The management of erectile dysfunction (ED) shows several grey zones, especially in terms of patient satisfaction and adherence to the treatment. The main and first-line treatment for ED is drug therapy, mainly phosphodiesterase-5 inhibitors (PDE-5is) but the adherence to the therapy is not optimal due to the low patient satisfaction reported in several cases. To address this issue, different administration routes and PDE-5is pharmacological formulations have been introduced in the pharmacological market. The pharmaceutical market has recently seen the introduction of a novel sildenafil oral suspension. This device offers access to all therapeutic regimens in one device, releasing 0.5 mL of suspension containing 12.5 mg of sildenafil with each pulse. This formulation enables tailored dosing based on clinical requirements and the demands of ED patients. Here, we aim to give a brief narrative review of the management of this new oral suspension in order to provide the readers with some suggestions to use in everyday clinical practice, on the basis of the recent evidence, by using an easy and rapid-to-consult questions and answers form. Also included are the conclusions of a board meeting of experienced andrologists regarding the most recent developments in this area.

Cerebral ischemic stroke poses a significant global cause of death, with ischemia-reperfusion injury contributing to neuronal cell death and tissue damage. However, significant therapeutic approaches with meaningful treatment effects for patients with ischemic stroke in actual clinical practice are lacking. This study investigated the potential neuroprotective effects of sildenafil, a phosphodiesterase-5 inhibitor, in a global cerebral ischemia model. We explored the impact of sildenafil on GFAP and AQP-4 expression, which are markers associated with astrocyte activation and water homeostasis, respectively. The immunofluorescence analysis revealed that the number of cells co-expressing the markers, which increased in the ischemia-induced group, was significantly reduced in sildenafil-treated groups, suggesting a potential mitigating effect on ischemia-induced astrocyte activation. Additionally, we conducted diverse behavioral tests, including the open-field test, novel object recognition, Barnes maze, Y-maze, and passive avoidance tests, to assess the effect of sildenafil on the cognitive function impaired by ischemia. Cognitive improvements were observed following sildenafil administration (20mg/kg) compared to the untreated group. Taken together, the results presented here suggest sildenafil's potential as a neuroprotective agent for alleviating delayed neuronal cell death and cognitive function impaired by ischemia.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.

Orodispersible film (ODF) is one of the novel formulations that have been currently made available that disintegrates rapidly in the mouth without the requisite for water and offer several benefits over conventional oral solid dosage formulations. This delivery system serves as a discreet and convenient mode of administration, especially in patients who have dysphagia, fluid restriction, being beneficial to pediatric, geriatric, and bedridden patients. A novel sildenafil ODF containing sildenafil citrate is formulated to be used in patients with erectile dysfunction (ED). This review discusses the advantages of ODF in improving compliance and satisfaction in these patients and describes the bioequivalence and stability studies of sildenafil ODF. This formulation offers unique benefit to patients with ED by improving their acceptance, compliance, and respecting their privacy. Moreover, the comparison of pharmacokinetic parameters between the sildenafil ODF administered with and without water and the conventional film-coated tablet were similar. It also demonstrated reliable performance that yielded a consistent product, meeting all specifications at release and after three weeks of storage under stressed conditions (60oC). Sildenafil ODF warrants improved ease of intake, taste, portability, storage, and compliance among ED patients, making it the potential most preferred formulation and drug of choice.

(1) Background: Globally, about 600 million people are afflicted with diabetes, and one of its most prevalent complications is neuropathy, a debilitating condition. At present, the exploration of novel therapies for alleviating diabetic neuropathy-associated pain is genuinely captivating, considering that current therapeutic options are characterized by poor efficacy and significant risk of side effects. In the current research, we evaluated the antihyperalgesic effect of sildenafil (phosphodiesterase-5 inhibitor) – metformin (antihyperglycemic agent) combination and its impact on biochemical markers in alloxan-induced diabetic neuropathy in rats; (2) Methods: The study comprised a cohort of 70 diabetic rats and 10 non-diabetic rats which were submitted to hot, cold, and tactile stimulus tests. Morover, we investigated the influence of this combination on TNF-α, IL-6 nitrites and thiols levels in brain and liver tissues; (3) Results: The results demonstrated that all sildenafil-metformin combinations decreased the pain sensitivity in von Frey test, Hot-plate test and Cold-plate test. Furthermore, alterations in nitrites and thiols concentrations and pro-inflammatory cytokines (specifically TNF-α and IL-6) were noted following a 15-day regimen of various sildenafil-metformin combinations. (4) Conclusions: The combination of sildenafil and metformin has a synergistic effect in alleviating pain in alloxan-induced diabetic neuropathy rats. Additionally, the combination effectively decreased inflammation, inhibited the rise in NOS activity, and provided protection against glutathione depletion.

Background and objectives: Contrast-induced nephropathy (CIN), is an acute renal damage due to contrast agents. This study is conducted to determine the potential diagnostic value of hypoxia-inducible factor 2-alpha (HIF2-α) and to evaluate the renal protective effects of N-acetyl cysteine (NAC) and sildenafil in a rat CIN model. Material/Methods: This randomized, controlled, interventional animal study was conducted on Wistar rats. Totally, rats (n = 36) were randomly assigned to four groups: control (n = 9), CIN group (n = 9), CIN+NAC group (n = 9), and sildenafil (n = 9). The rat model was used to form iohexol-originated CIN. During the modelling, prophylactic treatment was performed at 24th and 48th hours. After 48 hours of the modelling; blood, urine, tissue samples were obtained for biochemical analyses. HIF-2-α levels were measured in renal tissue, serum and urine samples. Renal sections were performed in order for histopathologic and immunohistochemical evaluations. Results: In the CIN model, HIF-2α levels and other biochemical parameters were significantly increased (p < 0.01). Both sildenafil and NAC, efficiently decreased the renal damage due to contrast agents (p < 0.05). Similarly, after treatment with sildenafil and NAC, HIF-2α levels were significantly decreased (p < 0.05). Conclusions: The current study constructs an experimental base for the use of HIF-2α for clinical prevention and treatment of CIN. Several mechanisms may be postulated for the changes in HIF-2α levels. Besides, the increased HIF-2α levels with CIN and decreased HIF-2α levels after treatment may be used for the treatment and follow-up of patients with CIN.

Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of various conditions, including erectile dysfunction and pulmonary hypertension. Despite their clinical efficacy, these drugs quite often cause visual disturbances due to off-target effects on Phosphodiesterase type 5 (PDE6) in the retina. This review explores the application of a general intermolecular binding affinity calculator (GIBAC)-based binding selectivity strategy in the design of PDE5 inhibitors, aiming to enhance binding selectivity and minimize visual side effects. This GIBAC strategy integrates computational structural biological approaches to iteratively refine drug-target binding affinities, thereby improving target specificity and the structural biophysical limit for the efficacy-safety balance of PDE5 inhibitors. Through detailed analysis of PDE5’s and PDE6’s biological role and the molecular mechanisms underlying visual disturbances, this article underscores the necessity of target binding selectivity in PDE5 inhibitor design in future. Additionally, this article discusses the practical applications of GIBAC in computational drug discovery and design, along with the future directions and the potential for GIBAC to transform PDE5 inhibitor development, ultimately enhancing therapeutic outcomes and patient safety. Finally, this article calls for a GIBAC-based paradigm shift in computational drug discovery and design towards the continued development of the pharmaceutical industry.