Search Results (55)

Introduction: Intermittent claudication, an early symptom of peripheral artery disease, can be treated by cilostazol to alleviate symptoms and improve walking distance. Our previous investigation focused on cilostazol-induced alterations in the thermodynamic properties of plasma, utilizing differential scanning calorimetry (DSC) as a potential monitoring tool. The current proof-of-concept study aimed to enhance the interpretation of DSC data through deconvolution techniques, specifically examining protein transitions within the plasma proteome during cilostazol therapy. Results: Notable differences in thermal unfolding profiles were found between cilostazol-treated patients and healthy controls. The fibrinogen-associated transition exhibited a downward shift in denaturation temperature and decreased enthalpy by the third month. The albumin-related transition shifted to higher temperatures, accompanied by lower enthalpy. Transitions associated with globulins showed changes in thermal stability, while the transferrin-related peak demonstrated increased structural rigidity in treated patients compared to controls. Discussion: These observations suggest that cilostazol induces systemic changes in the thermodynamic behavior of plasma proteins. DSC, when combined with deconvolution methods, presents a promising approach for detecting subtle, therapy-related alterations in plasma protein stability. Materials and methods: Ten patients (median age: 58.6 years) received 100 milligrams of cilostazol twice daily. Blood samples were collected at the baseline and after 2 weeks, 1 month, 2 months, and 3 months of therapy. Walking distances were also assessed. The DSC curves were retrieved from the thermal analysis investigated by deconvolution mathematical methods. Conclusions: Although the exact functional consequences remain unclear, the observed biophysical changes may reflect broader molecular adaptations involving protein–protein interactions, post-translational modifications, or acute phase response elements. Full article

Background: Since clazosentan was approved for insurance coverage in Japan, the postoperative management of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has changed as each facility gains experience. Here, we investigate the prevention, treatment, and management of DCI after SAH throughout Japan in 2023. Methods: In 2024, we conducted an anonymous questionnaire survey—emailed to certified neurosurgeons in hospitals across Japan—regarding management for preventing DCI after aneurysmal SAH. Of them, 78 hospitals responded and were included in this study. These results were compared with the findings of a survey conducted prior to the approval of clazosentan in Japan (2022). Results: The proportion of institutions with a standardized protocol for DCI after aneurysmal SAH at a level of ≥50% was 93.0%. For both craniotomy and endovascular surgery, clazosentan was used most frequently, followed by cilostazol, fasudil, and statins. The most common drug for both direct and endovascular procedures was clazosentan. The predominant reason for discontinuing clazosentan was respiratory complications—such as pulmonary edema—followed by cardiac complications. However, 62.1% of facilities felt that the number of cases wherein clazosentan was discontinued was deceasing. While 77.5% of respondents felt that clazosentan was effective for preventing DCI after aneurysmal SAH, only 49.3% felt that it improved outcomes. Conclusions: Since its approval, clazosentan has been the most common treatment for DCI prevention after aneurysmal SAH. The impression of the effectiveness in preventing DCI and the outcomes of clazosentan have been mixed. As data accumulate, clazosentan use and management protocols will be refined and developed. Full article

Background/Objectives: Aneurysmal subarachnoid hemorrhage (aSAH) remains a life-threatening cerebrovascular event with high rates of mortality and long-term morbidity. Among its complications, delayed cerebral ischemia (DCI) is a major contributor to poor clinical outcomes. Although cerebral vasospasm has traditionally been considered the primary mechanism underlying DCI, recent studies have revealed the multifactorial nature of this condition. This review aims to provide a comprehensive overview of the pathophysiology, preventive strategies, and current treatment options for DCI following aSAH. Methods: A narrative literature review was conducted using the PubMed database to identify peer-reviewed articles relevant to the prevention and treatment of DCI following aSAH. The search strategy employed the following terms: (“Subarachnoid Hemorrhage” [MeSH]) AND “Delayed Cerebral Ischemia” AND (“Prevention and Control” [Subheading] OR “Secondary Prevention” [MeSH]). This search strategy was designed to capture studies addressing both pharmacological and non-pharmacological preventive measures for DCI. Results: A comprehensive PubMed search identified a total of 113 relevant articles. Among these, 40 publications primarily addressed pharmacological interventions, while 22 focused on neuromonitoring techniques. An additional 20 articles explored the pathophysiological mechanisms underlying DCI, and 15 involved preclinical studies utilizing animal models. The remaining 16 articles encompassed diverse topics, including prophylactic endovascular therapies, newly proposed definitions of DCI, treatment algorithm development, functional outcome analyses, and entries in clinical trial registries. Emerging evidence highlights that vasospasm alone does not account for all cases of DCI. Pharmacological approaches such as nimodipine, clazosentan, and fasudil have shown varying degrees of efficacy. Circulatory management and removal of subarachnoid hematoma via CSF drainage or thrombolytics may reduce DCI risk, although their impact on long-term neurological outcomes remains controversial. Endovascular therapy and adjunctive agents such as cilostazol or anticoagulants have demonstrated potential but require further validation through large-scale trials. Conclusions: Effective DCI prevention and treatment require a multimodal approach targeting diverse pathological mechanisms beyond vasospasm. Improved risk stratification, early detection, and individualized therapy are essential for advancing the management of patients with aSAH. Full article

Background/Objective: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer’s disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer’s disease. Methods: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin. Results: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin–NFAT pathway, like cyclo-sporine A, providing a potential mechanism. Conclusions: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer’s disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer’s disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration. Full article

Objective: The contralateral hippocampus, a critical region for cognitive function, is often overlooked in everyday clinical practice and stroke research. This study aimed to evaluate the effect of specific antiplatelet agents on the hippocampus (ipsilateral and contralateral) during the hyperacute phase of stroke. Materials and Methods: Twelve-week-old rats were randomly assigned to four groups, each containing six rats: a cilostazol group, an aspirin group, an aspirin plus cilostazol group, and a control group. Each substance was administered for four weeks. Permanent brain ischemia was induced over 2 h using intraluminal middle cerebral artery occlusion. A neurologic examination was conducted, followed by euthanasia and histological examination of the CA1 hippocampal region. The hematoxylin and eosin stain was used to assess the total number of intact neuronal cell bodies and pyknotic nuclei, an indicator of early irreversible neuronal injury. Results: In the ipsilateral hippocampus, monotherapy with either aspirin or cilostazol significantly reduced pyknotic nuclei compared with the control group (p = 0.0016 and p = 0.0165, respectively). However, combination therapy showed no significant difference from the controls (p = 0.2375). In the contralateral hippocampus, cilostazol monotherapy demonstrated significantly reduced pyknotic nuclei (p = 0.0098), whereas aspirin monotherapy and combination therapy did not (p = 0.1009 and p = 0.9999, respectively). A cumulative analysis of both hemispheres revealed that monotherapy with aspirin or cilostazol markedly reduced injury markers (p = 0.0002 and p = 0.0001, respectively), whereas combined therapy revealed no significant benefit (p = 0.1984). A neurological assessment indicated that the most severe deficits were in the combination therapy group. Conclusions: To the best of our knowledge, this is the first study to compare acute histopathological changes in the affected and unaffected hippocampus after a stroke in a rat model. Dual antiplatelet therapy resulted in worse outcomes (histopathological and neurological) than monotherapy. Full article

Background/Objectives: The outcome for aneurysmal subarachnoid hemorrhage (SAH) remains poor, particularly for patients presenting with World Federation of Neurological Surgeons (WFNS) grades IV–V. This study was designed to identify independent prognostic factors in this group of patients with poor-grade SAH. Methods: We prospectively analyzed 357 SAH patients with admission WFNS grades IV–V enrolled in nine primary stroke centers in Mie prefecture, Japan, from 2013 to 2022. This study compared clinical variables, including treatments for angiographic vasospasm and delayed cerebral ischemia (DCI), between patients with favorable (modified Rankin Scale [mRS] scores 0–2) and unfavorable (mRS scores 3–6) outcomes at 90 days post-onset. Multivariate analyses were then performed to identify independent determinants of favorable 90-day outcomes, followed by propensity score matching analyses. Results: The median age was 68 years, and 53.5% of patients had admission WFNS grade V. DCI occurred in 12.9% of patients, and 66.9% had unfavorable outcomes. Independent variables related to unfavorable outcomes were older age, admission WFNS grade V, ventricular drainage, edaravone administration, and delayed cerebral infarction, while those for favorable outcomes were spinal drainage (adjusted odds ratio [aOR] 6.118, 95% confidence interval [CI] 2.687–13.927, p < 0.001), modified Fisher grade 3 (aOR 2.929, 95% CI 1.668–5.143, p < 0.001), and triple prophylactic anti-DCI medication consisting of cilostazol, fasudil hydrochloride and eicosapentaenoic acid (aOR 1.869, 95% CI 1.065–3.279, p = 0.029). Nimodipine is not approved in Japan, and statin and cerebral vasospasm did not influence outcomes. As spinal drainage and the triple prophylactic anti-DCI medication were intervenable variables, propensity score matchings were performed, and they confirmed that both spinal drainage and the triple prophylactic anti-DCI medication were useful to achieve favorable outcomes. Conclusions: In poor-grade SAH, spinal drainage and the triple prophylactic anti-DCI medication may be effective in improving outcomes, possibly by suppressing DCI pathologies other than cerebral vasospasm. Full article

Background and Objectives: Hip surgery is increasingly performed among elderly patients. Oral antithrombotics, which are taken for patients’ underlying diseases, are a main concern regarding perioperative bleeding. Postoperative venous thromboembolism (VTE) is a leading cause of mortality after hip surgery. Therefore, administration of preoperative oral antithrombotics is a double-edged sword in hip surgery. In this study, we examined the correlation between the occurrence of postoperative VTE and the type of oral antithrombotics administered preoperatively. Materials and Methods: We analyzed the medical records of 601 patients aged 19 and over who underwent hip surgery from January 2021 to June 2023. The patients were assigned to two groups as follows: Groups VTE+ (patients who developed postoperative VTE) and VTE- (patients who did not develop postoperative VTE), respectively. Results: Of the 139 patients who had been taking oral antithrombotics for 6 months or more, 24 were allocated to group VTE+ and 115 to group VTE-, respectively. The number of patients who took clopidogrel and cilostazol was significantly higher in groups VTE- and VTE+, respectively (12.5 vs. 33.9%, p = 0.038, odds ratio (OR) = 0.278, 95% confidence interval (CI) = 0.078–0.991; 20.8 vs. 5.2%, p = 0.010, 95% CI = 1.325–17.245; group VTE+ vs. group VTE-). Preoperative albumin levels were significantly lower in group VTE+ (3.4 ± 0.6 g/dL vs. 3.7 ± 0.4 g/dL, p = 0.004, OR = 0.285, 95% CI = 0.115–0.702). In multivariate regression analysis, the results were statistically significant for clopidogrel, cilostazol, and preoperative albumin levels (p = 0.035, OR = 0.237, 95% CI = 0.062–0.901; p = 0.011, OR = 6.479, 95% CI = 1.542–27.226; p = 0.002, OR = 0.211, 95% CI = 0.080–0.558). Conclusions: Among the patients who had been taking oral antithrombotics for ≥6 months, clopidogrel had a prophylactic effect, but cilostazol showed an aggravating effect on postoperative VTE in hip surgery. Preoperative hypoalbuminemia increases the risk of postoperative VTE in hip surgery. Full article

Impaired function of Polymerase-γ (Pol-γ) results in impaired replication of the mitochondrial genome (mtDNA). Pathogenic mutations in the POLG gene cause dysfunctional Pol-γ and dysfunctional mitochondria and are associated with a spectrum of neurogenetic disorders referred to as POLG spectrum disorders (POLG-SDs), which are characterized by neurologic dysfunction and premature death. Pathomechanistic studies and human cell models of these diseases are scarce. SH-SY5Y cells (SHC) are an easy-to-handle and low-cost human-derived neuronal cell model commonly used in neuroscientific research. Here, we aimed to study the effect of reduced Pol-γ function using stable lentivirus-based shRNA-mediated knockdown of POLG in SHC, in both the proliferating cells and SHC-derived neurons. POLG knockdown resulted in approximately 50% reductions in POLG mRNA and protein levels in naïve SHC, mimicking the residual Pol-γ activity observed in patients with common pathogenic POLG mutations. Knockdown cells exhibited decreased mtDNA content, reduced levels of mitochondrial-encoded proteins, and altered mitochondrial morphology and distribution. Notably, while chemical induction of mtDNA depletion via ddC could be rescued by the mitochondrial biosynthesis stimulators AICAR, cilostazol and resveratrol (but not MitoQ and formoterol) in control cells, POLG-knockdown cells were resistant to mitochondrial biosynthesis-mediated induction of mtDNA increase, highlighting the specificity of the model, and pathomechanistically hinting towards inefficiency of mitochondrial stimulation without sufficient Pol-γ activity. In differentiated SHC-derived human neurons, POLG-knockdown cells showed impaired neuronal differentiation capacity, disrupted cytoskeletal organization, and abnormal perinuclear clustering of mitochondria. In sum, our model not only recapitulates key features of POLG-SDs such as impaired mtDNA content, which cannot be rescued by mitochondrial biosynthesis stimulation, but also reduced ATP production, perinuclear clustering of mitochondria and impaired neuronal differentiation. It also offers a simple, cost-effective and human (and, as such, disease-relevant) platform for investigating disease mechanisms, one with screening potential for therapeutic approaches for POLG-related mitochondrial dysfunction in human neurons. Full article

Cilostazol (CIL), a BCS class II antiplatelet aggregation and vasodilator agent, is used for cerebrovascular diseases to minimize blood–brain barrier dysfunction, white matter-lesion formation, and motor deficits. The current work aimed to develop and optimize cilostazol-loaded spanlastics (CIL-SPA) for nose-to-brain delivery to overcome the low solubility and absorption, the first pass-metabolism, and the adverse effects. The optimal CIL-SPA formulation was loaded into Phytagel^® (SPA-PG), Poloxamer-407 (SPA-P407), and chitosan (SPA-CS) gel bases and characterized in terms of colloidal properties, encapsulation efficiency (EE%), mucoadhesive properties, and biopharmaceutical aspects. The developed in situ gelling formulations showed a <300 nm average hydrodynamic diameter, <0.5 polydispersity index, and >|±30| mV zeta potential with a high EE% (>99%). All formulations met the droplet size-distribution criteria of nasal requirements (<200 µm), and all formulations showed adequate mucoadhesion properties. Both the BBB-PAMPA and horizontal permeability study through an artificial membrane revealed that all formulations had higher CIL flux and cumulative permeability at in vitro nose-to-brain conditions compared to the initial CIL. The in vitro drug-release study showed that all formulations released ca. 100% of CIL after 2 h. Therefore, the developed formulations could be promising for improving the low bioavailability of CIL through nose-to-brain delivery. Full article

Objective: Peripheral artery disease (PAD) is a prevalent vascular condition characterized by arterial narrowing, which impairs blood flow and manifests as intermittent claudication, a pain or cramping sensation induced by physical activity or ambulation. Walking distance is a crucial clinical indicator of peripheral artery disease, and it correlates with the disease severity and risk of mortality. It reflects the severity of the disease, with reduced mobility indicating an increased risk of morbidity. It can also inform on the efficacy of the treatment. Cilostazol, a phosphodiesterase III inhibitor, has been demonstrated to enhance walking distance in patients with peripheral artery disease through the dilation of blood vessels and the inhibition of platelet aggregation. With this preliminary study, we aimed to elucidate other possible effects of cilostazol, specifically its influence on the structural properties of red blood cells. Methods: 10 patients (5 men, 5 women) with PAD were treated with cilostazol over a three-month period. Its biochemical effects on RBCs were determined using differential scanning calorimetry (DSC). Patient’s blood samples were collected at the start of treatment, then after two weeks, one month, two months, and three months of therapy. Results: The DSC analysis revealed shifts in thermal properties, including change in peak (melting or denaturation) temperature (T_p) and calorimetric enthalpy (ΔH_cal), which indicate significant structural changes in red blood cells. These thermal property changes correlated with clinical improvements in walking distance reported by patients. Conclusions: Our findings suggest that cilostazol induces substantial biochemical modifications in red blood cells, enhancing their functional properties and contributing to improved clinical outcomes. This study highlights the potential of differential scanning calorimetry as an adjunctive method for assessing the effectiveness of treatments for peripheral artery disease at the cellular level. However, further investigation with larger patient cohorts is required to confirm these initial results. Full article

Diabetes mellitus (DM) is a global health concern with a rising incidence, particularly in aging populations and those with a genetic predisposition. Over time, DM contributes to various complications, including nephropathy, retinopathy, peripheral arterial disease (PAD), and neuropathy. Among these, diabetic neuropathy and PAD stand out due to their high prevalence and significant impact on patients’ quality of life. Diabetic distal symmetric polyneuropathy, the most common form of diabetic neuropathy, is driven by neuroinflammation stemming from prolonged hyperglycemia. Simultaneously, hyperglycemia significantly increases the risk of PAD, a condition further exacerbated by factors like smoking, age, and sedentary lifestyles. PAD frequently manifests as claudication, a debilitating symptom marked by pain and cramping during physical activity, which limits mobility and worsens patients’ outcomes. Cilostazol, a phosphodiesterase-3 inhibitor, has proven effective in managing intermittent claudication in PAD by improving walking distances and enhancing blood flow. Recent studies have also explored its potential benefits for diabetic neuropathy. Cilostazol’s mechanisms include vasodilation, platelet inhibition, and increased cyclic adenosine monophosphate (cAMP) levels, which may contribute to improved neurological outcomes. However, variability in the clinical evidence due to inconsistent treatment protocols highlights the need for further investigation. This review explores cilostazol’s mechanisms of action and therapeutic applications for managing neuropathy and PAD in diabetic patients, aiming to provide insights into its potential as a dual-purpose pharmacological agent in this high-risk population. Full article

Cilostazol is a phosphodiesterase III inhibitor characterized by poor solubility. This limitation can be overcome by using a drug carrier capable of delivering the drug to the target site. Cyclodextrins are essential as drug carriers because of their outstanding complexation abilities and their capacity to improve drug bioavailability. This study comprises two stages: The first involves verifying different cyclodextrins and their complexation abilities towards cilostazol. This was accomplished using molecular docking simulations (MDS) and density functional theory (DFT). Both techniques indicate that the largest Sulfobutyl Ether-β-Cyclodextrin forms the most stable complex with cilostazol. Additionally, other important parameters of the complex are described, including binding sites, dominant interactions, and thermodynamic parameters such as complexation enthalpy, Gibbs free energy, and Gibbs free energy of solvation. The second stage involves a binding study between cilostazol and Phosphodiesterse3 (PDE3). This study was conducted using molecular docking simulations, and the most important energetic parameters are detailed. This is the first such report, and we believe that the results of our predictions will pave the way for future drug development efforts using cyclodextrin–cilostazol complexes as potential therapeutics. Full article

This study investigated the effects of cilostazol on motor dysfunction, spinal motor neuron abnormalities, and schwannopathy in rats with diabetes. Diabetes mellitus (DM) was induced in rats via femoral intravenous streptozotocin (STZ) injection (60 mg/kg). After successful DM induction, cilostazol was administered on day 15 via oral gavage (100 mg/kg/day) for 6 weeks until sacrifice. Behavioral assays, including motor function, were performed weekly. The sciatic nerve, L5 spinal cord, and spinal ventral root were collected to evaluate the expression of the glial fibrillary acidic protein (GFAP), myelin protein zero (P0), and choline acetyltransferase (ChAT) by immunofluorescence and Western blotting. DM rats displayed decreased running speeds, running distances, and toe spread but increased foot pressure. In addition, loss of non-myelinating Schwann cells and myelin sheaths was observed in the sciatic nerve and L5 spinal ventral root. Reduced numbers of motor neurons were also found in the L5 spinal ventral horn. Cilostazol administration significantly potentiated running speed and distance; increased hind paw toe spread; and decreased foot pressure. In the sciatic nerve and L5 spinal ventral root, cilostazol treatment significantly improved non-myelinated Schwann cells and increased myelin mass. ChAT expression in motor neurons in the spinal ventral horn was improved, but not significantly. Cilostazol administration may protect sensorimotor function in diabetic rats. Full article

Lorlatinib is a pharmaceutical ALK kinase inhibitor used to treat ALK driven non-small cell lung cancers. This paper analyses the intersection of past published data on the physiological consequences of two unrelated drugs from general medical practice—itraconazole and cilostazol—with the pathophysiology of ALK positive non-small cell lung cancer. A conclusion from that data analysis is that adding itraconazole and cilostazol may make lorlatinib more effective. Itraconazole, although marketed worldwide as a generic antifungal drug, also inhibits Hedgehog signaling, Wnt signaling, hepatic CYP3A4, and the p-gp efflux pump. Cilostazol, marketed worldwide as a generic thrombosis preventative drug, acts by inhibiting phosphodiesterase 3, and, by so doing, lowers platelets’ adhesion, thereby partially depriving malignant cells of the many tumor trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by (i) reducing or stopping a Hedgehog-ALK amplifying feedback loop, by (ii) increasing lorlatinib’s brain levels by p-gp inhibition, and by (iii) inhibiting growth drive from Wnt signaling. Cilostazol, surprisingly, carries minimal bleeding risk, lower than that of aspirin. Risk/benefit assessment of the combination of metastatic ALK positive lung cancer being a low-survival disease with the predicted safety of itraconazole-cilostazol augmentation of lorlatinib favors a trial of this drug trio in ALK positive lung cancer. Full article

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal^® SR 200 mg capsules have higher drug release rates than Cilostan^® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC_0-t, and AUC_0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal^® SR 200 mg capsules compared with Cilostan^® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal^® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan^® CR 200 mg tablets. Full article