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. Fall 2007;9(4):197-206.

Extending the Rationale of Combination Therapy to Unresponsive Erectile Dysfunction

Free PMC article

Extending the Rationale of Combination Therapy to Unresponsive Erectile Dysfunction

Christopher Reece et al. Rev Urol. .
Free PMC article


Combination therapies aim to overcome the limitations of individual drugs by selecting diverse targets of action to enhance effectiveness synergistically. This article reviews the principles of combination therapy and its applications for benign prostatic hyperplasia and overactive bladder. It then examines pathophysiological, pharmacological, and clinical evidence for currently available drug and device combinations for erectile dysfunction that has not responded to first-line, single-agent therapy.

Keywords: Benign prostatic hyperplasia; Combination therapy; Erectile dysfunction; Intracavernosal therapy; Intraurethral therapy; Overactive bladder.


Figure 1
Figure 1
Intracellular mechanisms of various neurotransmitters, vasoactive factors, and sites of action of pharmacotherapy for erectile dysfunction. Nitric oxide (NO), synthesized via nonadrenergic, noncholinergic (NANC) nerves and endothelial cells, diffuses into the smooth-muscle cell, a process that activates guanylate cyclase and increases intracellular cyclic guanosine monophosphate (cGMP) synthesis. Sildenafil inhibits phosphodiesterase type 5 and blocks this breakdown. Prostaglandin (PGE1) and vasoactive intestinal peptide (VIP) bind to specific Gs-protein-coupled receptors, which activate adenylate cyclase and increase intracellular cyclic adenosine monophosphate (cAMP) synthesis. Forskolin directly activates adenylate cyclase. Increased cAMP and cGMP levels eventually lead to smooth-muscle relaxation. Both cAMP and cGMP are hydrolyzed to adenosine monophosphate (AMP) and guanosine monophosphate (GMP), respectively, by phosphodiesterases, terminating their effects. Papaverine non-selectively blocks both cAMP and cGMP phosphodiesterases. Alpha1-adrenergic receptors normally signal through Gq/11 heterotrimeric proteins, an outcome that activates protein kinase C-γ (PLC), liberates inositol triphosphates (IP3), and results in elevation of intracellular calcium (CA2+) and smooth-muscle contraction. Phentolamine blocks this process. ACh, acetylcholine; ATP, adenosine triphosphate; GTP, guanosine triphosphate. Reprinted from Nehra A et al with permission from Mayo Clinic Proceedings.

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