sildenafil-citrate and Hearing-Loss

Blast-induced tinnitus, along with associated auditory impairment and traumatic brain injury, is a primary concern facing military service members. To search for treatment, we investigated the therapeutic effects of sildenafil, a phosphodiesterase-5 inhibitor, given its vasodilatory effects and evidence suggesting its beneficial effects on noise-induced hearing loss. Rats were subjected to three consecutive blast exposures at 22 psi and were monitored for tinnitus using a gap-detection acoustic startle reflex paradigm. Hearing thresholds and detection were tested using auditory brainstem responses and prepulse inhibition, respectively. Blasted rats were either treated with sildenafil or tap water following blast exposure, while age-matched sham control rats were treated with sildenafil and no blast exposure. Our results showed that sildenafil did not effectively prevent acute tinnitus onset and hearing impairment. Instead, sildenafil significantly suppressed high-frequency tinnitus from 3 to 6 weeks after blast exposure and reduced hearing impairment during the first week after blast exposure. Complex results were observed in the startle force data, where sildenafil-treated rats displayed significantly reduced startle force compared to the untreated blasted group, suggesting possible mitigation of traumatic brain injury and suppression of hyperacusis-like percepts. Taken together, sildenafil showed a therapeutic effect on blast-induced tinnitus and audiological impairment in a time-dependent manner. Other regimens such as higher dosage prior to blast exposure and combination with other treatments deserve further investigation to optimize the therapeutic effects.

Topics: Acoustic Stimulation; Animals; Auditory Threshold; Blast Injuries; Evoked Potentials, Auditory, Brain Stem; Functional Laterality; Hearing Loss; Male; Motor Activity; Neuroprotective Agents; Phosphodiesterase 5 Inhibitors; Piperazines; Prepulse Inhibition; Purines; Rats, Sprague-Dawley; Reflex, Startle; Sildenafil Citrate; Sulfones; Time Factors; Tinnitus

Drug-induced ototoxicity, particularly those involving phosphodiesterase type 5 (PDE-5) inhibitors, is considered to be rare and to our knowledge such an adverse effect has not been reported in Canada. Here we present a case of a 77-year old man initiated on a sildenfil regimen for the treatment of pulmonary hypertension, who developed sudden bilateral hearing loss after taking sildenafil, in the setting of high dose furosemide and diltiazem. We outline the likely interplay of patient characteristics, drug synergy and drug-drug interactions in the development of his ototoxicity. Importantly, given the extent and popularity of PDE-5 inhibitors for erectile dysfunction as well as a newer therapeutic option for pulmonary hypertension, clinicians should be aware of the risk for drug-induced ototoxicity, particularly in the setting of concomitant loop diuretics and CYP3A4 inhibiting medications.

Topics: Aged; Canada; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Diltiazem; Diuretics; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Enzyme Inhibitors; Furosemide; Hearing Loss; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Sildenafil citrate (Viagra), a phosphodiesterase 5 inhibitor (PDE5i), is a commonly prescribed drug for erectile dysfunction. Since the introduction of Viagra in 1997, several case reports have linked Viagra to sudden sensorineural hearing loss. However, these studies are not well controlled for confounding factors, such as age and noise-induced hearing loss and none of these reports are based on prospective double-blind studies. Further, animal studies report contradictory data. For example, one study (2008) reported hearing loss in rats after long-term and high-dose exposure to sildenafil citrate. The other study (2012) showed vardenafil, another formulation of PDE5i, to be protective against noise-induced hearing loss in mice and rats. Whether or not clinically relevant doses of sildenafil citrate cause hearing loss in normal subjects (animals or humans) is controversial. One possibility is that PDE5i exacerbates age-related susceptibility to hearing loss in adults. Therefore, we tested sildenafil citrate in C57BL/6J, a strain of mice that displays increased susceptibility to age-related hearing loss, and compared the results to those obtained from the FVB/N, a strain of mice with no predisposition to hearing loss. Six-week-old mice were injected with the maximum tolerated dose of sildenafil citrate (10 mg/kg/day) or saline for 30 days. Auditory brainstem responses (ABRs) were recorded pre- and post injection time points to assess hearing loss. Entry of sildenafil citrate in the mouse cochlea was confirmed by qRT-PCR analysis of a downstream target of the cGMP-PKG cascade. ABR data indicated no statistically significant difference in hearing between treated and untreated mice in both backgrounds. Results show that the maximum tolerated dose of sildenafil citrate administered daily for 4 weeks does not affect hearing in the mouse. Our study gives no indication that Viagra will negatively impact hearing and it emphasizes the need to revisit the issue of Viagra related ototoxicity in humans.

Topics: Aging; Animals; Cochlea; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Erectile Dysfunction; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Humans; Male; Mice; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones

Topics: Carbolines; Hearing Loss; Humans; Imidazoles; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Time Factors; Triazines; Vardenafil Dihydrochloride; Vision Disorders