Abstract
Yonkenafil hydrochloride, a novel synthetic phosphodiesterase type 5 inhibitor, is a promising drug for the treatment of erectile dysfunction. The repeated-dose toxicity of yonkenafil hydrochloride was assessed in male and female beagle dogs. Twenty-four dogs were randomly allocated to four groups and administered yonkenafil hydrochloride orally at dosages of 0, 7, 30 or 120 mg/kg/day for 90 days followed by a 28-day recovery period. During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, electrocardiography, hematology, serum biochemistry, urinalysis, organ weights, gross findings and histopathology were examined. There were no abnormal changes in the clinical observations except that gastrointestinal intolerance was observed in the 120 mg/kg/day group. The laboratory and histopathological examinations revealed yonkenafil hydrochloride toxicity to various organs, including the thyroid gland, liver, prostate, uterus and breast; at the end of the recovery period, this damage was resolved. The level of yonkenafil hydrochloride that resulted in no observable adverse effects in beagle dogs was 7 mg/kg/day.
Highlights
According to the definition of the National Institutes of Health Consensus Development Conference on Impotence, erectile dysfunction (ED), which will affect the lives of approximately 300 million men worldwide by the year 2025, is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance [1,2]
All beagle dogs survived until the scheduled necropsy
Increases in eye discharge were observed in the 120 mg/kg/day group during the treatment period; these symptoms resolved by the end of recovery
Summary
According to the definition of the National Institutes of Health Consensus Development Conference on Impotence, erectile dysfunction (ED), which will affect the lives of approximately 300 million men worldwide by the year 2025, is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance [1,2]. According to the suggestion of the American Urological Association (AUA) guideline on ED, the first-line treatment of ED should be phosphodiesterase type 5 (PDE5) inhibitors, which include sildenafil, tadalafil and vardenafil [3]. Treatment of ED with PDE5 inhibitors is generally well tolerated, some side effects, such as headache, flushing, dyspepsia, nasal congestion and unusual visual disturbances, have been reported [4,5]. Inhibition of PDE5 in human corpus cavernosum increases intracellular cGMP levels in trabecular smooth muscle cells to achieve relaxation and increased blood flow to the penis [6,7,8,9]. Recent studies have shown that PDE5 inhibitors have remarkable therapeutic effects on many other diseases, such as benign prostatic hyperplasia, pulmonary hypertension, and Alzheimer’s disease [10,11,12]
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