Benefits of Treating PE and ED Simultaneously

0% found this document useful (0 votes) This research article presents the development and validation of a rapid and sensitive RP-HPLC method for the simultaneous estimation of Sildenafil Citrate and Dapoxetine Hydrochloride in ph… 0% found this document useful (0 votes) This research article presents the development and validation of a rapid and sensitive RP-HPLC method for the simultaneous estimation of Sildenafil Citrate and Dapoxetine Hydrochloride in pharmaceutical dosage forms. The study highlights the importance of these drugs in treating premature ejaculation and erectile dysfunction, detailing the methodology for sample preparation and chromatographic conditions. The results indicate that the method is effective for the analysis of these compounds, ensuring accuracy and reliability in pharmaceutical applications. 0% found this document useful (0 votes) This research article presents the development and validation of a rapid and sensitive RP-HPLC method for the simultaneous estimation of Sildenafil Citrate and Dapoxetine Hydrochloride in ph… DAPOXETINE IN SEXUAL DYSFUNCTIONS PRESENTOR DR.

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Desire Reflects person’s motivations, drives & Hypoactive sexual desire personality; characterized by sexual disorder; sexual aversion fantasies & desire to have sex disorder (male or female) 2. Subjective sense of sexual pleasure & Female sexual arousal Excitement accompanying physiological responses disorder (sexual flush, erection by vasocongestion, Male erectile disorder; tightening & lifting of scrotal sac, increase dyspareunia size of testes ) 3. Orgasm Peaking of sexual pleasure, release of Orgasmic disorder (male & sexual dapoxetine 5mg tension & rhythmic contraction of female); premature perineal muscles and pelvic reproductive ejaculation organs 4. A sense of general relaxation, wellbeing & Post coital dysphoria; post Resolution muscle relaxation coital headache PHYSIOLOGY OF EJACULATION Normal ante grade ejaculation:- 3 basic mechanism (Lipshultz 1981) (1) Emission:- Result of a sympathetic spinal cord reflex Initiated by genital/cerebral erotic stimuli Involves sequential contraction of accessory sexual organs (2) Ejection:- Involve bladder neck closure Rhythmic contraction of bulbocavernosus, bulbospongiosus and other pelvic floor muscles Relaxation of external urethral sphincter (Yeates 1987) (3) Orgasm:- Result of cerebral processing of pudendal nerve sensory stimuli resulting from increased pressure in posterior urethra, contraction of urethral bulb & accessory sexual Neurology of ejaculation Seminal emission & ejection are integrated by medial preoptic area(MPOA) and nucleus paragigantocellularis (nPGI) Descending serotonergic pathway from nPGI to lumbosacral motor nuclei tonically inhibit ejaculation (Yells 1992) Disinhibition of nPGI by MPOA facilitates ejaculation Lumbar spinothalamic neurons send projection to autonomic nuclei & motor neurons involved in emission and ejection, while they receive sensory projection from pelvis Neurobiology of ejaculation(Ahlenius 1981) Ejaculatory reflex is controlled by central serotonergic & dopaminegric neurons with secondary involvement of cholinergic, adrenergic, nitregic, oxytocinergic neurons Speed of ejaculation appears to be determined by 5HT2C & 5HT1A receptors Stimulation of postsynaptic 5HT2C receptor by its agonist delays ejaculation Stimulation of somatodendritic 5HT1A receptors decreases ejaculation latency The Male SexualResponse Sexual Ejaculation Interest/ Orgasm Accompanied by Stimulation Orgasm Penile Penile Penetration tumescence Detumesence Plateau Resolution High arousal/ Erection Excitement Time Premature Ejaculation (PE)[ICD-10 F52.4] WHO 2nd International consultation on sexual health:- “Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it, over which the sufferer has little or no voluntary control, which causes the sufferer and/or his partner bother or distress” (Leu et al 2004) International Society for Sexual Medicine(ISSM) :- “ Male sexual dysfunction characterized by ejaculation which always or nearly always occurs before or within approximately 1 minute of vaginal penetration; the inability to delay ejaculation on all or nearly all vaginal penetration; and negative personal consequences such as distress, bother, frustration and/or the avoidance of sexual intimacy” Recent normative data suggest that men with an :- Intravaginal Ejaculatory Latency Time (IELT) less than 1 min have “definite PE” IELT between 1 and 1.5 min have “probable PE” (Waldiner, Zwinderman 2005) DSM IV TRDiagnostic criteria for dapoxetine sex PE A. Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it.

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The clinician must take into account factors that affect duration of excitement phase, such as age, novelty of sexual partner or situation, and recent frequency of sexual activity.B. The disturbance causes marked distress or interpersonal difficulty. C. The premature ejaculation is not due to exclusively to the direct effect of the substance (e.g., withdrawal from opioids) PE sub classification:- (Schapiro1943) Lifelong(Primary) PE :- Commences with onset of sexual activity Acquired(secondary) PE :- Develops following a period of normal ejaculatory response. Most cases are due to performance anxiety Etiology:- Combination of Psychogenic and Organic factor is presumed, with role of endocrinopathy, Peyronie disease & Prostatitis PE is a psychosomatic disturbance & due to over Biological anxious personality Young Genes age Cultural Etiology of PrematureEjaculation Low 5HT Hyposensitivity of neurotransmission 5HT2C Ejaculatory threshold genetically "set" at a lower point Ejaculate quickly and with minimal stimulation Epidemiology:- PE isthe most prevalent male sexual dysfunction (4-39% of men in general community) Distribution of IELT values in a random cohort of 491 men demonstrated median IELT of 5.4 min. ANANT KUMAR RATHI 2nd YEAR RESIDENT GUIDE DR.

D. K. SHARMA PROF. & HEAD, DEPTT. NORMAL PHYSIOLOGY (GanongPhysiology) ERECTION EJACULATION AUTONOMIC PARASYMPATHETIC SYMPATHETIC NERVOUS SYSTEM SYSTEM SYSTEM AFFERENT PUDENDAL NERVE & PUDENDAL NERVE SACRAL PLEXUS RELAY SACRAL SEGMENTS LUMBAR SEGMENTS OF SPINAL CORD OF SPINAL CORD EFFERENT PELVIC SPLANCHNIC HYPOGASTRIC & NERVE (NERVI PELVIC SYMPATHETIC ERIGENTIS) PLEXUS NEUROTRANSMITOR NITRIC OXIDE (NO) CARBON MONOXIDE (CO) Phases of SexualResponse Cycle & Associated Sexual Dysfunctions PHASES CHARACTERSTICS DYSFUNCTION 1.

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0% found this document useful (0 votes) This research article presents the development and validation of a rapid and sensitive RP-HPLC method for the simultaneous estimation of Sildenafil Citrate and Dapoxetine Hydrochloride in ph… 0% found this document useful (0 votes) This research article presents the development and validation of a rapid and sensitive RP-HPLC method for the simultaneous estimation of Sildenafil Citrate and Dapoxetine Hydrochloride in pharmaceutical dosage forms. The study highlights the importance of these drugs in treating premature ejaculation and erectile dysfunction, detailing the methodology for sample preparation and chromatographic conditions. The results indicate that the method is effective for the analysis of these compounds, ensuring accuracy and reliability in pharmaceutical applications. 0% found this document useful (0 votes) This research article presents the development and validation of a rapid and sensitive RP-HPLC method for the simultaneous estimation of Sildenafil Citrate and Dapoxetine Hydrochloride in ph… DAPOXETINE IN SEXUAL DYSFUNCTIONS PRESENTOR DR. ANANT KUMAR RATHI 2nd YEAR RESIDENT GUIDE DR.

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D. K. SHARMA PROF. & HEAD, DEPTT. NORMAL PHYSIOLOGY (GanongPhysiology) ERECTION EJACULATION AUTONOMIC PARASYMPATHETIC SYMPATHETIC NERVOUS SYSTEM SYSTEM SYSTEM AFFERENT PUDENDAL NERVE & PUDENDAL NERVE SACRAL PLEXUS RELAY SACRAL SEGMENTS LUMBAR SEGMENTS OF SPINAL CORD OF SPINAL CORD EFFERENT PELVIC SPLANCHNIC HYPOGASTRIC & NERVE (NERVI PELVIC SYMPATHETIC ERIGENTIS) PLEXUS NEUROTRANSMITOR NITRIC OXIDE (NO) CARBON MONOXIDE (CO) Phases of SexualResponse Cycle & Associated Sexual Dysfunctions PHASES CHARACTERSTICS DYSFUNCTION 1. Desire Reflects person’s motivations, drives & Hypoactive sexual desire personality; characterized by sexual disorder; sexual aversion fantasies & desire to have sex disorder (male or female) 2.

• The development of dapoxetine was unique as it was designed specifically for PE.
• Most other SSRIs were developed for depression and found to have this side effect.
• Sildenafil was originally developed for angina pectoris (heart pain).
• Its effect on erectile function was discovered during clinical trials.
• This led to its repurposing and approval for erectile dysfunction.
• The accidental discovery of sildenafil's benefits revolutionized ED treatment.
• The targeted development of dapoxetine represented a new approach to PE.
• Combining two repurposed drugs is a common strategy in modern pharmacology.
• This approach can rapidly provide new treatment options for patients.
• It also carries risks that must be carefully managed by clinicians.
• The history of these drugs underscores the importance of clinical observation.

Subjective sense of sexual pleasure & Female sexual arousal Excitement accompanying physiological responses disorder (sexual flush, erection by vasocongestion, Male erectile disorder; tightening & lifting of scrotal sac, increase dyspareunia size of testes ) 3. Orgasm Peaking of sexual pleasure, release of Orgasmic disorder (male & sexual dapoxetine 5mg tension & rhythmic contraction of female); premature perineal muscles and pelvic reproductive ejaculation organs 4.

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(range 1-45 min) Median IELT decreased with age Median IELT varied between countries (Waldinger, Quinn 2005) In a study vardenafil with dapoxetine tablets of 1326 men with PE:- lifelong PE was present in 74.4% men acquired PE was found in 25.6% men (McMohan 2002) Men with PE appear younger than those without. (Fasolo, Mirone 2005) No association found with HTN, Cardiac disease, Peripheral or central neuropathy MANAGEMENT OF PE Detailed medical & sexual history should be taken Physical examination Appropriate investigation Identify obvious biological causes as genital & urinary tract infection Treatment encompasses:- Behavioral aspect Pharmacological aspect Psychological aspect TREATMENT OF PREMATURE EJACUALTION Incorporate into sexual practice Behavioural techniques - stop/start, squeeze Oral medication - SSRI, clomipramine, PDE5i Intra-cavernosal injections Anaesthetic cream Pelvic floor exercises Surgery to dorsal nerve (Brazil) Treatment PE cont’d Sensate focus: Tailor to clients, work on intimacy Sexual script change: Extend foreplay, modify rigid sex patterns, “partner first” Treatment aim: Restore IELT, address relationship issues, restore confidence Pharmacological management SSRIs has been used as off the label drugs for the treatment of PE for past 15 to 20 years utilizing its side effect delayed ejaculation as therapeutic effect Paroxetin, Fluoxetin, Sertraline, Cetalopram, Fluvoxamine and Clomipramine has revolutionized the approach to treat PE Yet daily dosing, long half life, accumulation of drug, gradual receptor desensitization and other side effects of long acting SSRIs were the drawbacks However lack of approved drug & total reliance on off Ejaculo-Selective Serotonin TransportInhibitor (ESSTIs) Drugs under investigation are Dapoxetine UK-390 UK-957 Tramadol Dapoxetine, an SSRI is first oral pharmacological agent indicated for treatment of men aged 18- 64 years with PE Has been approved in various European countries, South America & Asia Pacific It is novel potent SSRI structurally similar to Fluoxetin Pharmacokinetics Oral formulation Rapidly absorbed Absolute bioavailability 42% Tmax of 1.4-2 hrs Cmax of 1.01-1.27 hrs Initial half life 1.3-1.5 hrs Terminal half life 15-19 hrs Steady state plasma conc. reaches in 4 days Rapid, biphasic elimination Less than 4% peak conc. present in plasma after 24 hrs Dose dependant pharmacokinetics Metabolized by liver via glucuronidation, N- demethylation, N- oxidation & sulphation Enzymes CYT P 450 3A4, CYP2D6 are involved Metabolites excreted in urine Pharmacokinetics of singledose of dapoxetine and effect of food Dapoxetine 30 mg Dapoxetine 60 mg Cmax (ng/ml) 297 349 Tmax (h) 1.01 1.27 Initial T half 1.31 1.42 Terminal T half 18.7 21.0 Effect of high fat meal Cmax (fasted) - 443 Cmax (high fat meal) - 398 Tmax (h) (fasted) - 1.30 Tmax (h) (high fat meal) - 1.83 Mechanism of action Dapoxetine ↑ 5HT Activation of neurotransmission 5HT2C Elevates ejaculatory threshold "set" point Delays Ejaculation Indian J Urol 2007;23:97-108 Pharmacodynamic profile Inhibit neuronal reuptake of serotonin Potentiation of neurotransmitter’s action at pre & post synaptic receptors Modulate ejaculatory expulsion reflex by elevating latency & reducing amplitude of pudendal motor neuron reflex discharge (Giuliano et al 2006) Not associated with clinically significant ECG changes Blood pressure, heart rate not affected Moderate to severe (Child Pugh class B & C) Drug interactions Co-administration of moderate or potent CYP3A4 inhibitor as erythromycin, fluconazole, verapamil, ketoconazole resulted in elevation in dapoxetin Cmax & AUC Concomitant potent CYP2D6 inhibitors results in higher incidence & severity of adverse events Concurrent fluoxetin, desipramine therapy also increases Cmax & AUC by 50% & 88% No clinically significant alteration of pharmacokinetics of dapoxetin with co administration of sildenafil/tadalafil.

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A sense of general relaxation, wellbeing & Post coital dysphoria; post Resolution muscle relaxation coital headache PHYSIOLOGY OF EJACULATION Normal ante grade ejaculation:- 3 basic mechanism (Lipshultz 1981) (1) Emission:- Result of a sympathetic spinal cord reflex Initiated by genital/cerebral erotic stimuli Involves sequential contraction of accessory sexual organs (2) Ejection:- Involve bladder neck closure Rhythmic contraction of bulbocavernosus, bulbospongiosus and other pelvic floor muscles Relaxation of external urethral sphincter (Yeates 1987) (3) Orgasm:- Result of cerebral processing of pudendal nerve sensory stimuli resulting from increased pressure in posterior urethra, contraction of urethral bulb & accessory sexual Neurology of ejaculation Seminal emission & ejection are integrated by medial preoptic area(MPOA) and nucleus paragigantocellularis (nPGI) Descending serotonergic pathway from nPGI to lumbosacral motor nuclei tonically inhibit ejaculation (Yells 1992) Disinhibition of nPGI by MPOA facilitates ejaculation Lumbar spinothalamic neurons send projection to autonomic nuclei & motor neurons involved in emission and ejection, while they receive sensory projection from pelvis Neurobiology of ejaculation(Ahlenius 1981) Ejaculatory reflex is controlled by central serotonergic & dopaminegric neurons with secondary involvement of cholinergic, adrenergic, nitregic, oxytocinergic neurons Speed of ejaculation appears to be determined by 5HT2C & 5HT1A receptors Stimulation of postsynaptic 5HT2C receptor by its agonist delays ejaculation Stimulation of somatodendritic 5HT1A receptors decreases ejaculation latency The Male SexualResponse Sexual Ejaculation Interest/ Orgasm Accompanied by Stimulation Orgasm Penile Penile Penetration tumescence Detumesence Plateau Resolution High arousal/ Erection Excitement Time Premature Ejaculation (PE)[ICD-10 F52.4] WHO 2nd International consultation on sexual health:- “Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it, over which the sufferer has little or no voluntary control, which causes the sufferer and/or his partner bother or distress” (Leu et al 2004) International Society for Sexual Medicine(ISSM) :- “ Male sexual dysfunction characterized by ejaculation which always or nearly always occurs before or within approximately 1 minute of vaginal penetration; the inability to delay ejaculation on all or nearly all vaginal penetration; and negative personal consequences such as distress, bother, frustration and/or the avoidance of sexual intimacy” Recent normative data suggest that men with an :- Intravaginal Ejaculatory Latency Time (IELT) less than 1 min have “definite PE” IELT between 1 and 1.5 min have “probable PE” (Waldiner, Zwinderman 2005) DSM IV TRDiagnostic criteria for dapoxetine sex PE A.

Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it.

• Dapoxetin works quickly, with effects lasting around 1-3 hours.
• Sildenafil's effects typically last 4-6 hours.
• Both drugs require a prescription and medical consultation before use.

The clinician must take into account factors that affect duration of excitement phase, such as age, novelty of sexual partner or situation, and recent frequency of sexual activity.B. The disturbance causes marked distress or interpersonal difficulty. C. The premature ejaculation is not due to exclusively to the direct effect of the substance (e.g., withdrawal from opioids) PE sub classification:- (Schapiro1943) Lifelong(Primary) PE :- Commences with onset of sexual activity Acquired(secondary) PE :- Develops following a period of normal ejaculatory response. Most cases are due to performance anxiety Etiology:- Combination of Psychogenic and Organic factor is presumed, with role of endocrinopathy, Peyronie disease & Prostatitis PE is a psychosomatic disturbance & due to over Biological anxious personality Young Genes age Cultural Etiology of PrematureEjaculation Low 5HT Hyposensitivity of neurotransmission 5HT2C Ejaculatory threshold genetically "set" at a lower point Ejaculate quickly and with minimal stimulation Epidemiology:- PE isthe most prevalent male sexual dysfunction (4-39% of men in general community) Distribution of IELT values in a random cohort of 491 men demonstrated median IELT of 5.4 min. (range 1-45 min) Median IELT decreased with age Median IELT varied between countries (Waldinger, Quinn 2005) In a study vardenafil with dapoxetine tablets of 1326 men with PE:- lifelong PE was present in 74.4% men acquired PE was found in 25.6% men (McMohan 2002) Men with PE appear younger than those without.

• In summary, dapoxetine and sildenafil together treat PE and ED.
• This is an off-label use that carries significant interaction risks.
• Strict medical supervision is absolutely essential for safety.
• Dosing must be individualized starting from the lowest possible amounts.
• Contraindications include heart problems, nitrate use, and liver disease.
• Common side effects are headache, dizziness, flushing, and nausea.
• Patients must be aware of the signs of hypotension and priapism.
• A healthy lifestyle and open communication with a partner are important.
• Alternative treatments exist and should be discussed with a doctor.
• This combination can significantly improve quality of life when used correctly.
• Always consult a healthcare professional for personalized advice.

(Fasolo, Mirone 2005) No association found with HTN, Cardiac disease, Peripheral or central neuropathy MANAGEMENT OF PE Detailed medical & sexual history should be taken Physical examination Appropriate investigation Identify obvious biological causes as genital & urinary tract infection Treatment encompasses:- Behavioral aspect Pharmacological aspect Psychological aspect TREATMENT OF PREMATURE EJACUALTION Incorporate into sexual practice Behavioural techniques - stop/start, squeeze Oral medication - SSRI, clomipramine, PDE5i Intra-cavernosal injections Anaesthetic cream Pelvic floor exercises Surgery to dorsal nerve (Brazil) Treatment PE cont’d Sensate focus: Tailor to clients, work on intimacy Sexual script change: Extend foreplay, modify rigid sex patterns, “partner first” Treatment aim: Restore IELT, address relationship issues, restore confidence Pharmacological management SSRIs has been used as off the label drugs for the treatment of PE for past 15 to 20 years utilizing its side effect delayed ejaculation as therapeutic effect Paroxetin, Fluoxetin, Sertraline, Cetalopram, Fluvoxamine and Clomipramine has revolutionized the approach to treat PE Yet daily dosing, long half life, accumulation of drug, gradual receptor desensitization and other side effects of long acting SSRIs were the drawbacks However lack of approved drug & total reliance on off Ejaculo-Selective Serotonin TransportInhibitor (ESSTIs) Drugs under investigation are Dapoxetine UK-390 UK-957 Tramadol Dapoxetine, an SSRI is first oral pharmacological agent indicated for treatment of men aged 18- 64 years with PE Has been approved in various European countries, South America & Asia Pacific It is novel potent SSRI structurally similar to Fluoxetin Pharmacokinetics Oral formulation Rapidly absorbed Absolute bioavailability 42% Tmax of 1.4-2 hrs Cmax of 1.01-1.27 hrs Initial half life 1.3-1.5 hrs Terminal half life 15-19 hrs Steady state plasma conc.

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ATC (Anatomical Therapeutic Chemical Classification)

reaches in 4 days Rapid, biphasic elimination Less than 4% peak conc. present in plasma after 24 hrs Dose dependant pharmacokinetics Metabolized by liver via glucuronidation, N- demethylation, N- oxidation & sulphation Enzymes CYT P 450 3A4, CYP2D6 are involved Metabolites excreted in urine Pharmacokinetics of singledose of dapoxetine and effect of food Dapoxetine 30 mg Dapoxetine 60 mg Cmax (ng/ml) 297 349 Tmax (h) 1.01 1.27 Initial T half 1.31 1.42 Terminal T half 18.7 21.0 Effect of high fat meal Cmax (fasted) - 443 Cmax (high fat meal) - 398 Tmax (h) (fasted) - 1.30 Tmax (h) (high fat meal) - 1.83 Mechanism of action Dapoxetine ↑ 5HT Activation of neurotransmission 5HT2C Elevates ejaculatory threshold "set" point Delays Ejaculation Indian J Urol 2007;23:97-108 Pharmacodynamic profile Inhibit neuronal reuptake of serotonin Potentiation of neurotransmitter’s action at pre & post synaptic receptors Modulate ejaculatory expulsion reflex by elevating latency & reducing amplitude of pudendal motor neuron reflex discharge (Giuliano et al 2006) Not associated with clinically significant ECG changes Blood pressure, heart rate not affected Moderate to severe (Child Pugh class B & C) Drug interactions Co-administration of moderate or potent CYP3A4 inhibitor as erythromycin, fluconazole, verapamil, ketoconazole resulted in elevation in dapoxetin Cmax & AUC Concomitant potent CYP2D6 inhibitors results in higher incidence & severity of adverse events Concurrent fluoxetin, desipramine therapy also increases Cmax & AUC by 50% & 88% No clinically significant alteration of pharmacokinetics of dapoxetin with co administration of sildenafil/tadalafil.