Commercial products and compounded options for the treatment of erectile dysfunction. Brief overview regarding the pathophysiology, medical, and physical causes behind these disorders as well as epidemiology and prevalence of the disease.

1. ERECTILE DYSFUNCTION
Pharmaceutical Compounding Treatment Strategies
Anthony J. Campbell, PharmD,CAP
24th AnnualWorld Congress on Anti-Aging Medicine
LasVegas, NV
December 9, 2016

2. TALKING POINTS
 Discuss the Epidemiology and Prevalence of Erectile Dysfunction
 Brief overview regarding the pathophysiology, medical, and physical causes
behind Erectile Dysfunction
 Reveal risk factors and any associated medication contributing to the
development and/or progression of Erectile Dysfunction
 Present current treatment options with an emphasis on pharmaceutical
compounding treatment strategies for oral, injectable, and topical use

3. IT’S NOTYOU . . . IT’S ME
 Incidence by Race Not Significantly Different (40+)
 Whites – 22%
 Blacks – 24%
 Hispanics – 20%
 Increased Incidence
 Age
 Diabetes Mellitus
 Hypertension
 Moderate/Severe LUTS
 Decreased Incidence
 Exercise and college education – vs – less than HS
 Journal of Sexual Medicine 2007 Jan:4(1):57:65 Epub 2006 Nov 1

4. SERIOUSLY . . . IT’S ME
 National Health & Nutrition Examination Survey (NHANES)
 > 18 million men in U.S. over age of 20 (~18.4% of male population)
 Never able or sometimes able to get and keep erection for satisfactory intercourse
 90% with ED ≥ 1 CV RF; including DM (51%), HTN, ↑LDL/↓HDL, or smoker
 Significantly & independently associated with DM, lower education, & ↓ physical activity
 The American Journal of Medicine (2007) 120, 151-157
 Massachusetts Male Aging Study (MMAS)
 Overall rate of any degree of ED = 52% [40+ = 39%; 70+ = 67%]
 ↑ risk of ED associated with DM, HTN, CVD, PUD, Arthritis, Depression; ↔ smoker
 Increased incidence with treatment
 ↓ with education; ↓ with income
 Extrapolation of data reveals ~30 million (white) men in U.S. with some form of ED
 The Journal of Urology (2000) 163, 460-463

5. ERECTING AN ERECTION
 Complex event involving integration of:
 Psychologic
 Neurologic
 Endocrine/Hormonal
 Vascular & Local anatomic systems
 Release of NO from NANC nerves and endothelial cells
 Stimulates guanylate cyclase enzyme system in penile smooth muscle
 ↑ levels of cGMP & ↓ Ca2+
 Smooth muscle relaxation
 Enhancement of arterial inflow / veno-occlusion → adequate firmness
 Return to flaccid state: cGMP is hydrolyzed to GMP by phosphodiesterase type 5

6. THE USUAL SUSPECTS &TYPES OF ED
1. Psychogenic  Performance Anxiety, Depression  Loss of libido, Impaired NO release
2. Neurogenic  Stroke, SpinalCord Injury, DR  Lack of nerve impulse/transmission
3. Hormonal  Hypogonadism, Hyperprolactinoma  Inadequate NO release
4. Vasculogenic  Atherosclerosis, Hypertension  Impaired arterial or venous flow
5. Medication-Induced  Antihypertensives,Antidepressants, etc.  Central suppression,Vascular Insuff

7. DRUG INDUCED IMPOTENCE
 Antipsychotics, Antidepressants
 Disruption of serotonergic, noradrenergic, and dopamine neurotransmitter
pathways involved in sexual function
 Amitriptyline, Buspirone, Fluoxetine, Sertraline
 Antihypertensives
 β-adrenergic Blockers – Potentiation of α-1 adrenergic activity in the penis
 Atenolol, Metoprolol, Propranolol, etc.
 Thiazide Diuretics – Unknown, but thought to be due to increased uric acid levels
 Ca2+-channel blockers, ACE-I, A2RBs
 JACC Vol 62/18/Suppl C Oct 26-29, 2013
 Kubin, M, et.al. IJIR (2003) 15, 63-71

8. DRUG INDUCED IMPOTENCE
 Proton Pump Inhibitors
 Inhibits DDAH; leads to increase of ADMA (inhibitor of NO)  decreases NO synthase
 Induction of hepatic CYP-dependent testosterone metabolism in vitro
 Conversion to β-hydroxytestosterone
 Esomeprazole, Lansoprazole
 Rosenshein B et.al. Am J Med Sci 2004;327(5):289-93
 Coulson, M et.al. Toxicol App Pharm 2003;192(2):154-63
 Ghebremariam, Y et.al Circulation. 2013 Aug 20; 128(8)
 H2-receptor Antagonists
 ↓ libido; ↑ E ↑ prolactin (gynecomastia; galactorrhea)
 Erectile failure via an antiandrogenic effect
 Erection promoting action of histamine likely due to H2 receptor activation
 Cimetidine
 http://medlineplus.gov/ency/article/004024.htm
 Cará AM Br Jour Urol. 1995 Feb;75(2):220-4

9. COMMERCIALTREATMENT OPTIONS
 Phosphodiesterase type 5 (PDE5) Inhibitors in U.S.
 Sildenafil Citrate – 1998
 25/50/100mg – max dose: 100mg*
 $30-$45
 Vardenafil HCl – 2003;2010
 2.5/5/10/20mg – max dose: 20mg*
 ~$45
 Tadalafil – 2003; (qd use, 2008)
 2.5/5/10/20mg – max dose: 20mg*/5mg daily
 ~$60
 Avanafil – 2012
 50/100/200mg – max dose: 200mg*
 ~$70 *Assuming no CYP3A4 inhibitors

10. IN CLINICAL DEVELOPMENT
Compound Company Development Stage Mechanism of Action
RX 10100; (Zoraxel®)
Clavulanic Acid
Rexahn Pharmaceuticals Phase IIa Enhancement of Dopamine Release in CNS
PT-141; Bremelanotide Palatin Technologies Phase IIb Melanocortin-receptor agonist
Udenafil (Zydena®) Dong-A Pharmaceuticals
Warner Chilcott (US)
Phase III (US)
Launched (S. Korea)
PDE5-I t ½ : 12hr Tmax: 1 - 1.3hr
SK3530; Mirodenafil (Mvix®) SK chemical Launched (S. Korea) PDE5-I t ½ : 2.4hr Tmax: 1.5hr
Lodenafil Carbonate Cristalia/Quimicos Phase III PDE5-I t ½ : 2.3hr Tmax: 1.2hr
SLX-2101 Surface Logix Phase IIa PDE5-I t ½ : 9-14hr Tmax: 1hr
Icariin n/a Herbal Preparation PDE4-I, PDE5-I
HA-1077; Fasudil Asahi Kasei Pharma Launched for other ROCK Inhibition (rho-kinase inhibition)
SAR-407889 Sanofi-Aventis Phase IIa ROCK Inhibition
BMS-223131 Bristol-Myers Squibb Phase IIa Maxi-K channel opener
Adapted from: Expert Opin Emerg Drugs. 2010 September;15(3): 467-480

11. COMMERCIALTREATMENT OPTIONS
 Prostaglandin E1
 Alprostadil
 Physicians who prescribe intracavernous injection therapy should:
 (1) inform patients of the potential occurrence of prolonged erections
 (2) have a plan for the urgent treatment of prolonged erections and
 (3) inform the patient of the plan.
 (See AUA guideline on priapism: http://www.auanet.org/guidelines/priapism.cfm)
 Alternative Options
 Papaverine, Pumps, Prosthesis/Implants
 Arginine, Yohimbine, Maca, Ginko biloba, Panax Ginseng
 Trazodone, Apomorphine, VIP, Testosterone, DHEA

12. COMPOUNDED MEDICATIONS
 Sildenafil Compounds (C22H30N6O4S · C6H8O7; MW – 666)
 Combined with Oxytocin (and/or Paroxetine for PE)
 Oxytocin Benefits (125u – 250u)
 Paroxetine Benefits (5mg)
 Tablets, Gelatin-based Troches
 Extremely bitter; not water soluble
 Vardenafil Compounds (C23H33CIN6O4S; MW – 488)
 Combined with Oxytocin and/or Paroxetine
 Sublingual Tablets, PEG-based mini-troches, or ODT
 Very water soluble; reduced bitterness

13. COMPOUNDED MEDICATIONS
 Tadalafil Compounds (C22H19N3O4; MW – 389)
 Oxytocin, Paroxetine, Arginine, Testosterone
 Sublingual dissolving tablets; mini-troches, gelatin troches, capsules, chewable
tablets
 Increasing bitterness with strength
 Very slightly water soluble (1mg/mL suspension)
 Intracavernosal Injection compounds
 Papaverine, Alprostadil
 Bimix (Papaverine/Phentolamine)
 Trimix (Papaverine/Phentolamine/Alprostadil)
 Quad (Papaverine/Phentolamine/Alprostadil/Atropine; +/- Forskolin)

14. COMPOUNDED MEDICATIONS
 Intracavernosal Injection Compounds
 Alprostadil
 10mcg – 40mcg/mL
 $50 - $90
 Bimix
 30mg/1mg to 30mg/4mg
 $45 - $75
 Trimix
 30-1-10 / 30-2-20 / 30-2-40 / 30-4-40
 $45 - $90
 Quad
 +Atropine: 10mcg to 200mcg/mL
 +Forskolin: 20mcg to 100mcg/mL
 Product Stability
 Papaverine & Phentolamine
 Room Temp: 100% @ 1 month
 Refrigerated: 100% @ 1 month
 Frozen: 100% @ 1 month / 95% @ 6 months
 Alprostadil
 Room Temp: 91% @ 5 days / 87% @ 7 days
 Refrigerated: 98% @ 5 days / 88% @ 2 months
 Frozen: 99% @ 1 month / 97% @ 6 months
 Retains Stability w/Freeze-Thaw Cycling
 Int J of Pharm Cmpd Vol 8;3 May/June 2004 231-235

15. COMPOUNDED MEDICATIONS
 Lyophilized Trimix
 Ideal for travel use
 No refrigeration required before reconstitution
 Single-use or Multi-dose vials
 Oxytocin Nasal Spray
 60-120iu; 15-30 minutes prior to sexual intercourse
 Study results suggest that oxytocin induces penile erection by activating NO synthase in the
paraventricular nucleus of the hypothalamus
Argiolas A, Melis M Adv Exp Med Biol 1995;395:247-254
 Alprostadil 1% Topical Gel
 0.25mL (2.5mg) applied to glans
 39% efficacy (P=0.005) Goldstein, I et.al. UROLOGY 57:301-305, 2001

16. SUMMARY
 ED is becoming increasingly prevalent and
reported cases are expected to rise (+600k/year)
 Highly related to other disease states and may
be preventable via non-pharmacologic
interventions and lifestyle changes
 Drug Utilization Review should be considered
when diagnosing/treating ED as many drugs can
contribute to ED
 Commercial options are currently limited, but
quickly growing
 Partnering with a compounding lab can provide
several alternatives and has ability to customize
therapy while improving and/or maximizing
patient outcomes

17. QUESTIONS

18. REFERENCES
• Selvin, Elizabeth, Arthur L. Burnett, and Elizabeth A. Platz. "Prevalence and Risk Factors for Erectile Dysfunction in the US." The American Journal of Medicine 120 (2007): 151-57.
• Laumann EO, West S, Glasser D, et.al “Prevalence and correlates of erectile dysfunction by race and ethnicity among men aged 40 or older in the United States: from the male attitudes regarding sexual health survey”
Journal of Sexual Medicine 2007 Jan;4(1):57-65. Epub 2006 Nov 1
• Johannes C, Araujo A, Feldman H, et.al. “Incidence of Erectile Dysfunction in Men 40 to 69 years old: Longitudinal Results from the Massachusetts Male Aging Study” The Journal of Urology 2000 Feb Vol. 163 460-463
• Ponholzer A, Temml C, Mock K. et.al Prevalence and Risk Factors for Erectile Dysfunction in 2869 Men Using a Validated Questionnaire” European Urology 47 (2005) 80-86
• Kubin M, Wagner G, Fugl-Meyer AR “Epidemiology of Erectile Dysfunction” International Journal of Impotence Research (2003) 15, 63-71
• Aribas, Alpay, Mehmet Kayrak, and Seref Ulucan. "The Relationship among Thiazide like Diuretic, Uric Acid, and Erectile Dysfunction in Hypertensive Subjects." OP-037 N.p., 26 Oct. 2013. Web. 4 Nov. 2016.
<http://content.onlinejacc.org/>.
• "Drugs That May Cause Impotence." MedlinePlus - Health Information from the National Library of Medicine. N.p., n.d. Web. 04 Nov. 2016. <https://medlineplus.gov//ency/article/004024.htm>.
• Ghebremariam, Y et.al. “An Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor ADMA” Circulation. 2013 August 20; 128(8)
• Rosenshein B, Flockhart DA, Ho H. “Induction of testosterone metabolism by esomeprazole in a CYP2C19*2 heterozygote” American Journal of Medical Science 2004;327(5):289-93
• Coulson M, Gibson GG, Plant N, et.al “Lansoprazole increases testosterone metabolism and clearance in male Sprague-Dawley rats: implicaitons for Leydig cell carcinogenesis” Toxicological Applications in Pharmacology
2003;192(2):154:63
• Cará AM, Lopes-Martin RA, Antunes E et.al “The role of histamine in human penile erection” British Journal of Urology 1995 Feb;75(2):220-4
• Khan MA, Thompson CS, Sullivan ME, et.al. “The role of prostaglandins in the aetiology and treatment of erectile dysfunction” Prostaglandins, Leukotrienes and Essential Fatty Acids (1999) 60(3), 169-174
• Minhas S, Cartledge J, Eardley I “The role of prostaglandins in penile erection” Prostaglandins, Leukotrienes and Essential Fatty Acids (2000) 62(3), 137-146
• Wright PJ “Comparison of phosphodiesterase type 5(PDE5) inhibitors” International Journal of Clinical Practice August 2006, 60, 8, 967-975
• “Erectile Dysfunction: The Management of Erectile Dysfunction, An Update” American Urological Association AUA guideline on erectile dysfunction Copyright @2005
• Kaufmann, Melissa, Ranjith Ramasamy, and Paul Turek. "Erectile Dysfunction." American Urological Association. American Urological Association, 2016. Web. 4 Nov. 2016. <http://www.auanet.org/>.
• Albersen M, Shindel A, Mwamukonda K, Lue T. “The Future is Today: Emerging Drugs for the Treatment of Erectile Dysfunction” Expert Opinion on Emerging Drugs 2010 September;15(3):467-480
• Goldstein, Irwin, Terry Payton, and Paul Schechter. "A Double-blind, Placebo-controlled, Efficacy and Safety Study of Topical Gel Formulation of 1% Alprostadil (topiglan) for the In-office Treatment of Erectile
Dysfunction." Urology 57.2 (2001): 301-05. Web. 9 Nov. 2016.
• Trissell, Lawrence A., and Yanping Zhang. "Long-Term Stability of Trimix: A Three-Drug Injection Used to Treat Erectile Dysfunction." International Journal of Pharmaceutical Compounding May/June 8.3 (2004): 231-35. Print.

19.  What is the reasoning behind having the tadalafil/oxytocin as a rapid dissolve tablet, and the sildenafil/oxytocin as a chewable tablet?
 Every drug has a specified solubility profile. Tadalafil has a solubility profile greater than that of Sildenafil. Additionally, the required strength for biological activity has much to do with it’s ability to
with it’s ability to function as a sublingual dosage form. Finally, palatability must be considered for patient use and/or compliance. Sildenafil is an extremely bitter drug as compared to Tadalafil.