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This study evaluated the impact of mucin on supersaturation and permeation of BCS Class 2 basic drugs in a pH-shift, 2-stage model using three model compounds, dipyridamole, ricobendazole, and Compound A. The three compounds showed various degrees of supersaturation (DoS) in Stage 2 and modest to no increases in flux with the presence of mucin in the dissolution media. Mucin's impact on DoS and flux, if any, appeared to be compound specific and possibly related to its pKa and ionization state. Overall, the increases in supersaturation and permeation due to mucin ranged from modest to minimal for the three model compounds under the conditions tested. The pH-shift model using MacroFLUX was able to monitor gastric and intestinal dissolution and simultaneously assess the effect of intestinal mucin on supersaturation and flux. [ABSTRACT FROM AUTHOR]

Post-traumatic tendon adhesions significantly affect patient prognosis and quality of life, primarily stemming from the absence of effective preventive and curative measures in clinical practice. Current treatment modalities, including surgical excision and non-steroidal anti-inflammatory drugs, frequently exhibit limited efficacy or result in severe side effects. Consequently, the use of anti-adhesive barriers for drug delivery and implantation at the injury site to address peritendinous adhesion (PA) has attracted considerable attention. Electrospun nanofiber membranes (ENMs) have been extensively employed as drug-delivery platforms. In this study, we fabricated a polylactic acid (PLA)–dipyridamole (DP)-graft copolymer ENM called PLC-DP. This membrane exhibits enzyme-sensitive features, allowing more controlled and sustained drug release compared with conventional drug-loaded ENMs. In experiments, PLC-DP implantation reduced tissue adhesion by 47 % relative to the control group while not adversely affecting tendon healing. Mechanistically, PLC-DP effectively activates the FXYD domain containing ion-transport regulator 2 (FXYD2) protein, thereby downregulating the fibroblast-transforming growth factor beta (TGF-β)/Smad3 signaling pathway. PLC-DP leverages the anti-adhesive properties of DP and the enzyme-sensitive characteristics of graft copolymers, providing a promising approach for the future clinical treatment and prevention of PA. Peritendinous adhesions (PA) are a common and disabling condition that seriously affects the prognosis and quality of life of post-trauma patients. Current treatments often have limited efficacy or severe side effects, leaving a serious gap in clinical practice. We developed a significant biomaterial, poly(lactic acid)-dipyridamole graft copolymer electrospun nanofibrous membrane (PLC-DP), specifically for PA inhibition. In addition, this study uniquely combines dipyridamole, an anti-adhesive agent, and enzyme-sensitive copolymers in electrospun nanofibrous membrane. Unlike conventional drug-loaded electrospun nanofibrous membranes, PLC-DPs have enzyme-sensitive drug properties that allow for sustained drug release on demand. Our experiments showed that implantation of PLC-DP was effective in reducing tissue adhesions by 47 % without affecting tendon healing. We elucidated the mechanism behind this phenomenon, suggesting that PCD activates FXYD2 to inhibit TGF-β-induced expression of Col III, which is a key factor in PA development. [Display omitted] [ABSTRACT FROM AUTHOR]

A new molecularly imprinted polymer (MIP)-based disposable electrochemical sensor for dipyridamole (DIP) determination was obtained. The sensor was rapidly prepared by potentiodynamic electrochemical polymerization on a pencil graphite electrode (PGE) using curcumin (CUR) as a functional monomer and DIP as a template molecule. After the optimization of the conditions (pH, monomer–template ratio, scan rate, number of cyclic voltammetric cycles applied in the electro-polymerization process and extraction time of the template molecule) for MIP formation, DIP voltammetric behavior at the modified electrode (MIP_PGE) was investigated. DIP oxidation took place in a pH-dependent, irreversible mixed diffusion-adsorption controlled process. Differential pulse voltammetry (DPV) and adsorptive stripping differential pulse voltammetry (AdSDPV) were used to quantify DIP from pharmaceutical and tap water samples. Under optimized conditions (Britton–Robinson buffer at pH = 3.29), the obtained linear ranges were 5.00 × 10−8–1.00 × 10−5 mol/L and 5.00 × 10−9–1.00 × 10−7 mol/L DIP for DPV and AdSDPV, respectively. The limits of detection of the methods were 1.47 × 10−8 mol/L for DPV and 3.96 × 10−9 mol/L DIP for AdSDPV. [ABSTRACT FROM AUTHOR]

Background Regarding the less-known effects of beta-blocker consumption on the diagnostic value of the myocardial perfusion scan with dipyridamole stress in coronary artery disease (CAD), we aimed to compare the findings of the scans done on the beta-blocker consumption course and after discontinuation of this medications. Materials and Methods Thirty patients with probably CAD and abnormal myocardial perfusion scans (presence of reversible defect), who had been treated with beta-blockers for at least 3 months, were studied. Dipyridamole stress phase of myocardial perfusion single-photon emission computed tomography (SPECT) was performed two times with an interval of about 1 week, once after discontinuation of all antianginal and anti-ischemic medications, statins, and beta-blockers for 72 hours prior to the study, and again after discontinuation of all these medications except for beta-blockers. Imaging was done with the same protocol, radiopharmaceutical dose, and imaging parameters. Summed stress score (SSS), summed stress rest, and summed difference scores (SDS), total perfusion deficit (TPD), severity, and extension of myocardial perfusion defects in three coronary artery territories were analyzed, using quantitative perfusion SPECT software. Results Most variables such as SSS, SDS, TPD, severity, and extension of defects showed a significant difference between the two conditions including beta-blocker consumption and after discontinuing beta-blocker consumption before stress imaging (p < 0.05). Moreover, in patients on treatment with metoprolol, all studied factors including SSS, SDS, TPD, severity, and extension of perfusion defects were significantly reduced when patients consumed beta-blockers before SPECT evaluation (p < 0.05). Conclusion Beta-blocker consumption can lead to a decrease in the severity and extent of myocardial perfusion defects and therefore probably a decrease in the sensitivity of myocardial scans. Discontinuation of beta-blocker prior to the dipyridamole myocardial perfusion scan can improve diagnostic accuracy. [ABSTRACT FROM AUTHOR]

The mechanisms of adenosine and specific adenosine receptor subtypes in promoting penile rehabilitation remain unclear. Single‐cell RNA sequencing of human corpus cavernosum, adenosine deaminase (ADA) and adenosine receptors knock‐out mice (ADA−/−, A1−/−, A2a−/−, A2b−/−, and A3−/−), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine‐induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age‐related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus‐induced ED. In single‐cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, A2b receptor knock‐out abolishes adenosine‐induced erection but not that of A1, A2a, or A3 receptor. Under hypoxic conditions in vitro, activating the A2b receptor increases HIF‐1α and decreases PDE5 expression. In refractory ED models, activating the A2b receptor with Bay 60–6583 improves erectile function and down‐regulates HIF‐1α and TGF‐β. Administering Dipyridamole (40 mg Kg−1) to BCNC rats improve penile adenosine levels and erectile function. Our study reveals that the A2b receptor mediates adenosine‐induced penile erection. Activating the A2b receptor promotes penile rehabilitation of refractory ED by alleviating hypoxia and fibrosis. [ABSTRACT FROM AUTHOR]

In a double‐blind, randomized controlled trial, we investigated the effectiveness of adding antiplatelet drugs to up‐dosing antihistamines for the treatment of chronic spontaneous urticaria (CSU) in patients with elevated D‐dimer levels who had an inadequate response to conventional antihistamine doses. Twenty patients with Urticaria Activity Score over 7 days (UAS7) ≥16 and D‐dimer >500 ng/mL were randomized to receive either antiplatelet therapy (cilostazol 150 mg/day + dipyridamole 50 mg/day) with antihistamine (desloratadine 20 mg/day) or antihistamine alone for 4 weeks. The antiplatelet group demonstrated a greater decrease in UAS7 compared to the control group (28.10 to 8.90 vs. 22.90 to 16.40, p < 0.001 vs. p = 0.054). Both groups experienced improved quality of life (DLQI), but the improvement was greater in the antiplatelet group (p = 0.046). D‐dimer levels decreased only in the antiplatelet group (1133.67 ng/mL to 581.89 ng/mL, p = 0.013) with no significant change observed in the control group. This suggests that combining dipyridamole and cilostazol with up‐dosing antihistamines may be more effective for CSU patients with high D‐dimer levels compared to up‐dosing antihistamines alone. This could be due to a reduction in platelet activation, as evidenced by the decrease in D‐dimer levels observed in the antiplatelet group. [ABSTRACT FROM AUTHOR]

Introduction. In recent years, the incidence of pediatric nephrotic syndrome (NS) has been increasing, and timely and effective treatment is critical to protect the health of children with NS. This study is an attempt to compare the therapeutic effects of prednisone (Pred) plus dipyridamole (DIP) versus Pred plus valsartan (VAL) on pediatric NS. Methods. Two hundred pediatric cases of NS were selected as the research participants, including 109 cases (group A) receiving Pred + DIP and 91 cases (group B) receiving Pred + VAL. The clinical efficacy, adverse reactions, and renal, coagulation functions and blood lipid levels, as well as the pre- and post-treatment levels of inflammatory factors (IFs) and immunoglobulins (Igs) were comparatively analyzed. Results. No statistically significant differences were found between groups in terms of clinical efficacy, incidence of adverse reactions and renal function (P > .05). After receiving the corresponding treatment, group A showed better coagulation and immune functions than group B, but higher levels of IFs and poorer blood lipid function (P < .05). Conclusion. Both Pred + DIP and Pred + VAL combination therapies can be used for the treatment of pediatric NS, with the former contributing to more obviously enhanced coagulation and immune functions, and the latter leading to more significantly inhibited inflammation and better regulated blood lipid function. [ABSTRACT FROM AUTHOR]

Introduction: Ischemic etiology accounts for two thirds of all strokes in which platelet activation and aggregation play a major role. A variety of antiplatelet therapies have been tested for primary, secondary, and tertiary prevention, with certain patient subtypes benefiting more than others from a specific regimen. Areas covered: This review aims at synthetizing current evidence on pharmacology of antiplatelet agents approved for primary, secondary, and tertiary stroke prevention and their application among possible patient subtypes that may benefit more from their administration. Expert opinion: Management of ischemic stroke has largely evolved over the past decades. A better understanding of stroke pathophysiology has allowed to identify patients who can benefit most from antiplatelet therapies, with varying degrees of benefit depending on whether these agents are being used for primary, secondary, or tertiary prevention. Importantly, the antiplatelet treatment regimens currently available have expanded and no longer limited to aspirin but include other drugs such as P2Y12 and phosphodiesterase inhibitors, also used in combination, as well as precision medicine approaches using genetic testing aiming at optimizing the safety and efficacy in this population. [ABSTRACT FROM AUTHOR]

This systematic review investigates the diagnostic and prognostic utility of coronary flow reserve (CFR) assessment through echocardiography in patients with left bundle branch block (LBBB), a condition known to complicate the clinical evaluation of coronary artery disease (CAD). The literature search was performed on PubMed, EMBASE, Web of Science, Scopus, and Google Scholar, was guided by PRISMA standards up to March 2024, and yielded six observational studies that met inclusion criteria. These studies involved a diverse population of patients with LBBB, employing echocardiographic protocols to clarify the impact of LBBB on coronary flow dynamics. The findings emphasize the importance of CFR in stratifying cardiovascular risk and guiding clinical decision‐making in patients with LBBB. Pooled results reveal that patients with LBBB and significant left anterior descending (LAD) artery stenosis exhibited a marked decrease in stress‐peak diastolic velocity (MD = ‐19.03 [‐23.58; ‐14.48] cm/s; p <.0001) and CFR (MD = ‐.60 [‐.71; ‐.50]; p <.0001), compared to those without significant LAD lesions, suggesting the efficacy of stress echocardiography CFR assessment in the identification of clinically significant CAD among the LBBB population. This review highlights the clinical relevance of echocardiography CFR assessment as a noninvasive tool for evaluating CAD and stratifying risk in the presence of LBBB and underscores the need for standardized protocols in CFR measurement. [ABSTRACT FROM AUTHOR]

This study explores developing and optimizing a nanoemulsion (NE) system loaded with dipyridamole and roflumilast, aiming to improve skin penetration and retention. The NE formulation was further transformed into a nanoemulgel to enhance its application as a topical treatment for psoriasis. Solubility studies were conducted to select the oil, surfactant, and co-surfactant. Phase diagrams were constructed using the aqueous phase titration method. All the formulations were in nanoscale, and Formula (F2) (which contains oleic acid oil as the oil phase, a mixture of Surfactant Tween 80 and co-surfactant (ethanol) at a ratio of 1:2 in addition to distilled water as an aqueous phase in a ratio of 1:5:4, respectively) was the selected formula depending on the particle size, PDI, and zeta potential. Formula (F2) has the best ratio because it gives the smallest nanoemulsion globule size (particle size average of 167.1 nm), the best homogenicity (lowest PDI of 0.195), and the highest stability (higher zeta potential of −32.22). The selected formula was converted into a nanoemulgel by the addition of 0.5% (w/w) xanthan gum (average particle size of 172.7 nm) and the best homogenicity (lowest PDI of 0.121%) and highest stability (higher zeta potential of −28.31). In conclusion, the selected formula has accepted physical and chemical properties, which enhanced skin penetration. [ABSTRACT FROM AUTHOR]

Bone regeneration remains a significant clinical challenge, often necessitating surgical approaches when healing bone defects and fracture nonunions. Within this context, the modulation of adenosine signaling pathways has emerged as a promising therapeutic option, encouraging osteoblast activation and tempering osteoclast differentiation. A literature review of the PubMed database with relevant keywords was conducted. The search criteria involved in vitro or in vivo models, with clear methodological descriptions. Only studies that included the use of indirect adenosine agonists, looking at the effects of bone regeneration, were considered relevant according to the eligibility criteria. A total of 29 articles were identified which met the inclusion and exclusion criteria, and they were reviewed to highlight the preclinical translation of adenosine agonists. While preclinical studies demonstrate the therapeutic potential of adenosine signaling in bone regeneration, its clinical application remains unrealized, underscoring the need for further clinical trials. To date, only large, preclinical animal models using indirect adenosine agonists have been successful in stimulating bone regeneration. The adenosine receptors (A1, A2A, A2B, and A3) stimulate various pathways, inducing different cellular responses. Specifically, indirect adenosine agonists act to increase the extracellular concentration of adenosine, subsequently agonizing the respective adenosine receptors. The agonism of each receptor is dependent on its expression on the cell surface, the extracellular concentration of adenosine, and its affinity for adenosine. This comprehensive review analyzed the multitude of indirect agonists currently being studied preclinically for bone regeneration, discussing the mechanisms of each agonist, their cellular responses in vitro, and their effects on bone formation in vivo. [ABSTRACT FROM AUTHOR]

BACKGROUND: There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review. METHODS: We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents. RESULTS: Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties. DISCUSSION: Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication.

Objective: To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development. Methods: GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (Cmax) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model. Results: GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, Cmax, and AUC from the clinical studies. Conclusions: This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models. [ABSTRACT FROM AUTHOR]

Glycophorin A and glycophorin B are structural membrane glycoproteins bound in the band 3 multiprotein complexes on human red blood cells (RBCs). Band 3 is an erythroid-specific anion exchanger (AE1). AE1-mediated HCO3− transport provides the substrate for the enzyme-catalyzed conversion HCO3− (aq) # CO2(g), which takes place inside the RBCs. Bicarbonate transport via AE1 supports intravascular acid–base homeostasis and respiratory excretion of CO2. In the past decade, we conducted several comparative physiology studies on Taiwanese people having the glycophorin variant GPMur RBC type (which accompanies greater AE1 expression). We found that increased anion transport across the erythrocyte membrane not only enhances gas exchange and lung functions but also elevates blood pressure (BP) and reduces nitric oxide (NO)- dependent vasodilation and exhaled NO fraction (FeNO) in healthy individuals with GP.Mur. Notably, in people carrying the GPMur blood type, the BP and NO-dependent, flow-mediated vasodilation (FMD) are both more strongly correlated with individual hemoglobin (Hb) levels. As blood NO and nitrite (NO2− ) are predominantly scavenged by intraerythrocytic Hb, and NO2− primarily enters RBCs via AE1, could a more monoanion-permeable RBC membrane (i.e., GPMur/ increased AE1) enhance NO2− /NO3− permeability and Hb scavenging of NO2− and NO to affect blood pressure? In this perspective, a working model is proposed for the potential role of AE1 in intravascular NO availability, blood pressure, and clinical relevance. [ABSTRACT FROM AUTHOR]

Aims To assess the potential association of reversible ischaemia and Doppler coronary flow velocity reserve in the left anterior descending coronary artery (CFVR-LAD) during stress echocardiography (SE) with all-cause mortality and non-fatal myocardial infarction (MI), after correction for anatomic coronary artery disease (CAD) burden and other significant clinical variables. Methods and results We selected 3191 patients (mean age 66 ± 12 years) from our multicentre SE registry, who underwent both high-dose dipyridamole SE (comprehensive of CFVR-LAD measurement) and coronary angiography within 2 months. All-cause mortality and non-fatal MI were the primary end points. The association of the primary end point with ischaemia severity and CFVR-LAD was assessed, after multivariable adjustment for all other significant clinical and imaging variables, including anatomic CAD severity by the modified Duke Prognostic Index. The primary end point occurred in 767 (24%) patients (death in 409 and non-fatal MI in 375 patients) during a median follow-up of 42 months. Multivariable Cox regression analyses indicated that, among other significant variables, anatomic CAD severity, reversible ischaemia, and CFVR-LAD were all independently associated with the primary end point; reversible ischaemia was also associated with subsequent MI, while CFVR-LAD with mortality, independent of anatomic CAD severity. Conclusion Our study suggests that reversible ischaemia by wall motion assessment and CFVR-LAD on dipyridamole SE are independently associated with dismal outcome in patients with suspected or known stable CAD, even after accounting for angiographic anatomic CAD severity and also independently from which coronary artery is diseased. [ABSTRACT FROM AUTHOR]

White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether dipyridamole could alleviate WMLs by regulating the phenotype of disease-associated microglia (DAM) through equilibrative nucleoside transporter 2 (ENT2) and adenosine A2A receptor (Adora2a) and to clarify the underlying molecular mechanisms. CCH rat models were constructed to mimic VaD. Morris water maze and Luxol Fast Blue staining were employed to assess cognitive function and quantify the severity of WMLs, respectively. Immunofluorescent staining was performed to analyze the activation of glial cells and the phenotypic transformation of DAM. Additionally, levels of ENT2, proteins in the NF-κB and ERK1/2 pathways and inflammatory cytokines were detected. The results indicated that dipyridamole diminished the activation and proliferation of microglia and astrocytes, increased the expression of myelin basic protein and ameliorated WMLs and cognitive decline in CCH rats. Further study revealed that dipyridamole decreased the expression of ENT2 and inhibited the activation of ERK1/2 and NF-κB signaling pathways, which ultimately converted DAM to anti-inflammatory phenotype and suppressed the levels of TNF-α, IL-1β, IL-6 in WMLs. However, Adora2a inhibitor (SCH58261) attenuated above effects. Our study demonstrates that dipyridamole facilitates the conversion of DAM to the anti-inflammatory phenotype through ENT2/Adora2a pathway and inhibits the activation of ERK1/2 and NF-κB signaling pathways, thereby alleviating neuroinflammation in WMLs. The current findings establish the basis for using dipyridamole to treat VaD. [ABSTRACT FROM AUTHOR]

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility. [ABSTRACT FROM AUTHOR]

Abstract The mechanisms of adenosine and specific adenosine receptor subtypes in promoting penile rehabilitation remain unclear. Single‐cell RNA sequencing of human corpus cavernosum, adenosine deaminase (ADA) and adenosine receptors knock‐out mice (ADA−/−, A1−/−, A2a−/−, A2b−/−, and A3−/−), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine‐induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age‐related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus‐induced ED. In single‐cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, A2b receptor knock‐out abolishes adenosine‐induced erection but not that of A1, A2a, or A3 receptor. Under hypoxic conditions in vitro, activating the A2b receptor increases HIF‐1α and decreases PDE5 expression. In refractory ED models, activating the A2b receptor with Bay 60–6583 improves erectile function and down‐regulates HIF‐1α and TGF‐β. Administering Dipyridamole (40 mg Kg−1) to BCNC rats improve penile adenosine levels and erectile function. Our study reveals that the A2b receptor mediates adenosine‐induced penile erection. Activating the A2b receptor promotes penile rehabilitation of refractory ED by alleviating hypoxia and fibrosis.

Antiplatelet therapy is one of the mainstays for secondary stroke prevention. This narrative review aimed to highlight the current evidence and recommendations of antiplatelet therapy for stroke prevention.We conducted advanced literature search for antiplatelet therapy. Landmark studies and randomised controlled trials evaluating antiplatelet therapy for secondary stroke prevention are reviewed. Results from Cochrane systematic review, pooled data analysis and meta-analysis are discussed.Single-antiplatelet therapy (SAPT) with aspirin, aspirin/extended-release dipyridamole or clopidogrel reduces the risk of recurrent ischaemic stroke in patients with non-cardioembolic ischaemic stroke or transient ischaemic attack (TIA). Dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel or ticagrelor for 21-30 days is more effective than SAPT in patients with minor acute noncardioembolic ischaemic stroke or high-risk TIA. Prolonged use of DAPT is associated with higher risk of haemorrhage without reduction in stroke recurrence than SAPT. Compared with placebo, aspirin reduces the relative risk of recurrent stroke by approximately 22%. Aspirin/dipyridamole and cilostazol are superior to aspirin but associated with significant side effects. Cilostazol or ticagrelor might be more effective than aspirin or clopidogrel in patients with intracranial stenosis.SAPT is indicated for secondary stroke prevention in patients with non-cardioembolic ischaemic stroke or TIA. DAPT with aspirin and clopidogrel or ticagrelor for 21-30 days followed by SAPT is recommended for patients with minor acute noncardioembolic stroke or high-risk TIA. Selection of appropriate antiplatelet therapy should also be based on compliance, drug tolerance or resistance.

Transient global amnesia (TGA) is a rare symptom complex characterized by a brief episode of severe fixation, anterograde and retrograde amnesia. The prevalence of TGA increases with age. Risk factors for this disease include physical overexertion, severe emotional stress, exposure to cold or hot water, hypothermia and pain. The diagnosis of TGA is based on the Kaplan and Hodges–Warlow criteria, according to which TGA is characterized by: complete resolution of mnestic disturbances within 24 hours; absence of other neurological and cognitive impairments; absence of previous head trauma or seizures. In cases where the clinical picture of TGA does not meet the criteria for the disease, a differential diagnosis should be performed, especially with cases of ischemic stroke in the vertebrobasilar region and transient epileptic amnesia. If acute ischemia is confirmed by the brain MRI results, further comprehensive diagnostic investigation must be performed to determine the subtype of acute cerebrovascular accident with further appropriate secondary prevention of cardiovascular complications. If a non-cardioembolic stroke type is identified, antiplatelet therapy has a crucial role. The clinical case of a patient with a left-sided hippocampal infarction clinically manifested by a TGA is presented.

A new molecularly imprinted polymer (MIP)-based disposable electrochemical sensor for dipyridamole (DIP) determination was obtained. The sensor was rapidly prepared by potentiodynamic electrochemical polymerization on a pencil graphite electrode (PGE) using curcumin (CUR) as a functional monomer and DIP as a template molecule. After the optimization of the conditions (pH, monomer–template ratio, scan rate, number of cyclic voltammetric cycles applied in the electro-polymerization process and extraction time of the template molecule) for MIP formation, DIP voltammetric behavior at the modified electrode (MIP_PGE) was investigated. DIP oxidation took place in a pH-dependent, irreversible mixed diffusion-adsorption controlled process. Differential pulse voltammetry (DPV) and adsorptive stripping differential pulse voltammetry (AdSDPV) were used to quantify DIP from pharmaceutical and tap water samples. Under optimized conditions (Britton–Robinson buffer at pH = 3.29), the obtained linear ranges were 5.00 × 10−8–1.00 × 10−5 mol/L and 5.00 × 10−9–1.00 × 10−7 mol/L DIP for DPV and AdSDPV, respectively. The limits of detection of the methods were 1.47 × 10−8 mol/L for DPV and 3.96 × 10−9 mol/L DIP for AdSDPV.

Introduction: Myocardial perfusion imaging (MPI) with pharmacologic stress is a useful technique for evaluation of suspected coronary artery disease (CAD). Heart rate responses (HRR) to vasodilators such as dipyridamole mirror autonomic activity and may provide important prognostic information in CAD patients. In this study, the impact of baseline characteristics of patients including age and gender on the expected HRR has been assessed. Methods: This retrospective study included database of 2584 patients (1575 female, 1009 male) who were referred to the nuclear medicine department for pharmacologic MPI. The HRR to dipyridamole was calculated as ratio of maximal heart rate (HR) during or shortly after dipyridamole infusion to baseline HR. The association of HRR with age, gender, presence of other known CAD risk factors and perfusion findings was evaluated. Results: Significant correlation was found between HRR and sex, age, diabetes mellitus (DM), hypertension (HTN), and chronic kidney disease (CKD) (P < 0.001) in both univariate and multivariate analysis. The mean HRR was also significantly higher in patients with normal perfusion on SPECT MPI as compared to patients with abnormal findings, however, multivariate regression analysis showed no significant correlation. In the subgroup of patients with no CAD risk factors, HRR was significantly higher in women under age 55 years. Conclusion: The HRR during dipyridamole infusion depends on age and gender, irrespective of presence of other CAD risk factors and should be considered in the interpretation of. Besides, DM, HTN and CKD are also correlated with lower HRR to dipyridamole stress. [ABSTRACT FROM AUTHOR]

Introduction: Helicobacter pylori is a risk factor for the development of peptic ulcers with autophagy dysfunction. Omeprazole was widely known as the first-line regimen for H. pylori-associated gastritis. Objectives: The objective of this work was to assess the role of omeprazole on cell pyroptosis and autophagy. Methods: The clinical samples were collected. Quantitative polymerase chain reaction, western blotting, enzyme linked immunosorbent assay, and immunofluorescence (IF) analysis were conducted to reveal the mechanism of omeprazole on cell pyroptosis and autophagy. Results: The results revealed that omeprazole could decrease cell pyroptosis, which was attributed to the downregulation of cleaved caspase-1 expression, resulting in the inhibition of gasdermin E and interleukin-18/1β maturation and secretion as well as the resolution of inflammation. Mechanistically, omeprazole treatment led to drastic downregulation of mammalian target of rapamycin (mTOR) activity was observed in BGC823 cells, leading to enhanced autophagy characterized by increased LC3II expression, which further reduced cell pyroptosis. This omeprazole-mediated phenomenon was enhanced after phosphodiesterase-4 (PDE4) inhibitor dipyridamole (DIP) treatment. In addition, activation of mTOR by MHY1485 could rescue the suppression of cell pyroptosis induced by omeprazole. Most importantly, IF analysis suggested that phosphorylation of mTOR and PDE4 activity and caspase-1 were enhanced in H. pylori-infected gastric mucosa. Conclusion: These findings indicate that omeprazole suppresses cell pyroptosis through PDE4-mediated autophagy in gastric epithelial cells, and DIP enhanced the omeprazole-mediated inhibition of cell pyroptosis, implying that DIP is an alternative combined therapy strategy in improving the treatment of patients with H. pylori infection. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the effect of tartaric acid on the maintenance of dipyridamole supersaturation using Eudragit E100 as a carrier. Methods: The solubility of dipyridamole was determined in a buffer solution (pH = 6.8) containing Eudragit E100 and various concentrations of tartaric acid. Dissolution tests were conducted using a pH-shift method, transitioning from an acidic solution (pH = 1.2) to a buffer solution (pH = 6.8). The drug concentration in the buffer solution was measured to assess drug supersaturation. The dissolution behavior of binary and ternary combinations of dipyridamole, Eudragit E100, and tartaric acid was evaluated and compared. The interference of tartaric acid in the interaction between Eudragit E100 and dipyridamole was assessed using FT-IR and nuclear magnetic resonance (NMR) techniques. Results: The addition of tartaric acid to Eudragit E100 exhibited a strong synergistic effect in stabilizing the supersaturation of dipyridamole. The results demonstrated that tartaric acid, by lowering the pH, increased the affinity of Eudragit E100 for dipyridamole, thereby enhancing its ability to maintain drug supersaturation. Conclusion: The presence of acidifiers such as tartaric acid significantly improved the maintenance of drug supersaturation by Eudragit E100 due to the synergistic effect between Eudragit E100 and the acidifier. [ABSTRACT FROM AUTHOR]

Objective: Most studies regarding acidifiers focused on their role in improving the dissolution performance of a drug by altering the pH of the microenvironment. However, in the current research work, the impact of four different acidifiers (citric acid, tartaric acid, succinic acid, adipic acid) on the pH-induced precipitation behavior of dipyridamole, a model weakly basic drug, in the bulk dissolution medium with respect to improving the dissolution performance of the drug was studied. Methods: The dipyridamole-acidifier formulations were prepared by using the rotary evaporation method. To study the dissolution behavior of the formulations, a pH-shift dissolution test from pH 1.2 to neutral pH 6.8 to simulate normal pH condition of the gastrointestinal tract, and the direct dissolution test at pH 6.8 to simulate an increased pH of the stomach was conducted. Results: In the pH-shift-based dissolution test, for all formulations containing acidifiers, the improved concentration of dipyridamole was observed proportional to the precipitation inhibitory effect of acidifies. In the direct dissolution test, the incorporation of acidifiers in formulations improved the dissolution performance of dipyridamole, dependent on the type of acidifier. Conclusion: From these results, the formulation of a weakly basic drug with an appropriate acidifier, as a simple way, appears to be a promising technique to enhance the dissolution performance of the drugs with less dependency on stomach pH. [ABSTRACT FROM AUTHOR]

Glycophorin A and glycophorin B are structural membrane glycoproteins bound in the band 3 multiprotein complexes on human red blood cells (RBCs). Band 3 is an erythroid-specific anion exchanger (AE1). AE1-mediated HCO3− transport provides the substrate for the enzyme-catalyzed conversion HCO3−(aq) ⇌ CO2(g), which takes place inside the RBCs. Bicarbonate transport via AE1 supports intravascular acid–base homeostasis and respiratory excretion of CO2. In the past decade, we conducted several comparative physiology studies on Taiwanese people having the glycophorin variant GPMur RBC type (which accompanies greater AE1 expression). We found that increased anion transport across the erythrocyte membrane not only enhances gas exchange and lung functions but also elevates blood pressure (BP) and reduces nitric oxide (NO)-dependent vasodilation and exhaled NO fraction (FeNO) in healthy individuals with GP.Mur. Notably, in people carrying the GPMur blood type, the BP and NO-dependent, flow-mediated vasodilation (FMD) are both more strongly correlated with individual hemoglobin (Hb) levels. As blood NO and nitrite (NO2−) are predominantly scavenged by intraerythrocytic Hb, and NO2− primarily enters RBCs via AE1, could a more monoanion-permeable RBC membrane (i.e., GPMur/increased AE1) enhance NO2−/NO3− permeability and Hb scavenging of NO2− and NO to affect blood pressure? In this perspective, a working model is proposed for the potential role of AE1 in intravascular NO availability, blood pressure, and clinical relevance.

This study explores developing and optimizing a nanoemulsion (NE) system loaded with dipyridamole and roflumilast, aiming to improve skin penetration and retention. The NE formulation was further transformed into a nanoemulgel to enhance its application as a topical treatment for psoriasis. Solubility studies were conducted to select the oil, surfactant, and co-surfactant. Phase diagrams were constructed using the aqueous phase titration method. All the formulations were in nanoscale, and Formula (F2) (which contains oleic acid oil as the oil phase, a mixture of Surfactant Tween 80 and co-surfactant (ethanol) at a ratio of 1:2 in addition to distilled water as an aqueous phase in a ratio of 1:5:4, respectively) was the selected formula depending on the particle size, PDI, and zeta potential. Formula (F2) has the best ratio because it gives the smallest nanoemulsion globule size (particle size average of 167.1 nm), the best homogenicity (lowest PDI of 0.195), and the highest stability (higher zeta potential of −32.22). The selected formula was converted into a nanoemulgel by the addition of 0.5% (w/w) xanthan gum (average particle size of 172.7 nm) and the best homogenicity (lowest PDI of 0.121%) and highest stability (higher zeta potential of −28.31). In conclusion, the selected formula has accepted physical and chemical properties, which enhanced skin penetration.

Stroke is second to third most common cause of death in the population and the leading cause of disability. More than 12 million strokes are registered annually in the world. Cognitive impairments (CI) significantly contribute to the disability of patients after a stroke, which limit daily activities no less than movement disorders. The article presents data on the prevalence of post-stroke CI (PSCI), examines the issues of epidemiology, risk factors, the main clinical and pathogenetic data of disorders, the peculiarities of their diagnosis and treatment. The issues of the dipyridamole use for the prevention of stroke and in patients with PSCI are discussed.

Introduction: Antiplatelet drugs (AD) reversibly or irreversibly inhibit activation and platelet aggregation and hence inhibit genesis of thrombus. Methods: In this article, we review the administration of AD in acute stroke management as well as in the primary and secondary prevention of stroke and transient ischemic attack (TIA). Conclusions: For primary stroke prevention of the first ever stroke, aspirin is advised only when a 10-year vascular risk is more than 10%, patient has a likely survival of >10 years and has a low risk for hemorrhage. For patients with acute ischemic stroke (AIS) or TIA administration of aspirin is strongly recommended within 24-48 h of symptom onset. For patients managed with IV thrombolysis, aspirin administration should be deferred for 24 h. For patients with recent minor non cardioembolic AIS and a National Institutes of Health Stroke Scale (NIHSS) score =3 or patients with a high-risk TIA with ABCD2 score =4, dual Antiplatelet therapy with aspirin and clopidogrel should be started within 12-24 h of stroke or TIA onset and definitely within a week of onset and then should be continued for a period of 21-90 days, followed by switching to a single antiplatelet therapy. The US Food and Drug Administration has given approval for Ticagrelor usage to prevent the risk of for stroke recurrence in patients with AIS with a NIHSS score of =5 or high-risk TIA where ticagrelor - Aspirin combination maybe prescribed for 30 days. For patients who are carriers of CYP2C19 a 90-day ticagrelor - Aspirin offers better stroke prevention. ADs in dual combination for short term and single agent in the long term remain the dominant therapy for prevention of non-cardioembolic ischemic stroke. [ABSTRACT FROM AUTHOR]

The article examines the regularities of structure formation of ultrafine fibers based on poly-3-hydroxybutyrat under the influence of technological (electrical conductivity, viscosity), molecular (molecular weight), and external factors (low-molecular and nanodispersed substances of different chemical natures). Systems with polar substances are characterized by the presence of intermolecular interactions and the formation of a more perfect crystalline fiber structure. Changes in technological and molecular characteristics affect the fiber formation process, resulting in alterations in the morphology of the nonwoven fabric, fiber geometry, and supramolecular fiber structure. Polymer molecular weight, electrical conductivity, and solution viscosity influence fiber formation and fiber diameter. The fiber structure is heterogeneous, consisting of both crystalline and non-equilibrium amorphous phases. This article shows that with an increase in the molecular weight and concentration of the polymer, the diameter of the fiber increases. At the same time, the increase in the productivity of the electrospinning process does not affect the fiber geometry. The chemical structure of the solvent and the concentration of polar substances play a decisive role in the formation of fibers of even geometry. As the polarity of the solvent increases, the intermolecular interaction with the polar groups of poly-3-hydroxybutyrate increases. As a result of this interaction, the crystallites are improved, and the amorphous phase of the polymer is compacted. The action of polar molecules on the polymer is similar to the action of polar nanoparticles. They increase crystallinity via a nucleation mechanism. This is significant in the development of matrix-fibrillar systems for drug delivery, bioactive substances, antiseptics, tissue engineering constructs, tissue engineering scaffolds, artificial biodegradable implants, sorbents, and other applications. [ABSTRACT FROM AUTHOR]

Introduction: Sarcopenia is defined as a loss of muscle mass and strength. ATP homeostasis is crucial during myogenesis. We determined how the purinergic system modulates myogenesis using dipyridamole (blocks adenosine taken up by the cells) and tenofovir (inhibits ATP release) in a myoblast cell line. Methods: C2C12 cells were differentiated in the presence/absence of tenofovir/dipyridamole, with/without the A2B selective inhibitor PSB-603. Extra-/intracellular nucleotides were examined via HPLC. The expression of muscle differentiation proteins (Pax7, Mif5, MyoD, MyoG, and MHC), PKA/CREB, adenosine receptors (A1, A2A, A2B, and A3), ATP-channel pannexin-1 and the P2X7 receptor was analyzed via WB and RT-PCR. cAMP and AMPK activation was measured. Results: Tenofovir increased intracellular ATP and reduced extracellular adenosine, decreasing Pax7 expression and increasing MHC expression prematurely. Dipyridamole increased intracellular AMP and extracellular adenosine, counteracting the premature myogenesis promoted by tenofovir. All adenosine receptors were expressed during differentiation with dipyridamole, increasing A2B expression. Tenofovir maintained inactive AMPK and decreased cAMP levels, as well as PKAα and pCREB expression, which were recovered with dipyridamole. Discussion: Adenosine and ATP act as mediators in muscle myogenesis. The blockade of ATP release by tenofovir promotes premature myogenesis, with dipyridamole counteracting the premature differentiation promoted by tenofovir via the adenosine A2B receptor and cAMP/AMPK pathways. Therefore, dipyridamole might be of interest as a therapeutic approach in sarcopenia. [ABSTRACT FROM AUTHOR]

Cerebrovascular disease is one of the most common pathologies in the practice of a neurologist. Vascular cognitive impairment is the earliest and most objective sign of cerebrovascular pathology. The correction of vascular risk factors – antihypertensive, antiplatelet, lipid-lowering therapy, have the leading role in the treatment of patients with cerebrovascular diseases. It is necessary to pay special attention to non-drug methods of therapy, such as quitting smoking and alcohol abuse, regular physical activity. The possibilities of using dipyridamole for symptomatic and pathogenetic therapy are discussed.