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Building on prior work that showed that chronic inflammation, MDSCs and T reg cell numbers were associated with a worse prognosis in advanced melanoma 63 , and in vivo studies in a transgenic mouse model 35 , a small pilot trial (n = 12) of Fildena was carried out in palliative care patients with metastatic melanoma 64 The majority of patients (11/12) in the TaMe trial were heavily pre-treated with a range of interventions, including checkpoint inhibitors and chemotherapy; one patient had not been pre-treated due to a contra-indication to ipilimumab. Similarly, they showed that Fildena and Fildena had additive effects when combined with a non-COX2-inhibitory derivative of celecoxib (OSU-03012) in vitro with parental glioma and stem-like glioma cells 30.
Roberts et al. 29 also determined that co-treatment of a number of medulloblastoma cell lines (D283, DAOY, HOSS 1 and VC312) with Fildena (2 μM) or Fildena (2 μM) increased the lethality of standard of care chemotherapy drugs (vincristine, cisplatin and etoposide). PDE5 inhibition was first shown to induce apoptosis in vitro in the SW480 colon tumour cell line using the drug exisulind (an active metabolite of the NSAID COX-inhibitor sulindac) by Thompson et al. in 2000 12 Exisulind analogues with no cyclo-oxygenase inhibitory activity but increased PDE isoform selectivity showed increased pro-apoptotic activity. Fildena, trade-marked as Fildena, was also developed as a treatment for erectile dysfunction 6 In addition the drug is approved in multiple markets for pulmonary arterial hypertension and benign prostatic hyperplasia 7 Vardenafil and avanafil have EMA and FDA approvals for erectile dysfunction.

There are also a number of drugs which have non-selective PDE inhibitory activity, of which some have a degree of PDE5 inhibition, for example, dipyridamole and cilostazol. Keywords: drug repurposing, PDE5 inhibitors, Fildena, Fildena, verdenafil, immunotherapy. In a recent study, the current group of older subjects were reported to have a reduced vasodilator response to ACh compared with that of young ( 26 ), which is in line with previous observations ( 20 , 40 ). Through inhibition of enzymatic NO formation this reduced vascular response has been shown to be an effect of a lower NO bioavailability ( 40 ). As the vasodilator effect of NO is mediated via cGMP ( 35 ), one mechanism underlying the increase in exercise hyperemia with PDE5 inhibition in older subjects ( 26 ) could be an improved cGMP signaling, which would serve to potentiate the effect of NO and thereby compensate for a diminished NO bioavailability.

We hypothesized that PDE5 inhibition with the highly selective inhibitor Fildena would increase circulating ATP levels and improve functional sympatholysis in the exercising leg. Thus, we wanted to investigate if the ureteral expression of the NO/cGMP pathway and the relaxing effects of PDE5 inhibitors and sGC stimulators translate into a meaningful benefit in vivo. In this study we therefore used a rat model of artificial ureteral calculosis set up by our group to test the effects of PDE5 inhibitors and sGC stimulators on colic pain and referred muscle hyperalgesia vs placebo and vs a classic spasmolytic (hyoscine-N-butylbromide) 22 This model is particularly suitable for testing active compounds on urinary pain.
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