The rapid and accurate detection of illegal adulteration of chemical drugs into dietary supplements is a big challenge in the food chemistry field. Detection of compounds without a standard reference is even more difficult; however, this is a common situation. Here in this study, a novel \"standard-free detection of adulteration\" (SFDA) method was proposed and phosphodiesterase-5 inhibitor derivatives were used as an example to figure out the possibility and reliability of this SFDA method. After analysis by quadrupole coupled time of flight-tandem mass spectrometry detection and multivariable statistics, six common fragment ions were chosen to indicate whether adulteration was present or not, while 20 characteristic fragment ions indicated whether adulteration was by nitrogen-containing heterocycles or by anilines. Furthermore, the quantitative methods were conducted by high-performance liquid chromatography-tandem mass spectrometry. In a word, this strategy allows for a quick determination of dietary supplement adulteration without any need for standard materials, improving the efficacy of food safety testing.

UNASSIGNED: Our study aims to characterize the ocular safety profiles of phosphodiesterase type 5 (PDE5) inhibitors and explore the differences among different PDE5 inhibitors.
UNASSIGNED: We analyzed reports on ocular adverse events associated with sildenafil, vardenafil and tadalafil submitted to the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2023. Disproportionality analysis was conducted to evaluate reporting risk profiles.
UNASSIGNED: Among 61,211 reports qualifying for analysis, 5,127 involved sildenafil, 832 vardenafil, and 3,733 tadalafil. All PDE5 inhibitors showed increased reporting odds ratios (ROR) for ocular adverse events, with vardenafil highest (ROR 4.47) followed by sildenafil and tadalafil. Key ocular adverse events included cyanopsia, optic ischemic neuropathy, visual field defects, unilateral blindness and blindness. Sildenafil showed the highest disproportionality for cyanopsia (ROR 1148.11) while vardenafil and tadalafil showed the highest disproportionality for optic ischemic neuropathy. Time-to-onset analysis also revealed significant differences, with sildenafil having a later median time-to-onset compared to vardenafil and tadalafil.
UNASSIGNED: This comprehensive pharmacovigilance study reveals distinct patterns of ocular adverse events associated with PDE5 inhibitors. These findings contribute to a better understanding of the safety profiles of PDE5 inhibitors and may guide healthcare professionals in clinical decision-making.

PDE5 inhibitors was reported to play a protective role in both regulating lipid metabolism and reducing heart failure (HF). This study aimed to clarify the effectiveness of PDE5 inhibitors against hyperlipidemia-related HF by combining evidence from population-based study and animal models. The nationwide cohort study found that post-diagnostic use of PDE5 inhibitors was associated with a significantly lower risk of HF compared with patients who used alprostadil, especially among individuals with hyperlipidemia (adjusted HR = 0.56, 95% CI = 0.40-0.78). In animal models, sildenafil significantly recovered the cardiac structure and function induced by AAB surgery, as well as reversed liver dysfunction and ameliorated hyperlipidemia induced by HFD via reducing the level of ALT, AST and serum lipids. Lipidomic analysis identified four lipid metabolites involved in sildenafil administration, including FA 16:3, LPC O-18:1, DG24:0_18:0 and SE28:1/20:4. This study revealed the protective effect of PDE5 inhibitors against HF in hyperlipidemia, indicating the potential of being repurposed as an adjuvant for HF prevention in patients with hyperlipidemia if these findings can be further confirmed in clinical trials.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

UNASSIGNED: To evaluate the efficacy of a novel approach to achieve the optimal penile erection during the penile doppler ultrasound (PDU) examination, which was oral sildenafil combined alprostadil injection.
UNASSIGNED: A total of 60 ED patients were enrolled in our prospective study, and they were randomly assigned to two group with different PDU order. The approaches assisted the PDU included two models, mode A meaning injection of 15 μg alprostadil and model B meaning oral sildenafil 100 mg plus injection of 15 μg alprostadil. The PDU parameters were measured continuously before induced erection, and 5, 10, 15, 20, 25 min.
UNASSIGNED: Each group included 30 ED patients with similar clinical characteristics. After pooling the results together, the PSV, EDV, and RI were all improved significantly, when adding the oral sildenafil administration to assist PDU. Also, the clinical response of oral sildenafil administration plus alprostadil injection was better than that in alprostadil injection alone (p = 0.016). The arterial ED were decreased from 31.67% to 15.00% with the P value 0.031, and the mixed ED was also decreased statistically (23.33% vs 8.33%, p = 0.024).
UNASSIGNED: Oral sildenafil administration plus alprostadil injection could improve the diagnostic accuracy of PDU.

Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening disease. Despite being considered the gold standard treatment scheme, inhaled nitric oxide (iNO) is not readily available in settings with limited resources. Therefore, in recent years, research on related drugs is being actively pursued. Herein, we aimed to use random-effects network meta-analysis to evaluate the efficacy and associated mortality of different PPHN therapies.
We electronically searched the PubMed, Embase, and Cochrane Library for data up to January 27, 2023.
Randomized controlled trials involving neonates with PPHN assessing efficacy and mortality of various treatments.
Details of study population, treatments, and outcomes were extracted.
Direct pairwise comparisons and a network meta-analysis was performed under random effects. The ranking probability was further assessed based on the surface under the cumulative ranking curve (SUCRA). We analyzed 23 randomized clinical trials involving 902 newborns with PPHN. Sixteen different treatment strategies were compared with each other and conventional therapy (CON). A median concentration of 10-20 parts per million (ppm) iNO (MNO) coupled with sildenafil orally administered at a dose of 1-3 mg/kg/dose every 6-8 hours (OSID) demonstrated the best efficacy (MNO + OSID vs. CON: odds ratio [OR] = 27.53, 95% CI, 2.36-321.75; SUCRA = 0.818, ranking first; moderate quality). OSID combined with milrinone administered IV also performed well in terms of efficacy (OSID + milrinone vs. CON: OR = 25.13, 95% CI = 1.67-377.78; SUCRA = 0.811, ranking second; low quality) and mortality reduction (CON vs. OSID + milrinone: OR = 25.13, 95% CI = 1.67-377.78; SUCRA = 0.786, ranking last; low quality).
MNO + OSID is the most effective PPHN treatment. If iNO is not available, OSID + milrinone is preferred.

Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate.
This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world.
This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS).
The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens.
We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%.
By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.

The aim of this study was to design a novel matrix tablet with enhanced dissolution and pH-independent controlled release of sildenafil citrate (SIL), a drug with pH-dependent solubility, by using solid dispersions (SDs) and polyelectrostatic interactions. SIL-loaded SDs were prepared using various polymeric carriers such as poloxamer 188, poloxamer 407, Soluplus®, polyvinylpyrrolidone (PVP) K 12, and PVP K 17 by the solvent evaporation method. Among these polymers, Soluplus® was found to be the most effective in SDs for enhancing the drug dissolution over 6 h in pH 6.8 intestinal fluid. SIL was well dispersed in Soluplus®-based SDs in an amorphous form. When the Soluplus®-based SDs were added in the tablet containing positively charged chitosan and negatively charged Eudragit® L100, the drug release rate was further modulated in a controlled manner. The charge density of the tablet was higher at pH 6.8 than at pH 1.2 due to the polyelectrostatic interaction between chitosan and Eudragit® L100. This interaction could provide a pH-independent controlled release of SIL. Our study demonstrates that a combinatory approach of Soluplus®-based SDs and polyelectrostatic interactions can improve the dissolution and pH-independent release performance of SIL. This approach could be a promising pharmaceutical strategy to design a matrix tablet of poorly water-soluble drugs for the enhanced bioavailability.

UNASSIGNED: The role of phosphodiesterase 5 (Pde5) in obstructive sleep apnea-induced damage remains unclear. Our study aimed to investigate the role of Pde5 in the chronic intermittent hypoxia (CIH) model. C57BL/6J wild-type (WT) mice (n = 48) and Pde5 knockout (Pde5 -/- ) mice (n = 24) were randomly assigned to CIH group and room air group. After 6 weeks, some WT mice (n = 24) in CIH group were given sildenafil or saline gavage for another 4 weeks. Blood pressure was regularly measured during the experiment. Echocardiography was used to estimate cardiac function. We collected organs from each group of mice and measured their physical indicators. Histochemical staining was used to explore the size of cardiomyocyte and fibrosis area of various organs. Cyclic guanosine monophosphate and malondialdehyde concentrations in serum were measured by ELISA assay. Compared with the RA-treated group, the 6-week CIH resulted in a significant increase in blood pressure, altered heart structure, and reduced serum cyclic guanosine monophosphate in WT mice. Pde5 -/- mice and sildenafil intragastric administration significantly reduced systolic blood pressure in CIH condition and attenuated the damage of target organs. In CIH model, we found that the cardiomyocyte size and fibrosis area of heart and kidney significantly reduced in Pde5 -/- groups. Besides, endogenous and exogenous inhibition of Pde5 reduced malondialdehyde level and inflammatory and oxidative stress markers expression in CIH condition. In this study, we found that Pde5 inhibition could reduce blood pressure and alleviate target organ damage in the CIH model, which may be mediated through the oxidative stress pathway.

Various types of milk powder purportedly providing diverse health functions have emerged with the growth of the country\'s elderly population. Some manufacturers illegally add chemical drugs to their products to achieve their reported benefits, which poses a threat to consumer health. The existing standard methods are inapplicable to such complex sample matrices and require testing based on functional claims and classification. These limitations not only consume manpower and resources but also seriously impede daily regulatory efforts to detect unknown risk substances. In this study, a high-throughput method for the screening and quantitative analysis of 300 illegally added chemical drugs in functional milk powder and an identification strategy for unknown structural analogues were established using Zeno SWATH® data-independent acquisition (DIA) ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) technology combined with a QuEChERS sample purification method. The QuEChERS purification process was developed according to the characteristics of milk powder matrix. The supernatant was separated on a Kinetex F5 column (100 mm×3.0 mm, 2.6 μm) by gradient elution using 5 mmol/L ammonium formate aqueous solution (0.1% (v/v) formic acid, ) and methanol-acetonitrile (1∶1, v/v) as mobile phases. The method was validated in terms of selectivity, linearity, limits of detection and quantification (LODs and LOQs, respectively), matrix effect, accuracy, and precision. Based on a screening database for the 300 target substances, electron-activated dissociation (EAD) fragmentation was applied to obtain rich secondary MS fragmentation information, and unknown structural analogues were identified and confirmed through fragment attribution analysis. The results indicated that all compounds had good linear relationships in certain ranges with correlation coefficients >0.99. The LODs and LOQs were 0.04-2.7 and 0.2-8.0 μg/kg, respectively. The average recoveries at three spiked levels were in the range of 73.1%-125.2%, and the relative standard deviations were ≤14.8% (n=6). When the developed method was applied to detect illegally added chemicals in 60 functional milk powder samples, it detected benzoguanidine and sildenafil and successfully identified ethylphenidate, which is the structural analogue of an amphetamine. The proposed method is simple, sensitive, and accurate; thus, it may have practical application value for the daily supervision and law enforcement of milk powders with reported health functions.