Effect of Tadalafil on Seizure Threshold and Activity of Antiepileptic Drugs in Three Acute Seizure Tests in Mice

Katarzyna Socała,Elżbieta Wyska,Piotr Wlaź,Mateusz Pieróg,Dorota Nieoczym,Małgorzata Szafarz,Urszula Doboszewska

doi:10.1007/s12640-018-9876-4

Katarzyna Socała, Elżbieta Wyska + Show 5 more

Open Access

https://doi.org/10.1007/s12640-018-9876-4

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Abstract

Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first- and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20 mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with epilepsy.

Highlights

Erectile dysfunction, which is defined as a persistent or recurrent inability to obtain or maintain penile erection during sexual intercourse, is a highly prevalent disorder that is expected to reach 322 million cases by the year 2025 (McKinlay 2000)
Since there is no data on the interactions between tadalafil and antiepileptic drugs, we investigated the influence of tadalafil on the activity of several first- and second-generation antiepileptic drugs
Data are presented as a percentage of animals showing motor coordination impairment in the chimney test and as means ± SEM grip strengths in millinewtons per gram of mouse body weight from the gripstrength test, assessing skeletal muscular strength in mice

Summary

Introduction

Erectile dysfunction, which is defined as a persistent or recurrent inability to obtain or maintain penile erection during sexual intercourse, is a highly prevalent disorder that is expected to reach 322 million cases by the year 2025 (McKinlay 2000). It is closely associated with aging, lifestyle, and comorbid diseases such as cardiovascular disease, hypertension, diabetes mellitus, depression, or neurological disorders including. The three widely available drugs from this class are sildenafil citrate (Viagra®, Pfizer, USA), vardenafil (Levitra®; Bayer AG, Germany), and tadalafil (Cialis®; Eli Lilly and Company, USA) They share a similar mode of action. PDE5 inhibitors increase the intracellular level of cGMP by inhibiting its breakdown, which improves smooth muscle relaxation and prolongs penile erection (Coward and Carson 2008; Huang and Lie 2013)

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