Phosphodiesterase inhibition in the treatment of autoimmune and inflammatory diseases: current status and potential

Figures & data

Table 1 Phosphodiesterase superfamily

PDE family	Substrate	Tissue distribution	Inhibitors	Clinical applications
PDEi	cGMP.cAMP	Brain, heart, smooth muscle, lung	vinpocetine, nicardipine, nimodipine	Memory loss, dementia
PDE2	cGMP=cAMP	Adrenal gland, lung, heart, platelets, brain, liver, corpus cavernosum	EHNA	ARDS, sepsis, memory loss
PDE3	cAMP>cGMP	Heart, liver, lung, platelets, vascular smooth muscle, corpus cavernosum	Cilostamide, cilostazol, milrinone, enoxamone	CHF, pulmonary HTN, thrombosis, glomerulonephritis
PDE4	cAMP	Lung, mast cells, liver, kidney, brain	Rolipram cilomilast roflumilast	Glomerulonephritis, asthma, COPD, bipolar disease
PDE5	cGMP	Corpus cavernosum, lung, vascular smooth muscle, platelets, brain, esophagus	Sildenafil, tadalafil, vardenafil, zaprinast, dipyridamole	Erectile dysfunction, BPH, pulmonary HTN, chronic renal failure
PDE6	cGMP>cAMP	Retina	Sildenafil, tadalafil, vardenafil, dipyridamole, zaprinast	No clinical applications
PDE7	cAMP>cGMP	Skeletal muscle, T-cells, heart, kidney, brain, pancreas	Dipyridamole	Immunologic disorders, lung disease
PDE8	cAMP	Testes, thyroid, eye, liver, kidney, heart, skeletal muscle, pancreas, T-cells	Dipyridamole	Immunologic disorders
PDE9	cGMP	Brain, kidney, liver, lung	Zaprinast	Possible hypoglycemic effects
PDE10	cGMP>cAMP	Brain, testes	Dipyridamole, papaverine	Schizophrenia and psychiatric disorders
PDE11	cAMP=cGMP	Prostate, skeletal muscle, kidney, liver, testes, pituitary, salivary glands	Tadalafil, zaprinast, dipyridamole	Possible improvement in testicular function

Notes: Adapted by permission from Macmillan Publishers Ltd: INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH, Bischoff E, Potency, selectivity, and consequences of nonselectivity of PDE inhibition, Int J Impot Res. 2004;16(Suppl 1):S11–S14, Copyright © 2004;⁶⁹ International Journal of PharmTech Research, Ghosh R, Sawant O, Ganpathy P, Pitre S, Kadam VJ, Phosphodiesterase inhibitors: their role and implications, Int J Pharm Tech Res, 2009;1(4):1148–1160;³ and Boswell–Smith V, Spina D, Page CP, Phosphodiesterase inhibitors, British Journal of Pharmacology, 2006;147(Suppl 1):S252–S257, published by John Wiley and Sons, Copyright © 2006 British Pharmacological Society.⁴

Abbreviations: ARDS, acute respiratory distress syndrome; BPH, benign prostatic hyperplasia; cAMP, adenosine-3′,5′-cyclic monophosphate; cGMP, guanosine-3′,5′-cyclic monophosphate; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine; HTN, hypertension; PDE, phosphodiesterase.

Figure 1 Structures of phosphodiesterase type 5 inhibitors.

Note: Data from www.chemspider.com.⁷⁰

Table 2 Summary of trials with selective phosphodiesterase inhibitors for inflammatory disorders

Disease	PDEI	Drug	Reference	Patients (n)	Design	Result
Asthma	PDE4i	Cilomilast	Nieman et al^Citation17	27	Randomized, DB, PC, 1 week	34% reduction in exercise-induced asthma
		Cilomilast	Compton et al^Citation18	303	Randomized, DB, PC, 6 weeks	NS increase in FEV׀
		Cilomilast	Compton et al^Citation19	211	Randomized, DB, PC, 12 months	NS increase in FEV׀
		Roflumilast	Timmer et al^Citation22	16	Randomized, DB, PC, 28 days	41% reduction in FEV׀ (P=0.021)
		Roflumilast, beclomethasone	Bousquet et al^Citation23	499	Randomized, DB, 12 weeks	Similar improvements in lung function (Ρ≤0.001)
		Roflumilast	van Schalkwyk et al^Citation24	23	Randomized, DB, PC, 7–10 days	Reduced early and late reactions to allergen
		Roflumilast	Bateman et al^Citation25	693	Randomized, DB, PC, 12 weeks	Increase in lung function (P<0.001)
		Roflumilast	Gauvreau et al^Citation10	25	Randomized, DB, PC, 14 days (P=0.02)	Inhibited the maximum fall in FEV׀ after allergen challenge
	PDE3i	MSK492	Bardin et al^Citation26	18	Randomized, DB, PC	Decrease in early and late response to allergen
		Olprinone Salbutamol	Myou et al^Citation27	9	Randomized, DB, PC	Increase in FEV׀ with active treatments vs placebo
		Cilostazol	Ishiura et al^Citation28	11	Randomized, DB, PC	Cough threshold increased (P<0.05)
	PDE3/4i	RPL554	Franciosi et al^Citation30	18 12 21	Open-label, PC Single-blind, PC, 6 days Randomized, PC	14% increase in FEV׀ (P<0.0001) Increases in FEV׀ (P<0.001) Anti-inflammatory properties are seen
COPD	PDE4i	Roflumilast	Rabe et al^Citation33	1,411	Randomized, DB, PC, 24 weeks	Improved FEV׀ (P<0.0001)
		Roflumilast	Calverley et al^Citation34	1,513	Randomized, DB, PC, 1 year	Improved FEV׀ (P=0.001)
		Roflumilast	Calverley et al^Citation35	3,091	Randomized, DB, PC, 52 weeks (two studies)	Improved FEV׀ (P<0.001)
		Roflumilast, salmeterol	Fabbri et al^Citation36	933	Randomized, DB, PC, 24 weeks	Improved FEV׀ (P<0.001)
		Roflumilast, tiotropium	Fabbri et al^Citation36	743	Randomized, DB, PC, 24 weeks	Improved FEV׀ (P<0.001)
	PDE3/4i	RPL554	Franciosi et al^Citation30	12	Open-label, PC	Improved FEV׀
BPH	PDE5i	Tadalafil	McVary et al^Citation40	281	Randomized, DB, PC, 12 weeks	Improved IPSS (P=0.003)
		Tadalafil	Roehrborn et al^Citation41	1,058	Randomized, DB, PC, 12 weeks	Improved IPSS
		Tadalafil	Dmochowski et al^Citation42	200	Randomized, DB, PC, 12 weeks	Improved IPSS (P<0.001)
		Tadalafil	Porst et al^Citation43	325	Randomized, DB, PC, 12 weeks	Improved IPSS (P=0.004)
		Sildenafil	McVary et al^Citation44	369	Randomized, DB, PC, 12 weeks	Improved IPSS (P<0.0001)
		Vardenafil	Stief et al^Citation45	222	Randomized, DB, PC, 8 weeks	Improved IPSS (P=0.0013)
		Vardenafil	Helmy et al^Citation46	80	Randomized, DB, PC, 12 weeks	Improved IPSS (P=0.0014)
IBD	PDE4i	Tetomilast	Schreiber et al^Citation48	168	Randomized, DB, PC, 8 weeks	Improved DAI (P=0.041)
	Tetomilast ±5-ASA	Salari-Sharif and Abdollahi^Citation47	750	Randomized, DB, PC, 8 weeks Outcomes DB, PC	Improved DAI (not statistically significant)

Abbreviations: BPH, benign prostatic hyperplasia; COPD, chronic obstructive pulmonary disease; DAI, Disease Activity Index; DB, double-blind; FEV₁, forced expiratory volume in 1 second; IBD, inflammatory bowel disease; IPSS, International Prostate Symptom Score (measure of lower urinary tract symptoms); MA, meta-analysis; NS, not significant; PC, placebo-controlled; PDE, phosphodiesterase; PDEI, phosphodiesterase inhibitor; QOL, quality of life; 5-ASA, 5-aminosalicylic acid.

Table 3 Summary of trials with selective phosphodiesterase inhibitors for autoimmune disorders

Disease	PDEI	Drug	Reference	Patients (n)	Design	Result
Systemic sclerosis
Raynaud’s phenomenon	PDE51	Tadalafil, vardenafil, sildenafil (MA)	Roustit et al^Citation54	244	Randomized, DB, PC	Decreased symptoms, frequency, duration of attacks
Pulmonary arterial hypertension	PDE51	Sildenafil (MA)	Wang et al^Citation55	545	Randomized, DB, PC	Improved outcomes
		Tadalafil (MA)	Galie et al^Citation56	405	Randomized, DB, PC, 16 weeks	Improved exercise capacity and QOL (40 mg)
		Tadalafil	Oudiz et al^Citation57	357	Randomized, DB, PC, 1 year	Improved exercise capacity and QOL (40 mg)
		Vardenafil	Jing et al^Citation58	66	Randomized, DB, PC, 12 weeks Open-label, 12 weeks	Improved exercise capacity (Ρ<0.001) and hemodynamics
Psoriasis	PDE4i	Apremilast	Gottlieb et al^Citation62	19	Open-label, 29 days	Reduced epidermal thickness, T-cells, and improved PASI
		Apremilast	Gottlieb et al^Citation63	30	Open-label, 12 weeks	Improved epidermal thickness (P=0.083) and PASI
		Apremilast	Papp et al^Citation64	89	Randomized, DB, PC, 16 weeks Open-label, additional 8 weeks	Improved PASI for 20 mg and 30 mg (P<0.0001 for both)
		Apremilast	Papp et al^Citation65	259	Randomized, DB, PC, 12 weeks	Improved PASI and mean body surface involvement with 20 mg bid (P<0.001)
		Apremilast	Strand et al^Citation66	352	Randomized, DB, PC, 16 weeks	Improved QOL (P≤0.005) and pruritus scores (P≤0.005) with 20 mg and 30 mg
		Apremilast	Chaplin^Citation61	1,250 (two trials)	Randomized, DB, PC, 16 weeks	Improved PASI
Psoriatic arthritis	PDE4i	Apremilast	Schett et al^Citation68	204	Randomized, DB, PC, 12 weeks	Improved ARC20 with 20 mg bid (P<0.001) and 40 mg qd (P=0.002)
		Apremilast	Poole and Ballantyne^Citation67	1,493 (four trials)	Randomized, DB, PC, 16 weeks	Improved ACR 20, symptoms, and PASi scores

Abbreviations: ACR20, American College of Rheumatology criteria for 20% improvement; bid, twice daily; DB, double-blind; MA, meta-analysis; qd, once daily; PASI, Psoriasis Area and Severity Index; PC, placebo-controlled; PDE, phosphodiesterase; PDEI, phosphodiesterase inhibitor; QOL, quality of life.

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