Search Results (188)

Background/Objectives: Molnupiravir (MOV) and nirmatrelvir (NMV) are antiviral drugs that were FDA-approved under the emergency use authorization (EUA) for coronavirus disease-2019 (COVID-19) treatment. MOV and NMV target the viral RNA-dependent RNA polymerase and main protease, respectively. Paxlovid is a combination of NMV and ritonavir (RTV), an inhibitor of the human cytochrome P450-3A4 (hCYP3A4). In this study, the structural consequences in the hCYP3A4 caused by MOV-induced mutations (MIM) were evaluated using in silico tools. Methods: MOV-induced mutations (MIM) were inserted into all the possible hotspots in the active site region of the hCYP3A4 gene, and mutant protein models were built. Structural changes in the heme-porphyrin ring of hCYP3A4 were analyzed in the presence and absence of substrates/inhibitors, including RTV. Molecular dynamics (MD) simulations were performed to analyze the effect of MIM-induced structural changes in hCYP3A4 on drug binding. Results: MD simulations confirm that MIMs, R375G and R440G in hCYP3A4 severely affect the heme-porphyrin ring stability by causing a tilt that in turn affects RTV binding, suggesting a possible inefficiency in the function of hCYP3A4. Similar results were seen for amlodipine, atorvastatin, sildenafil and warfarin, which are substrates of hCYP3A4. Conclusions: The current in silico studies indicate that hCYP3A4 containing MIMs can create complications in the treatment of COVID-19 patients, particularly with co-morbidities due to its functional inefficiency. Hence, clinicians must be vigilant when using MOV in combination with other drugs. Further in vitro studies focused on hCYP3A4 containing MIMs are currently in progress to support our current in silico findings. Full article

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, with ovulation induction remaining the first-line treatment approach. Although letrozole has emerged as the most effective monotherapy, treatment resistance, side effects, and patient preferences have led to increasing interest in adjunctive or alternative approaches. This narrative review summarizes the current evidence for ovulation induction in patients with PCOS, including conventional pharmacologic agents, such as clomiphene citrate, letrozole, gonadotropins, and insulin-sensitizing agents, as well as complementary therapies, such as acupuncture and Chinese herbal medicine. We also examine emerging adjuvants, such as vitamin D, omega-3 fatty acids, sildenafil, and antioxidants that may enhance clinical pregnancy rates or improve endometrial receptivity. While robust evidence supports the use of letrozole as a first-line agent, complementary and integrative therapies may offer additional benefits, particularly in treatment-resistant or preference-driven contexts. Further high-quality studies are needed to clarify the role of combined therapeutic strategies in optimizing fertility outcomes for women with PCOS. Full article

Background: Heart failure (HF) with pulmonary hypertension due to left-sided heart disease (PH-LHD) is associated with poor prognosis. Dapagliflozin showed benefits in terms of ejection fraction (EF); meanwhile, sildenafil improved pulmonary pressures and right ventricular function in PH -LHD in recent clinical studies. This study assesses the potential additive effects of dapagliflozin and sildenafil on cardiac function and pulmonary hemodynamics in this population. Methods: In this prospective, randomized, controlled trial, 93 participating patients with HF and PH-LHD were randomly assigned to receive dapagliflozin (control group, n = 48) or dapagliflozin plus sildenafil 25 mg/day (test group, n = 45) in addition to conventional therapy for HF for 12 weeks. The primary outcomes were assessing changes in echocardiographic hemodynamic parameters. Secondary outcomes included outcomes, changes in cardiac enzyme (troponin), kidney function (serum creatinine), and lipid profile. Results: The average baseline median left ventricular ejection fraction (LVEF) for both groups was 30%, and the Pulmonary Artery Systolic Pressure (PASP) median was 50 mmHg. At follow-up, PASP had declined, and EF had improved compared to baseline. However, there were no statistically noticeable variations between the groups (p = 0.458, 0.331, respectively). No notable changes were observed in secondary and safety outcomes, including hospitalization rate, number of deaths, kidney function, and cardiac enzymes (p = 0.524, 1, 0.923, and 0.574, respectively). Conclusions: Addition of sildenafil to dapagliflozin did not demonstrate any significant clinical or hemodynamic benefit over dapagliflozin monotherapy in HF patients and PH-LHD. Further studies are warranted to evaluate the effects over the long term. Full article

Background: The nipple–areolar complex (NAC) necrosis is a rare yet significant complication following breast reduction surgery, primarily linked to compromised vascularization of the NAC, particularly in nipple-sparing techniques. While multiple therapeutic strategies have been described in the postoperative setting, their application remains limited in clinical practice. Case series: We report on three patients that developed early NAC venous distress following bilateral breast reduction. Following discussion of therapeutic options—ranging from conventional methods such as scarification and local heparin therapy to off-label pharmacologic treatment—all three patients received oral sildenafil citrate (20 mg every 6 h), after excluding contraindications and obtaining informed consent. In two patients, sildenafil alone was sufficient to restore venous outflow and salvage the NAC. In one case, adjunct scarification and heparin therapy were necessary due to partial response. No arterial damage or major adverse effects related to sildenafil were observed during the postoperative period. Conclusions: This small series supports the potential use of off-label sildenafil citrate as a valuable, non-invasive pharmacologic option for treating postoperative areolar venous congestion. Its favorable safety profile, widespread hospital availability, and mechanism of enhancing microvascular circulation make it a promising adjunct in managing this complication. Further studies are warranted to standardize its use and determine its place within a broader postoperative management spectrum of compromised vascularization in breast surgery. Full article

Introduction: Erectile dysfunction (ED) is strongly associated with metabolic and cardiovascular diseases and may serve as a marker of vascular pathology. Phosphodiesterase type 5 (PDE-5) inhibitors are the mainstay of treatment. Considering this link, cardiologists and internists might be expected to play a key role in therapy initiation. Purpose: This study evaluated prescription patterns of PDE-5 inhibitors in Poland, focusing on physician specialization and consultation type. Methods: We performed a retrospective analysis of electronic health records from over 300 outpatient clinics (2014–2024). Men >18 years with newly diagnosed ED were included. Data on the first prescriptions of sildenafil and tadalafil were assessed. Ethical approval was obtained. Results: A total of 11,998 patients were identified (mean age 42 years; mean BMI 26.54 kg/m²). Common comorbidities included hypercholesterolemia (67.0%), hypertension (58.5%), obesity (31.5%), and diabetes (12.4%). PDE-5 inhibitors (predominantly tadalafil (≈67%)) were prescribed in 71.5% of cases. Urologists accounted for 51.0% of prescriptions, sexologists 14.9%, internists 20.4%, and cardiologists only 0.10%. Treated patients were younger and had a lower BMI, fewer comorbidities, and more favorable metabolic profiles (all p < 0.05). Conclusions: Contrary to expectations, cardiologists and internists rarely initiate PDE-5 therapy. Prescribing is dominated by urologists despite high rates of cardiovascular comorbidities. A multidisciplinary approach incorporating metabolic and cardiovascular risk assessment is warranted. Full article

Erectile dysfunction (ED) and cognitive decline share overlapping vascular, metabolic, and neurodegenerative mechanisms, particularly in aging populations. Phosphodiesterase type 5 inhibitors (PDE5-Is), such as sildenafil and vardenafil, are widely used to treat ED by elevating cyclic guanosine monophosphate (cGMP) levels and enhancing vascular function. Emerging evidence suggests that PDE5-Is may also benefit cognitive function by promoting neurovascular coupling, synaptic plasticity, and neuroprotection. This review synthesizes clinical, preclinical, and mechanistic studies on PDE5-Is in the context of learning, memory, and Alzheimer’s disease, highlighting their potential as therapeutic agents for cognitive impairment. Full article

Persistent pulmonary hypertension of the newborn (PPHN) results from disrupted fetal–neonatal circulatory transition, characterized by elevated pulmonary vascular resistance (PVR), right-to-left shunting, and refractory hypoxemia. Despite improved perinatal care, PPHN remains a major source of neonatal morbidity and mortality. This review details PPHN phenotypes, pathophysiology, etiology, diagnostics including echocardiography and biomarkers like B-type Natriuretic Peptide (BNP) or N-terminal pro-B-type Natriuretic Peptide (NT-proBNP), and current therapeutic modalities, from lung recruitment and surfactant to targeted vasodilator therapy (iNO, sildenafil, milrinone, bosentan) and extracorporeal membrane oxygenation (ECMO). We emphasize the role of endothelial and molecular mechanisms in precision therapy and outline guidelines for clinical decision-making in diverse care settings. Full article

Background: Pulmonary hypertension (PH) in newborns is a rare but serious condition and potentially life-threatening disorder, often initially confused with congenital heart disease due to overlapping echocardiographic findings in the late third trimester. Evidence on prenatal predictors of postnatal PH is limited. We aimed to describe detailed third-trimester echocardiographic findings associated with postnatal PH in infants with prenatally suspected CoA based on a retrospective case series. Methods: We reviewed 18 years of fetal echocardiography (2004–2022) in a tertiary maternal–fetal–neonatal center. We identified fetuses with suspected coarctation of the aorta (CoA) in late gestation who were delivered at term (≥37 weeks) and had prolonged neonatal hospitalization (>10 days) without cardiac surgery or catheterization. Z-scores for cardiac dimensions were calculated. All examinations were performed by experienced fetal cardiologists. Postnatal evaluations confirmed PH based on echocardiographic and clinical findings. Results: Among 19,836 fetuses examined, 138 were prenatally suspected of CoA. In 70 cases, this diagnosis was not confirmed postnatally (false positives). Of these, eight infants (0.04% of the total cohort) developed postnatal PH. Postnatally, all eight neonates required intensive care. Prenatal features included ventricular/atrial disproportion (7/8), cardiomegaly (8/8), main pulmonary artery dilatation (10.2 ± 2.2 mm; Z-score +2.7 ± 1.3), tricuspid regurgitation (8/8), pulmonary regurgitation (4/8), and interventricular septal hypertrophy (>4.5 mm in 5/8). Postnatal evaluations confirmed PH based on echocardiographic criteria (elevated right ventricular pressure, septal flattening/bowing, right ventricular dilation or dysfunction, and abnormal shunt direction) combined with clinical compromise. All infants received prostaglandin E1 (PGE1) initially; none required extracorporeal membrane oxygenation-ECMO. Three died, while five survived with medical management (oxygen, inhaled nitric oxide, sildenafil). Conclusions: Specific functional abnormalities on late third-trimester echocardiography may indicate impaired pulmonary vascular adaptation and predict postnatal PH, particularly in cases initially suspected of CoA. Recognition and awareness of these findings can guide delivery planning, neonatal surveillance, and timely intervention. Prospective multicenter studies are needed to validate these associations and refine prenatal screening protocols. Full article

Traumatic brain injury (TBI) is a major global health concern and a leading cause of long-term disability and mortality. While the primary mechanical insult is often the focus of acute care, secondary injury mechanisms—particularly cerebrovascular dysfunction—play a critical role in ongoing neural damage and poor outcomes. Increasing research highlights the role of neurovascular changes in TBI pathophysiology. This narrative review compiles evidence from the past decade on mechanisms, diagnostic methods, and treatments related to cerebrovascular dysfunction after TBI. A structured search of PubMed and Embase identified relevant clinical and preclinical studies. Key mechanisms include blood–brain barrier disruption, impaired cerebral autoregulation, microthrombosis, and oxidative stress. Diagnostic tools discussed include perfusion imaging, cerebrovascular reactivity testing, and blood-based biomarkers of vascular injury. Therapeutic strategies targeting the neurovascular unit are categorized by mechanism: anti-inflammatory agents (e.g., celecoxib, minocycline), mitochondrial protectors (e.g., Tanshinone IIA), and vasomodulators (e.g., sildenafil). We propose an integrated therapeutic approach for a multimodal treatment plan that integrates these interventions. The findings emphasize the importance of patient-specific vascular therapies to reduce secondary ischemic injury and enhance neurological recovery. Although promising preclinical data exist, clinical application remains limited. More well-designed trials are needed to confirm the safety and effectiveness of emerging therapies. Full article

Pulmonary hypertension (PH) with chronic obstructive pulmonary disease (COPD) is associated with poor survival with no approved therapies. We report on the response to inhaled treprostinil (iTRE) of a small retrospective cohort of PH-COPD patients with a baseline “PH-right ventricular (RV) phenotype”, defined by a RV-dependent circulatory limitation derived from a combination of echocardiographic and hemodynamic criteria. Patients were started on inhaled treprostinil with significant improvement in six-minute walk distance, NT-proBNP, and improved RV metrics by echocardiography. The preliminary findings of this cohort provide evidence for the importance of precision phenotyping of PH-COPD. Full article

Background: In congenital diaphragmatic hernia (CDH), pulmonary hypoplasia and pulmonary hypertension are major causes of morbidity and mortality. Antenatal treatment with sildenafil has shown some promising protective effects in experimental CDH, but no systematic review has yet evaluated the preclinical evidence on this topic. Methods: PubMed and EMBASE databases were searched for studies using antenatal sildenafil in animal models of CDH. Bayesian model-averaged (BMA) meta-analysis was used to calculate Bayes factors (BFs). The BF₁₀ is the ratio of the probability of the data under the alternative hypothesis (presence of effect) over the probability of the data under the null hypothesis (absence of effect). Risk of bias was assessed by the SYRCLE tool. Results: We included 18 studies (14 nitrofen and 4 surgical CDH). The BMA analysis showed inconclusive evidence (BF₁₀ between 0.33 and 3) for the presence of an effect of sildenafil in fetal survival (7 studies, BF₁₀ = 1.25) or in lung hypoplasia as assessed by the lung-to-body weight ratio (16 studies, BF₁₀ = 2.04). In contrast, the BMA analysis showed conclusive evidence (BF₁₀ > 3) in favor of a positive effect of sildenafil on small pulmonary arteries medial wall thickness (12 studies, BF₁₀ = 1499), radial alveolar count (6 studies, BF₁₀ = 167.57), interalveolar septa thickness (4 studies, BF₁₀ = 56.86), distal airway complexity (3 studies, BF₁₀ = 7.95), mean saccular airspace diameter (2 studies, BF₁₀ = 7.61), total lung capacity (2 studies, BF₁₀ = 6.91), lung compliance (2 studies, BF₁₀ = 5.19), and VEGF expression (5 studies, BF₁₀ = 10.62). Conclusions: In preclinical models of CDH, antenatal sildenafil rescues pulmonary vascular remodeling and airway/airspace morphometric alterations. Full article

Background/Objectives: In the past two decades, the primary therapeutic use of sildenafil has shifted significantly, from the treatment of angina to managing erectile dysfunction, and since the early 2000s it has been used in the treatment of pulmonary hypertension, particularly pulmonary arterial hypertension. Sildenafil is used as a citrate salt; after oral administration, it presents an absorption of ~90% and an absolute bioavailability of 38%, due to the first-pass effect, such that it belongs to class II of the Biopharmaceutics Classification System. Currently, studies are seeking to obtain new pharmaceutical formulations with an optimized biopharmaceutical profile. In this study, an inclusion complex of sildenafil citrate and 2-hydroxypropyl-beta-cyclodextrin in a molar ratio of 1:1 was obtained and its pharmaceutical compatibility with six pharmaceutical excipients was assessed. For three of these excipients, the presence of chemical interactions with sildenafil citrate has been presented in the literature, and for the other three, compatibility has not been evaluated. Methods: To certify the stoichiometry of the obtained inclusion complex molecular modeling, Job’s method and the Benesi–Hildebrand method were employed. Furthermore, we have described the inclusion complex and the obtained binary mixtures via ATR-FTIR and thermal (TG/DTG and DSC) analysis. Results: The results indicated a lack of chemical interactions between the inclusion complex and the six pharmaceutical excipients at ambient temperature (confirmed by ATR–FTIR investigations) and the presence of chemical interactions between the inclusion complex and three of the excipients when the mixture was heated under non-isothermal conditions (TG/DTG and DSC investigations). Conclusions: This study describes the inclusion complex between sildenafil citrate and 2-hydroxypropyl-beta-cyclodextrin in a molar ratio of 1:1 and its compatibility with several pharmaceutical excipients, results with further applications in the preformulation stage of novel delivery systems. Full article

Background: Phosphodiesterase type 5 inhibitors (PDE5i), particularly tadalafil and sildenafil, are the first-line therapies for erectile dysfunction (ED). After the patent expiration of branded tadalafil in 2017, generic formulations became available. Despite equivalent efficacy, skepticism persists regarding the effectiveness and safety of generics. The SHIFT study aimed to evaluate the non-inferiority of a generic tadalafil (Dalerpen) compared with branded and other generic tadalafil in terms of clinical efficacy and patient satisfaction. Methods: A prospective, multicenter study was conducted involving 247 patients treated with tadalafil (either 5 mg or 20 mg) for ED. Patients switched from branded or other generic tadalafil to Dalerpen. Baseline and follow-up assessments included the International Index of Erectile Function—Erectile Function Domain (IIEF-EF) (primary endpoint), Sexual Encounter Profile (SEP-2 and SEP-3), and International Prostatic Symptom Score (IPSS). A one-month follow-up was performed. Results: A total of 247 patients were included in the final analysis. After switching to Dalerpen, significant improvements were observed in both IIEF-EF (18.8 ± 5.6 vs. 16.7 ± 5.4, p < 0.001) and IPSS scores (10.4 ± 6.7 vs. 11.2 ± 6.3, p < 0.001), though the minimal clinically important difference (MCID) was not reached. SEP-3 scores also significantly increased (3 ± 1.2 vs. 2 ± 1.1, p < 0.001). Multivariate analysis identified baseline IIEF, IPSS scores, and post-treatment IPSS as predictors of IIEF-EF improvement (p < 0.001). Switching to Dalerpen was an independent predictor of both IIEF-EF and IPSS improvement. No new adverse events were reported. Conclusions: The SHIFT study demonstrates that Dalerpen is non-inferior to branded tadalafil in terms of clinical efficacy, offering a reliable and cost-effective therapeutic option. Educating patients on bioequivalence and addressing concerns regarding generic drugs are essential to facilitate therapeutic switches. Full article

The development of functional endothelial monolayers on synthetic vascular grafts remains challenging, particularly for small-diameter vessels (<6 mm) prone to thrombosis. Here, we present a pharmacological strategy combining 8-(4-chlorophenylthio) adenosine 3′,5′-cyclic monophosphate sodium salt (pCPT-cAMP, a tight junction promoter) with nitric oxide/cGMP pathway agonists 3-morpholinosydnonimine (SIN-1), captopril, and sildenafil) to enhance endothelialization. In human umbilical vein endothelial cells (HUVECs), this four-agent cocktail induced a flat, extended phenotype with a 3-fold increased cell area and 57.5% fewer cells required for surface coverage compared to controls. Immunofluorescence analysis revealed enhanced ZO-1 expression and continuous tight junction formation, while sustained nitric oxide (NO) production (3.9-fold increase) and restored prostacyclin (PGI₂) secretion demonstrated preserved endothelial functionality. Anticoagulation assays confirmed a significant reduction in thrombus formation (p < 0.01) via dual inhibition of platelet activation and thrombin binding. These findings establish a synergistic drug combination that promotes rapid endothelialization while maintaining antithrombogenic activity, offering a promising solution for small-diameter vascular grafts. Further studies should validate long-term stability and translational potential in preclinical models. Full article

Phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil, tadalafil, and vardenafil, are primarily prescribed for erectile dysfunction and pulmonary hypertension. Emerging evidence suggests they may also modulate inflammatory pathways and improve vascular function, but their effects on inflammatory biomarkers in humans remain incompletely defined. A systematic review and meta-analysis were conducted to evaluate the impact of PDE5 inhibitors on inflammatory and endothelial markers in adult humans. Randomized controlled trials comparing PDE5 inhibition to placebo were identified through electronic database searches. Outcomes included pro-inflammatory markers (TNF-α, IL-6, IL-8, CRP, VCAM-1, ICAM-1, P-selectin) and anti-inflammatory or signalling markers (IL-10, NO, cGMP), assessed at short-term (≤1 week), intermediate-term (4–6 weeks), or long-term (≥12 weeks) follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. A total of 20 studies comprising 1549 participants were included. Meta-analyses showed no significant short-term effects of PDE5 inhibition on TNF-α, IL-6, or CRP. Long-term treatment was associated with reduced IL-6 (SMD = −0.64, p = 0.002) and P-selectin (SMD = −0.57, p = 0.02), and increased cGMP (SMD = 0.87, p = 0.0003). Effects on IL-10 and nitric oxide were inconsistent across studies. Most trials had low risk of bias. PDE5 inhibitors may exert anti-inflammatory effects in long-term use by reducing vascular inflammation and enhancing cGMP signalling. These findings support further investigation of PDE5 in chronic inflammatory conditions. Full article