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Biomedicine & Pharmacotherapy =... May 2024PDE5 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...
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.
PubMed: 38713942
DOI: 10.1016/j.biopha.2024.116710 -
Nagoya Journal of Medical Science Feb 2024Prostaglandin E1 intracavernous injection test is an established method for diagnosing erectile dysfunction. However, the evaluation is non-objective and often...
Prostaglandin E1 intracavernous injection test is an established method for diagnosing erectile dysfunction. However, the evaluation is non-objective and often influenced by the evaluator's subjectivity. Herein, we measured and objectively evaluated shear wave elastography results of the corpus cavernosum before and after injection in 16 patients who underwent prostaglandin E1 testing. The response score of prostaglandin E1 tests were "1" in 2 cases, "2" in 2 cases, and "3" in 12 cases. The average transmission velocity before the injection and at the time of maximum erection after the injection were 2.21 m/s and 1.57 m/s, respectively. Transmission velocity decreased during erection in 14 of 16 cases (87.5%). The overall rate of change in transmission velocity due to injection was -26.7% and was significantly different between the poor (responses 1 and 2: -16.1%) and good erection (response 3: -30.2%) groups. To the best of our knowledge, this is the first attempt to evaluate erectile phenomenon using percutaneous ultrasonic elastography in Japan. Rate of change in shear wave transmission velocity due to prostaglandin E1 injection in the corpus cavernosum penis was associated with the degree of erection. Therefore, the rate of change in shear wave transmission velocity in the corpus cavernosum penis could be used as an objective index of erectile phenomenon. Percutaneous ultrasonic elastography is a non-invasive and useful test method for diagnosing erectile dysfunction, determining the therapeutic effect, and predicting prognosis.
Topics: Male; Humans; Erectile Dysfunction; Alprostadil; Elasticity Imaging Techniques; Penile Erection; Penis
PubMed: 38505715
DOI: 10.18999/nagjms.86.1.104 -
The Journal of Pediatric Pharmacology... 2024This study aims to describe the effectiveness of low initial alprostadil dosages to maintain a patent ductus arteriosus (PDA) in infants with ductal-dependent congenital...
OBJECTIVES
This study aims to describe the effectiveness of low initial alprostadil dosages to maintain a patent ductus arteriosus (PDA) in infants with ductal-dependent congenital heart disease (DDCHD). Secondary objectives were to describe any adverse drug events, describe prescribing trends, describe ductus arteriosus diameter changes, and compare the safety and efficacy of very low and low initial alprostadil dosage regimens.
METHODS
This retrospective observational cohort study at the British Columbia's Women's and Children's Hospital neonatal intensive care unit and pediatric intensive care unit examined neonates admitted with DDCHD who received alprostadil to maintain ductal patency. Very low-dose alprostadil (less than 0.01 mcg/kg/min) versus low-dose alprostadil (equal to or greater than 0.01 mcg/kg/min) was examined. Effectiveness was defined as survival and infants not requiring a resuscitation event (cardiac arrest, cardiogenic shock, code blue, extracorporeal life support, requirement for emergent cardiac surgery, and respiratory acidosis). Adverse drug events with a Naranjo score of 3 or more were included.
RESULTS
Alprostadil was effective for 88% of patients, with no difference between the very low-dose and low-dose groups. Of the 75 patients included, 25 received very low-dose alprostadil. Adverse drug events were common (51%) with neonates in the low-dose group experiencing more apnea and pyrexia than neonates in the very low-dose group.
CONCLUSIONS
Alprostadil therapy was effective in maintaining the PDA in neonates with DDCHD with low-dosage regimens. Adverse drug events were common with both dosage regimens; however, the very low dosage appeared to have less apnea and pyrexia.
PubMed: 38332962
DOI: 10.5863/1551-6776-29.1.37 -
AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation.Nature Communications Feb 2024Gene therapies provide treatment options for many diseases, but the safe and long-term control of therapeutic transgene expression remains a primary issue for clinical...
Gene therapies provide treatment options for many diseases, but the safe and long-term control of therapeutic transgene expression remains a primary issue for clinical applications. Here, we develop a muscone-induced transgene system packaged into adeno-associated virus (AAV) vectors (AAV) based on a G protein-coupled murine olfactory receptor (MOR215-1) and a synthetic cAMP-responsive promoter (P). Upon exposure to the trigger, muscone binds to MOR215-1 and activates the cAMP signaling pathway to initiate transgene expression. AAV enables remote, muscone dose- and exposure-time-dependent control of luciferase expression in the livers or lungs of mice for at least 20 weeks. Moreover, we apply this AAV to treat two chronic inflammatory diseases: nonalcoholic fatty liver disease (NAFLD) and allergic asthma, showing that inhalation of muscone-after only one injection of AAV-can achieve long-term controllable expression of therapeutic proteins (ΔhFGF21 or ΔmIL-4). Our odorant-molecule-controlled system can advance gene-based precision therapies for human diseases.
Topics: Mice; Humans; Animals; Alprostadil; Transgenes; Cycloparaffins; Odorants; Receptors, G-Protein-Coupled; Dependovirus; Genetic Vectors
PubMed: 38321056
DOI: 10.1038/s41467-024-45383-z -
Cellular and Molecular Life Sciences :... Jan 2024In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its...
In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its antagonist, the tumor-suppressor microRNA (miRNA) let-7, play a key role in maintaining pluripotency. Muse cells are non-tumorigenic pluripotent-like stem cells residing in the bone marrow, peripheral blood, and organ connective tissues as pluripotent surface marker SSEA-3(+). They express pluripotency genes, differentiate into triploblastic-lineage cells, and self-renew at the single cell level. Muse cells do not express LIN28 but do express let-7 at higher levels than in iPSCs. In Muse cells, we demonstrated that let-7 inhibited the PI3K-AKT pathway, leading to sustainable expression of the key pluripotency regulator KLF4 as well as its downstream genes, POU5F1, SOX2, and NANOG. Let-7 also suppressed proliferation and glycolysis by inhibiting the PI3K-AKT pathway, suggesting its involvement in non-tumorigenicity. Furthermore, the MEK/ERK pathway is not controlled by let-7 and may have a pivotal role in maintaining self-renewal and suppression of senescence. The system found in Muse cells, in which the tumor suppressor let-7, but not LIN28, tunes the expression of pluripotency genes, might be a rational cell system conferring both pluripotency-like properties and a low risk for tumorigenicity.
Topics: Alprostadil; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Embryonic Stem Cells; Gene Expression
PubMed: 38261036
DOI: 10.1007/s00018-023-05089-9 -
Renal Failure Dec 2024To evaluate the efficacy, effectiveness and safety of fermented mycelium (FOSM) products for preventing contrast-associated acute kidney injury (CA-AKI).
BACKGROUND
To evaluate the efficacy, effectiveness and safety of fermented mycelium (FOSM) products for preventing contrast-associated acute kidney injury (CA-AKI).
METHODS
Randomized controlled trials were searched from four Chinese and four English electronic databases and three clinical trial registries up to July 2023. Methodological quality was assessed by using the Cochrane risk-of-bias tool 2.0. Risk difference (RD) or risk ratio (RR) and mean difference (MD) were calculated along with the 95% confidence intervals (CIs).
RESULTS
Fourteen trials testing three types of FOSM products (Bailing, Zhiling, and Jinshuibao capsules) involving 1271 participants injected contrast agents were included. For the risk of bias, all trials were rated as some concerns. Compared with routine preventive procedure (RPP) (saline hydration and alprostadil), FOSM products plus RPP showed beneficial effects in reducing the incidence of CA-AKI (14.62% and 5.35%, respectively; RD -0.06, 95% CI -0.09 to -0.03). Subgroup analysis showed that Bailing/Jinshuibao plus RPP demonstrated lower incidence of CA-AKI compared to RPP. However, there was no statistically significant difference between Zhiling with RPP and RPP in the incidence of CA-AKI. Additionally, only when FOSM products were taken before injection of the contrast, it was superior to RPP in reducing the incidence of CA-AKI. There was no statistical difference in adverse events between these two groups.
CONCLUSIONS
Low certainty evidence suggests that preventive oral use of FOSM products as an adjuvant agent was safe and might decrease the incidence of CA-AKI. However, high-quality placebo-controlled trials are needed to confirm its benefit.
Topics: Humans; Acute Kidney Injury; Adjuvants, Pharmaceutic; Cordyceps; Randomized Controlled Trials as Topic; Biological Products
PubMed: 38189088
DOI: 10.1080/0886022X.2023.2300302 -
BJUI Compass Jan 2024To investigate the risk factors for penile arterial insufficiency (PAI), which is a known cause of erectile dysfunction (ED).
OBJECTIVE
To investigate the risk factors for penile arterial insufficiency (PAI), which is a known cause of erectile dysfunction (ED).
METHODS
Patients who attended our urology clinic complaining of ED for more than 6 months were prospectively enrolled in this study over 1-year period. Patient consent was taken and ethical committee approval. Complete medical history and thorough general and local examination including body mass index (BMI), Peyronie's disease (PD) and penile size measurements (length and girth) were done for all of them. Laboratory tests included testosterone, lipid profile and glycated haemoglobin (HA1c). A penile duplex ultrasound study (PDU) was done for all patients after intracavernosal injection (ICI) with alprostadil. Peak systolic velocity (PSV) and end-diastolic velocity (EDV) were measured after 15 min. Statistical analysis was done using SPSS.
RESULTS
A total of 440 patients were enrolled in this analysis. The mean age was 48(23-81), and the mean BMI was 30 (18-51). Older patients had lower PSV ( = -0.361, = 0.000) and higher EDV ( = 0.174, = 0.001), and both correlations were highly statistically significant. Diabetics had lower PSV ( = -0.318, = 0.000) and higher EDV ( = 0.139, = 0.008), which were also highly statistically significant. Smokers had lower PSV ( = -0.140, = 0.008) and higher EDV ( = 0.178, = 0.001), which were highly statistically significant. Men with larger penises measured skin to tip had lower EDV ( = -0.119, = 0.024), which was less significant. Interestingly, there was neither a significant correlation between BMI and PSV (0.16, = 0.745) nor a significant correlation between testosterone and PSV (0.029, = 0.552). Also, there was no correlation between PSV and both dyslipidaemia and penile PD.
CONCLUSIONS
Ageing, tobacco consumption, DM and hypertension seem to have a negative impact on penile haemodynamics, which was statistically significant. In our patients, there was no statistically significant effect on penile haemodynamics in patients with increased BMI, low testosterone or PD or according to the size of the penis.
PubMed: 38179020
DOI: 10.1002/bco2.275 -
BMC Gastroenterology Jan 2024To comprehensively evaluate the efficacy, safety, patient symptoms, and quality-of-life (QoL) of lubiprostone, linaclotide, and elobixibat as treatment for chronic... (Comparative Study)
Comparative Study Meta-Analysis
Comparative profiles of lubiprostone, linaclotide, and elobixibat for chronic constipation: a systematic literature review with meta-analysis and number needed to treat/harm.
OBJECTIVE
To comprehensively evaluate the efficacy, safety, patient symptoms, and quality-of-life (QoL) of lubiprostone, linaclotide, and elobixibat as treatment for chronic constipation (CC).
DESIGN
Systematic literature review (SLR) and meta-analysis (MA). Literature searches were conducted on PubMed and Embase using the Ovid platform.
METHODS
SLR including randomized controlled trials (RCTs) and observational studies was conducted to identify the overall efficacy and safety of lubiprostone, linaclotide, and elobixibat. Thereafter, MA was performed using only RCTs. The number needed to treat (NNT) and number needed to harm (NNH) analyses were additionally conducted.
PRIMARY AND SECONDARY OUTCOME MEASURES
The primary outcome was efficacy regarding change in spontaneous bowel movements. Secondary outcomes included safety, constipation-related symptoms, and QoL.
RESULTS
Twenty-four studies met the inclusion criteria for the SLR: 17 RCTs, 4 observational studies, and 3 single-arm trials. Feasibility assessment for the MA resulted in 14 studies available for safety data analysis, and 8 available for efficacy analysis, respectively. Three drugs showed similar efficacy in the MA and NNT analysis. However, the NNH analysis revealed distinct safety profiles: lubiprostone, linaclotide, and elobixibat were linked to the highest risk of nausea, diarrhea, and abdominal pain, respectively.
CONCLUSION
The current study provides an updated overview of the efficacy, safety, patient symptoms, and QoL of the three drugs with different mechanisms of action for CC treatment.The findings could help physicians adopt an individualized approach for treating patients with CC in clinical practice.
Topics: Humans; Constipation; Lubiprostone; Peptides; Treatment Outcome
PubMed: 38166671
DOI: 10.1186/s12876-023-03104-8 -
International Journal of Molecular... Dec 2023Although several (chemotherapeutic) protocols to treat acute myeloid leukemia (AML) are available, high rates of relapses in successfully treated patients occur....
Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Create Dendritic Cells of Leukemic Origin from AML Patients' Whole Blood and Whole Bone Marrow That Mediate Antileukemic Processes after Mixed Lymphocyte Culture.
Although several (chemotherapeutic) protocols to treat acute myeloid leukemia (AML) are available, high rates of relapses in successfully treated patients occur. Strategies to stabilize remissions are greatly needed. The combination of the (clinically approved) immune-modulatory compounds Granulocyte-Macrophage-Colony-Stimulating-Factor (GM-CSF) and Prostaglandine E1 (PGE-1) (Kit-M) converts myeloid blasts into dendritic cells of leukemic origin (DC). After stimulation with DC ex vivo, leukemia-specific antileukemic immune cells are activated. Therefore, Kit-M treatment may be an attractive immunotherapeutic tool to treat patients with myeloid leukemia. Kit-M-mediated antileukemic effects on whole bone marrow (WBM) were evaluated and compared to whole blood (WB) to evaluate the potential effects of Kit-M on both compartments. WB and WBM samples from 17 AML patients at first diagnosis, in persisting disease and at relapse after allogeneic stem cell transplantation (SCT) were treated in parallel with Kit-M to generate DC/DC. Untreated samples served as controls. After a mixed lymphocyte culture enriched with patients' T cells (MLC), the leukemia-specific antileukemic effects were assessed through the degranulation- (CD107a T cells), the intracellular IFNγ production- and the cytotoxicity fluorolysis assay. Quantification of cell subtypes was performed via flow cytometry. In both WB and WBM significantly higher frequencies of (mature) DC were generated without induction of blast proliferation in Kit-M-treated samples compared to control. After MLC with Kit-M-treated vs. not pretreated WB or WBM, frequencies of (leukemia-specific) immunoreactive cells (e.g., non-naive, effector-, memory-, CD3β7 T cells, NK- cells) were (significantly) increased, whereas leukemia-specific regulatory T cells (T, CD152 T cells) were (significantly) decreased. The cytotoxicity fluorolysis assay showed a significantly improved blast lysis in Kit-M-treated WB and WBM compared to control. A parallel comparison of WB and WBM samples revealed no significant differences in frequencies of DC, (leukemia-specific) immunoreactive cells and achieved antileukemic processes. Kit-M was shown to have comparable effects on WB and WBM samples regarding the generation of DC and activation of (antileukemic) immune cells after MLC. This was true for samples before or after SCT. In summary, a potential Kit-M in vivo treatment could lead to antileukemic effects in WB as well as WBM in vivo and to stabilization of the disease or remission in patients before or after SCT. A clinical trial is currently being planned.
Topics: Humans; Alprostadil; Granulocyte-Macrophage Colony-Stimulating Factor; Dendritic Cells; Bone Marrow; Lymphocyte Activation; Leukemia, Myeloid, Acute; T-Lymphocytes, Regulatory; Granulocytes; Macrophages
PubMed: 38139264
DOI: 10.3390/ijms242417436 -
Journal of Vascular Surgery Cases and... Dec 2023We present a case of medication-induced priapism that was refractory to conventional urologic methods and required treatment with a caverno-saphenous bypass. The patient...
We present a case of medication-induced priapism that was refractory to conventional urologic methods and required treatment with a caverno-saphenous bypass. The patient had been misusing an injectable erectile dysfunction medication consisting of alprostadil, papaverine, and phentolamine (Trimix), resulting in multiple episodes of priapism. His initial episodes of priapism were successfully treated with the traditional urologic algorithm, including phenylephrine, aspiration, and distal shunting. However, due to his continued medication misuse, these became ineffective, requiring proximal shunt surgery. Priapism requiring an extra-anatomic bypass is exceedingly rare. Following our proximal shunt surgery, he maintained partial sexual function, and his bypass remained patent.
PubMed: 38106342
DOI: 10.1016/j.jvscit.2023.101359