Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants. MATERIALS AND METHODS: The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001. RESULTS: After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs. CONCLUSIONS: PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

Tadalafil Improves Haemodynamics and Arterial Stiffness but Not Flow- Mediated Dilation in Grade 1 Obesity. A Single-dose, Placebo-controlled Clinical Trial.

OBJECTIVE: Obesity, a major health issue worldwide, is associated with increased cardiovascular risk, endothelial dysfunction, and arterial stiffness. Tadalafil has been demonstrated to improve vascular parameters. AIM: To evaluate the effect of a single 20 mg dose of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. METHODS: A randomized, double-blind, placebo-controlled study was conducted on 80 participants (41 assigned to placebo and 39 to tadalafil) with grade 1 obesity, to evaluate the acute effect of a single dose of 20 mg of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. RESULTS: Tadalafil did not modify flow-mediated dilation. However, it significantly lowered systolic blood pressure (SBP) (130.6±17.1 vs. 125.0±12.7 mmHg, p=0.011), diastolic blood pressure (82.7±18.2 vs. 76.5±11.8 mmHg, p≤0.001), central systolic blood pressure (116.33±19.16 vs. 109.90±15.05 mmHg, p=0.001), the augmentation index (69.1±17.1 vs. 65.7±14.4, p=0.012), and brachial-ankle pulse wave velocity (1229.7±218.4 vs. 1164.0±181.7, p=0.001). CONCLUSION: A single dose of tadalafil did not modify flow-mediated dilation in patients with grade 1 obesity but improved blood pressure and brachial-ankle pulse wave velocity.

Tadalafil-loaded PLGA microspheres for pulmonary administration: preparation and evaluation

Tadalafil, a long-acting PED-5 inhibitor, is commonly used for the treatment of pulmonary arterial hypertension (PAH). However, its efficacy and clinical application are severely limited by the poor water solubility, low bioavailability and a series adverse effects (e.g. headaches, indigestion). In this study, tadalafil was prepared and loaded into biodegradable PLGA (poly(lactic-co-glycolic acid)) microspheres (TDF-PLGA-MS) via emulsification-solvent evaporation. The resulting microspheres were processed into pulmonary inhalant by freeze drying. The TDF-PLGA-MS was spherical and uniform, with an average particle diameter ~10.29 µm. The encapsulation efficiency and drug loading yield of TDF-PLGA-MS were 81.68% and 8.52%, respectively. The investigation of micromeritics showed that the TDF-PLGA-MS had low moisture content. The fluidity of powders was relatively good. The aerodynamic diameter and emptying rate of microspheres powders were 3.92 µm and 95.41%, respectively. Therefore, the microspheres powders were easy to be atomized, and can meet the requirements of pulmonary administration. In vitro release results showed that the microspheres group released slowly. The cumulative release in 24 h and 10 d was 46.87% and 84.06%, respectively. The in vitro release profile of TDF-PLGA-MS was in accordance with the Weibull model. The results of Pharmacokinetics showed that tadalafil from microspheres slowly released into the blood after intratracheal instillation. The pulmonary drug residue in 0.5 h was 3.5 times compared with solution group. The residual concentration in lung after 10d was still higher than that of solution group in 48 h. The t1/2β and MRT0-∞ were 3.10 times and 3.96 times that of solution group, respectively. Moreover, the Cmax and AUC of drug residues in lung ​​were 3.48 times and 16.36 times that of solution group, respectively. The results of tissue distribution showed that the Re in lung was 16.358, which indicated the lung targeting. In conclusion, the TDF-PLGA-MS for pulmonary administration in this study can significantly improve the pulmonary targeting, increase efficacy of tadalafil and reduce other non-target organs toxicity. This study will have an important clinical significance for PAH patients who need long-term drug therapy.

Surdez súbita em paciente em uso de tadalafil: um relato de caso clínico / Sudden deafness in a patient with tadalafil use: a clinical case report

Introdução: a Surdez Súbita (SS) é uma emergência médica de baixa prevalência, porém com potencial de perda auditiva irreversível para o paciente. Possui diversos e ainda incertos mecanismos etiopatológicos. Recentemente a literatura vem trazendo a associação da SS com a classe dos inibidores da fosdodiesterase-5 (IPDE-5), a qual inclui medicamentos para tratamento de impotência sexual. Objetivo: relatar caso clínico de paciente idoso que apresentou SS após fazer uso de medicamento da classe dos IPDE-5, pesquisando na literatura qual a provável fisiopatologia. Metodologia: trata-se de estudo qualitativo, descritivo do tipo relato de caso clínico, realizado através da coleta de dados do prontuário médico, que foram comparados com literatura especializada. Resultado: paciente masculino, 72 anos, engenheiro, procurou atendimento referindo hipoacusia e plenitude aural à direita notados subitamente há três dias. Relata ter feito uso de Tadalafil 5mg, anteriormente aos sintomas. Anamnese e exame físico direcionaram para hipótese diagnóstica de SS, de modo que exames complementares foram solicitados. À audiometria evidenciou-se perda auditiva sensorioneural moderada a severa em orelha direita. Após tratamento com prednisolona oral e mesilato de codergocrina, paciente apresentou melhora, com audiometria evidenciando perda sensorioneural leve em orelha direita. Conclusão: a relação entre SS e o uso de IPDE-5 está cada vez mais evidente de acordo com a literatura. É provável que possa haver ativação de vias de estresse celular, contribuindo para patologia