BACKGROUND: Erectile dysfunction (ED) is a common issue that affects older men and is often associated with various health conditions. Phosphodiesterase 5 inhibitors are commonly used to treat ED; however, their effectiveness may be limited, or the medication may be contraindicated. Therefore, topical gels are being developed as an alternative option for the pharmacologic treatment of ED.
OBJECTIVE: This review aimed to provide an overview of the efficacy and safety of topical agents for the treatment of ED.
METHODS: The PubMed, Cochrane, Embase, and Web of Science databases were searched. Articles were included that investigated ED and topical agents operating through the skin of the penis, evaluated the effectiveness of the treatment, and involved patients randomized into groups.
RESULTS: Topical alprostadil, glyceryl trinitrate (MED2005), and an over-the-counter formulation (MED3000) were used as alternative treatments for ED in 7 articles, which included 3475 patients. Topical alprostadil induced an erection in 67% to 75% of patients. Adequate erections for vaginal penetration were reported in 38.7% of the alprostadil-treated patients vs 6.9% of the placebo-treated patients. Topical alprostadil significantly and dose dependently improved the total score change on the International Index of Erectile Function as compared with the placebo. MED2005 exhibited a rapid onset of action, with nearly 70% effectiveness within 10 minutes. MED3000 met the minimal clinically important difference threshold of a 4-point increase on the erectile function domain of the International Index of Erectile Function, with an improvement of 5.73 points in 24 weeks. Topical therapy for ED also had acceptable safety profiles.
CONCLUSIONS: Topical agents via various mechanisms are effective and well-tolerated treatments for ED. A fast-acting drug that significantly reduces side effects as compared with other options has been discovered. However, its efficacy relative to current first-line therapies remains unclear. Topical agents present a viable therapeutic alternative for individuals who are unable or unwilling to take oral phosphodiesterase 5 inhibitors.

BACKGROUND: Sneddon syndrome is an occlusive vasculopathy that presents clinically with generalized livedo racemosa on the skin and transient ischemic attacks, strokes, and cognitive or motor deficits in the central nervous system. Antiplatelet or anticoagulant therapy is recommended. Due to the limited therapeutic efficacy and the resulting serious complications, we propose combination therapy with additional infusion cycles of alprostadil and captopril and report initial long-term results.
METHODS: We performed a systematic retrospective analysis of all patients with primary Sneddon syndrome who received combination therapy in our clinic between 1995 and 2020. Therapeutic outcomes were evaluated using descriptive statistics compared to historical controls receiving monotherapy. We also analyzed the event rate of complications when combination therapy was discontinued.
RESULTS: During the 99.7 patient-years of follow-up, there were no transient ischemic attacks and the stroke rate dropped to 0.02 per patient-year. In comparison, the rates of transient ischemic attacks and strokes in the historical controls ranged from 0.08 to 0.035 per patient-year. After discontinuation of alprostadil therapy, eight events occurred in three patients.
CONCLUSIONS: Combination therapy reduces the long-term incidence of ischemic events in patients with primary Sneddon syndrome.

BACKGROUND: Although several clinical guidelines recommend vasodilator therapy for non-occlusive mesenteric ischemia (NOMI) and immediate surgery when bowel necrosis is suspected, these recommendations are based on limited evidence.
METHODS: In this retrospective nationwide observational study, we used information from the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2018 to identify patients with NOMI who underwent abdominal surgeries on the day of admission. We compared patients who received postoperative vasodilator therapy (vasodilator group) with those who did not (control group). Vasodilator therapy was defined as venous and/or arterial administration of papaverine and/or prostaglandin E1 within 2 days of admission. The primary outcome was in-hospital mortality. Secondary outcomes included the prevalence of additional abdominal surgery performed ≥3 days after admission and short bowel syndrome.
RESULTS: We identified 928 eligible patients (149 in the vasodilator group and 779 in the control group). One-to-four propensity score matching yielded 149 and 596 patients for the vasodilator and control groups, respectively. There was no significant difference in in-hospital mortality between the groups (control vs. vasodilator, 27.5% vs. 30.9%; risk difference, 3.4%; 95% confidence interval, -4.9 to 11.6; p=0.42) and no significant difference in the prevalences of abdominal surgery, bowel resection ≥3 days after admission, and short bowel syndrome.
CONCLUSIONS: Postoperative vasodilator use was not significantly associated with a reduction in in-hospital mortality or additional abdominal surgery performed ≥3 days after admission in surgically treated NOMI patients.

Limaprost, an orally administered analogue of prostaglandin E1, possesses potent vasodilatory, antiplatelet, and cytoprotective properties. Due to its extremely low therapeutic doses and exceedingly low plasma concentrations, the pharmacokinetic and bioequivalence studies of limaprost necessitate a highly sensitive quantitative method with a sub-pg/mL level of lower limit of quantification. Moreover, the intensity of endogenous interferences can even exceed the maximum concentration level of limaprost in human plasma, presenting further challenge to the quantification of limaprost. As a result, existing methods have not yet met the necessary level of sensitivity, selectivity, and throughput needed for the quantitative analysis of limaprost in pharmacokinetic and bioequivalence investigations. This study presents a new methodology that combines differential mobility spectrometry (DMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and utilizes a distinctive strategy to achieve more accurate DMS conditions. This integration yields a method that is currently the most sensitive and features the shortest analytical time, making it the sole technique capable of meeting the requirements for limaprost pharmacokinetic and bioequivalence investigations. This method demonstrates robustness and is successfully employed in a pharmacokinetic investigation of limaprost in human subjects, underscoring that the combination of DMS with LC-MS/MS serves as an efficacious strategy for overcoming the challenges inherent in analyzing biological samples afflicted by multiple interferences.

BACKGROUND: Diabetes nephropathy (DN), as one of the common complications of diabetes, is characterized by persistent albuminuria, decreased glomerular filtration rate, and elevated arterial blood pressure. At present, Xuebijing injection is widely used in the treatment of DN. However, few systematic reviews and meta-analysis related to Xuebijing injection intervention in DN were published. In order to more systematically and objectively evaluate the clinical efficacy of Xuebijing injection intervention in DN, we conducted systematic reviews and meta-analysis to verify it.
OBJECTIVE: The purpose of the research was to systematically evaluate the clinical efficacy of Xuebijing injection combined with alprostadil in the treatment of diabetic nephropathy.
METHODS: We searched the China National Knowledge Infrastructure (CNKI), China Biomedical Database (SinoMed), Weipu Database (VIP), Wanfang Database, PubMed, The Cochrane Library, Embase, Web of Science and other databases by computer, and searched the randomized controlled trials of Xuebijing injection combined with alprostadil in the treatment of DN at home and abroad from the establishment of the database to 2022. The main outcome indicators included blood glucose, and the secondary outcome indicators included blood lipid, renal function, urinary protein, and safety. Two evaluators independently screened the literature, extracted the data and evaluated the risk of bias in the included studies. RevMan 5.3 software was used to analyze the data.
RESULTS: A total of 14 randomized controlled trials were included, including 1233 cases, 618 cases in the treatment group and 615 cases in the control group. The results of meta-analysis demonstrated that compared with the control group, the treatment group could effectively reduce fasting plasma glucose [mean difference [MD] = -1.90, 95% CI (-2.40, -1.40), P < .00001], glycosylated hemoglobin A1c [MD = -2.38, 95% CI (-2.51, -2.25), P < .00001], 2h postprandial blood glucose [MD = -2.92, 95% CI (-3.95, -1.89), P < .00001], triacylglycerol [MD = -1.08, 95% CI (-1.66, -0.50), P = .0003], total cholesterol [MD = -1.17, 95% CI (-1.39, -0.95), P < .00001], low-density lipoprotein cholesterol [MD = -1.19, 95% CI (-1.60, -0.78), P < .00001], high-density lipoprotein cholesterol [MD = 0.32, 95% CI (0.23, 0.42), P < .00001], serum creatinine [MD = -42.95, 95% CI (-57.46, -28.43), P < .00001], blood urea nitrogen [MD = -2.24, 95%CI (-2.62,-1.86), P < .00001], blood β2 microglobulin [SMD = -1.49, 95% CI (-1.70, -1.28), P < .00001], urine β2 microglobulin [SMD = -0.81, 95% CI (-1.04, -0.58), P < .00001], 24-hour urinary protein quantification [MD = -0.20, 95% CI (-0.26, -0.14), P < .00001], urinary albumin excretion rate [SMD = -1.15, 95% CI (-1.38, -0.93), P < .00001].
CONCLUSIONS: Xuebijing injection combined with alprostadil has more advantages in treating DN compared to routine Western medicine.

OBJECTIVE: The clinical advantage of alprostadil [prostaglandin E1 (PGE1)] in the treatment of microcirculatory disturbances (defined as no-reflow or slow-flow) in acute percutaneous coronary intervention (PCI) is still disputed. The purpose of our study was to review the efficacy of PGE1 supplements in patients with acute myocardial infarction (AMI) who had urgent PCI.
METHODS: This study was a meta-analysis of randomized controlled trials.
METHODS: PubMed, Embase, the Cochrane Library, Ovid, ProQuest, Scopus, the Chinese BioMedical Literature Database, China National Knowledge Internet, the China Science and Technology Journal Database, and the Wanfang Data Knowledge Service Platform were used as sources.
METHODS: We included randomized controlled trials including PGE1 for the treatment of intraoperative microcirculatory disorders and major cardiovascular adverse events in emergency PCI in people with AMI. Independent data extraction was conducted, and study quality was assessed. The meta-analysis was carried out by using random effects models to calculate the risk ratio (RR) of microcirculatory disorders between groups receiving PGE1 and those receiving placebo, nitroglycerin, or tirofiban.
METHODS: The primary endpoint of the study was the incidence of microcirculatory disturbances. Secondary outcomes included corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC), the percentage of patients with TIMI myocardial perfusion grade 3 (TMPG3), and the percentage of patients with myocardial blush grade 3 (MBG3) as efficacy indicators. Additionally, major adverse cardiovascular events (MACE) at 30 days and 180 days were assessed as safety indicators.
RESULTS: There were 18 trials involving a total of 1458 participants. PGE1 significantly reduced the occurrence of microcirculation disorders compared with conventional medications and placebo [risk ratio 0.48, 95% confidence interval (CI) 0.36-0.63, I2 = 46%; cTFC (RR -4.74, 95% -6.85 to -2.63, I2 93%); percentage of patients with TMPG3 (RR 1.34, 95% CI 1.07-1.68, I2 70%) or MBG3 (RR 1.33, 95% CI 1.19-1.49, I2 0%); major adverse cardiovascular events (MACEs) in 30 days (RR 0.48, 95% CI 0.27-0.86, I2 0%); and MACEs in 180 days (RR 0.41, 95% CI 0.28-0.60, I2 0%)].
CONCLUSIONS: We found that PGE1 decreased the occurrence of micro-circulation disturbance in AMI and enhanced the outcome of PCI. Additional studies should be conducted to confirm these findings.

This study aims to elucidate the effect of alprostadil (ALP) plus cilostazol (CIL) on the treatment outcomes and inflammatory factors in patients with lower extremity arteriosclerosis obliterans (LEASO) receiving evidence-based care. Firstly, 130 patients with LEASO were selected from February 2020 to February 2023 and then randomly divided into two groups with 65 patients each. Excluding the dropouts, 59 patients in the control group (6 cases of dropout) received ALP and 62 patients in the research group (3 cases of dropout) received ALP plus CIL. Both groups were cared for in accordance with the evidence-based care model. Treatment outcomes, arteriosclerosis indexes (blood flow of dorsalis pedis artery [DPA], ankle-brachial index [ABI] and toe-brachial index [TBI]), hemorheological parameters (erythrocyte aggregation index [EAI], erythrocyte deformation index [EDI], high blood viscosity [HBV] and haematocrit [HCT]), inflammatory factors (interleukin [IL]-6, IL-8 and tumour necrosis factor [TNF]-α) and complications (nausea, diarrhoea, headache and transaminase elevation) were compared between the control and research groups. Results show that the overall response rate was markedly higher in the research group (90.32%) than in the control group (74.58%). Additionally, the blood flow of DPA, ABI and TBI in the research group significantly increased after the treatment and were higher than those in the control group. Meanwhile, the EAI, EDI, HBV, HCT, IL-6, IL-8 and TNF-α were significantly lower. The two groups did not differ markedly in the complication rate. The above findings suggest that ALP plus CIL is effective for patients with LEASO receiving evidence-based care. It can significantly improve arteriosclerosis indexes and hemorheological parameters while inhibiting serum inflammatory responses, with some certain safety.

UNASSIGNED: Long peripheral catheters (LPCs) role in Difficult IntraVenous Access (DIVA) patients admitted to the emergency department has already been studied, resulting in a rapid, safe, and cost-effective procedure. Although their use in outpatient settings is established, there is a lack of studies assessing their benefits. In particular, rheumatologic outpatients affected by scleroderma, especially those affected by digital ulcers, are often treated with intravenous infusions of prostaglandin I2 (PGI2) analog (IV-PGI2A).
UNASSIGNED: From 1 October 2021 to 31 March 2024, we conducted a prospective study enrolling DIVA outpatients affected by systemic sclerosis or undifferentiated connective tissue disease who needed IV-PGI2A therapy at L. Sacco Hospital in Milan (Italy). Each treatment cycle consisted of four consecutive days of infusion of iloprost or alprostadil. The primary aim was to assess the efficacy and potential complications associated with LPCs for IV-PGI2A.
UNASSIGNED: Twenty-six patients were enrolled 23 were females (88.5%), and the median age was 72 years (IQR 56-78.7). In total, 97 LPCs were inserted, with a mean number of insertions per patient/year of 2.3. An increase in LPCs insertion during the 30 months of the enrollment period was observed. Eighteen patients required more than one LPC placement, and in 61% of them, the second venipuncture was executed at a different site. No procedural complications were registered (accidental puncture of the brachial artery, accidental median nerve puncture, bleeding) nor late complications (Catheter-Related Thrombosis, Catheter-Related Bloodstream Infections, Accidental Removal).
UNASSIGNED: Our experience shows that LPCs could be valuable and safe for rheumatologic outpatients. The increased number of insertions and new and total patients enrolled each year defines the satisfaction of patients and health care professionals.

BACKGROUND: Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982.
OBJECTIVE: To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine\'s History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy.
METHODS: Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed.
RESULTS: The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine.
CONCLUSIONS: After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.

The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour and cancer. Internalisation and intracellular trafficking are critical for shaping GPCR activity, yet little is known regarding the spatial programming of EP2 signalling and whether this can be exploited pharmacologically. Using three EP2-selective ligands that favour activation of different EP2 pathways, we show that EP2 undergoes limited agonist-driven internalisation but is constitutively internalised via dynamin-dependent, β-arrestin-independent pathways. EP2 was constitutively trafficked to early and very early endosomes (VEE), which was not altered by ligand activation. APPL1, a key adaptor and regulatory protein of the VEE, did not impact EP2 agonist-mediated cAMP. Internalisation was required for ~70% of the acute butaprost- and AH13205-mediated cAMP signalling, yet PGN9856i, a Gαs-biased agonist, was less dependent on receptor internalisation for its cAMP signalling, particularly in human term pregnant myometrial cells that endogenously express EP2. Inhibition of EP2 internalisation partially reduced calcium signalling activated by butaprost or AH13205 and had no effect on PGE2 secretion. This indicates an agonist-dependent differential spatial requirement for Gαs and Gαq/11 signalling and a role for plasma membrane-initiated Gαq/11-Ca2+-mediated PGE2 secretion. These findings reveal a key role for EP2 constitutive internalisation in its signalling and potential spatial bias in mediating its downstream functions. This, in turn, could highlight important considerations for future selective targeting of EP2 signalling pathways.