introductory Chapter: Sexual Dysfunction - Introduction and Perspective

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