RESUMO
BACKGROUND: Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat. METHODS: Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age. RESULTS: Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival (P=0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger (P<0.001) and more prompt responses (P<0.01), and less habituation upon repeated stimulation (P<0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles (P=0.015) and an increase in blood flow velocity (P=0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function (P<0.001) in the treated animals. CONCLUSIONS: Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease.
Assuntos
Bloqueadores dos Canais de Cálcio , Doenças de Pequenos Vasos Cerebrais , Cognição , Modelos Animais de Doenças , Nimodipina , Ratos Endogâmicos SHR , Animais , Nimodipina/farmacologia , Nimodipina/uso terapêutico , Masculino , Doenças de Pequenos Vasos Cerebrais/tratamento farmacológico , Ratos , Cognição/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/prevenção & controleRESUMO
This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A microsomal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the concentrations of blonanserin and its metabolite. Compared with wild type CYP34A, the relative clearance of blonanserin by CYP3A4.29 significantly increased to 251.3%, while it decreased notably with CYP3A4.4, 5, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 23, 24, 28, 31, 33, and 34, ranging from 6.09% to 63.34%. Among 153 tested drugs, nimodipine, felodipine, and amlodipine were found to potently inhibit the metabolism of blonanserin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half-maximal inhibitory concentration and enzymatic kinetics assay demonstrated that the metabolism of blonanserin was noncompetitively inhibited by nimodipine in rat liver microsomes and was inhibited in a mixed manner by felodipine and amlodipine in both rat liver microsomes and human liver microsomes. When nimodipine and felodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-∞), and C max of blonanserin increased. When amlodipine and blonanserin were combined, the C max of blonanserin C increased remarkably. The vast majority of CYP3A4 variants have a low ability to catalyze blonanserin. With combined administration of nimodipine, felodipine, and amlodipine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin. SIGNIFICANCE STATEMENT: The enzyme kinetics of novel CYP3A4 enzymes for metabolizing blonanserin were investigated. Clearance of blonanserin by CYP3A4.4, 5, 7-10, 12-14, 16-18, 23-24, 28, 31, 33, and 34 decreased notably, but increased with CYP3A4.29. Additionally, we established a drug interaction spectrum for blonanserin, in which nimodipine, felodipine, and amlodipine kinetics exhibited mixed inhibition. Moreover, their inhibitory potencies decreased with CYP3A4.4 and 5 compared to CYP3A4.1. This study provides essential data for personalized clinical use of blonanserin.
Assuntos
Citocromo P-450 CYP3A , Nimodipina , Humanos , Ratos , Animais , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Nimodipina/metabolismo , Nimodipina/farmacologia , Felodipino/metabolismo , Felodipino/farmacologia , Ratos Sprague-Dawley , Interações Medicamentosas , Anlodipino/metabolismo , Anlodipino/farmacologia , Microssomos Hepáticos/metabolismo , MetabolomaRESUMO
Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.
Assuntos
Bloqueadores dos Canais de Cálcio , Nimodipina , Farmacogenética , Hemorragia Subaracnóidea , Humanos , Nimodipina/administração & dosagem , Nimodipina/efeitos adversos , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/complicações , Pessoa de Meia-Idade , Feminino , Masculino , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Idoso , Farmacogenética/métodos , Resultado do Tratamento , Relação Dose-Resposta a Droga , Adulto , Medicina de Precisão/métodos , Vasoespasmo Intracraniano/tratamento farmacológicoRESUMO
Aging is associated with cognitive decline and memory loss in humans. In rats, aging-associated neuronal excitability changes and impairments in learning have been extensively studied in the hippocampus. Here, we investigated the roles of L-type calcium channels (LTCCs) in the rat piriform cortex (PC), in comparison with those of the hippocampus. We employed spatial and olfactory tasks that involve the hippocampus and PC. LTCC blocker nimodipine administration impaired spontaneous location recognition in adult rats (6-9 months). However, the same blocker rescued the spatial learning deficiency in aged rats (19-23 months). In an odor-associative learning task, infusions of nimodipine into either the PC or dorsal CA1 impaired the ability of adult rats to learn a positive odor association. Again, in contrast, nimodipine rescued odor associative learning in aged rats. Aged CA1 neurons had higher somatic expression of LTCC Cav1.2 subunits, exhibited larger afterhyperpolarization (AHP) and lower excitability compared with adult neurons. In contrast, PC neurons from aged rats showed higher excitability and no difference in AHP. Cav1.2 expression was similar in adult and aged PC somata, but relatively higher in PSD95- puncta in aged dendrites. Our data suggest unique features of aging-associated changes in LTCCs in the PC and hippocampus.
Assuntos
Nimodipina , Córtex Piriforme , Humanos , Ratos , Animais , Idoso , Nimodipina/metabolismo , Córtex Piriforme/metabolismo , Células Piramidais/fisiologia , Hipocampo/fisiologia , Canais de Cálcio Tipo L/metabolismo , Envelhecimento/fisiologiaRESUMO
This critique discusses neuroprotective strategies for aneurysmal subarachnoid hemorrhage (SAH), excluding Nimodipine, emphasizing alternatives like verapamil, albumin, and cilostazol. While these options show potential, their efficacy lacks robust confirmation from randomized controlled trials (RCTs), relying mainly on observational studies and small trials. The letter underscores the need for comprehensive safety assessments and long-term outcome studies to enhance practical application. Highlighting ongoing trials and emerging therapies like clazosentan and TAK-044, it advocates for future research directions focused on large-scale RCTs and combination therapies, such as cilostazol and Nimodipine, which have demonstrated synergistic benefits in reducing delayed cerebral ischemia (DCI) and improving patient outcomes.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Nimodipina , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/prevenção & controle , Vasoespasmo Intracraniano/etiologia , Nimodipina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Neuroproteção/efeitos dos fármacos , Cilostazol/uso terapêuticoRESUMO
The clinical management of aneurysmal subarachnoid hemorrhage (SAH)-associated vasospasm remains a challenge in neurosurgical practice, with its prevention and treatment having a major impact on neurological outcome. While considered a mainstay, nimodipine is burdened by some non-negligible limitations that make it still a suboptimal candidate of pharmacotherapy for SAH. This narrative review aims to provide an update on the pharmacodynamics, pharmacokinetics, overall evidence, and strength of recommendation of nimodipine alternative drugs for aneurysmal SAH-associated vasospasm and delayed cerebral ischemia. A PRISMA literature search was performed in the PubMed/Medline, Web of Science, ClinicalTrials.gov, and PubChem databases using a combination of the MeSH terms "medical therapy," "management," "cerebral vasospasm," "subarachnoid hemorrhage," and "delayed cerebral ischemia." Collected articles were reviewed for typology and relevance prior to final inclusion. A total of 346 articles were initially collected. The identification, screening, eligibility, and inclusion process resulted in the selection of 59 studies. Nicardipine and cilostazol, which have longer half-lives than nimodipine, had robust evidence of efficacy and safety. Eicosapentaenoic acid, dapsone and clazosentan showed a good balance between effectiveness and favorable pharmacokinetics. Combinations between different drug classes have been studied to a very limited extent. Nicardipine, cilostazol, Rho-kinase inhibitors, and clazosentan proved their better pharmacokinetic profiles compared with nimodipine without prejudice with effective and safe neuroprotective role. However, the number of trials conducted is significantly lower than for nimodipine. Aneurysmal SAH-associated vasospasm remains an area of ongoing preclinical and clinical research where the search for new drugs or associations is critical.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Nimodipina , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Nimodipina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Neuroproteção/efeitos dos fármacos , Cilostazol/uso terapêutico , Nicardipino/uso terapêutico , Dioxanos/uso terapêutico , Vasodilatadores/uso terapêutico , Pirimidinas/uso terapêutico , Piridinas , Sulfonamidas , TetrazóisRESUMO
This letter commends the article by Luzzi et al. on alternative neuroprotection strategies for aneurysmal subarachnoid hemorrhage (SAH). It highlights the pharmacological advantages of nicardipine, cilostazol, and clazosentan over nimodipine in managing cerebral vasospasm and delayed cerebral ischemia. Emphasizing the need for personalized medicine, it advocates for integrating genetic screening and advanced monitoring techniques to tailor treatments to individual patient profiles. This approach could significantly improve clinical outcomes by optimizing drug efficacy and minimizing adverse effects.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Nimodipina , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/prevenção & controle , Vasoespasmo Intracraniano/etiologia , Nimodipina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Nicardipino/uso terapêutico , Neuroproteção/efeitos dos fármacos , Cilostazol/uso terapêutico , Dioxanos/uso terapêutico , Vasodilatadores/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas , Sulfonamidas , TetrazóisRESUMO
Nimodipine dose reduction is recommended in case of high vasopressor demand after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to assess potential adverse effects of nimodipine reduction during the high-risk period for delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) between days 5 and 10 after hemorrhage. Demographic and clinical data as well as daily nimodipine dose of aSAH patients admitted between 2010 and 2019 were retrospectively analyzed. Univariable and multivariable regression analyses were performed to identify factors associated with DCI, angiographic CVS, DCI-related infarction, and unfavorable outcome. A total of 205 patients were included. Nimodipine dose reduction occurred in 108 (53%) patients ('nimodipine reduction group'), while 97 patients (47%) received the full dose ('no nimodipine reduction group'), Patients in the 'nimodipine reduction group' had significant worse WFNS and Fisher grades and developed significantly more often DCI and angiographic CVS. DCI-related infarction and unfavorable outcome were also significantly increased in the 'nimodipine reduction group.' 'Reduced nimodipine dose' was the only independent predictor for the occurrence of DCI and angiographic CVS in multivariable regression analysis. 'Poor WFNS grade' and 'reduced nimodipine dose' were identified as independent risk factors for DCI-related infarction while 'older age,' 'poor WFNS grade,' and 'reduced nimodipine dose' were associated with unfavorable outcome at 3 months after discharge. Nimodipine dose reduction during the high-risk period of DCI and CVS between days 5 and 10 after hemorrhage might abrogate the positive prognostic effects of nimodipine and should be critically evaluated.
Assuntos
Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Nimodipina/uso terapêutico , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/cirurgia , Redução da Medicação , Estudos Retrospectivos , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/etiologia , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologiaRESUMO
In recent years, researchers have shown a growing interest in the interactions between different pharmaceutical agents. An intriguing instance lies in the possible interaction between nimodipine and vitamin C. To investigate the pharmacokinetic and pharmacodynamic effects of vitamin C on nimodipine in rats, rats were randomly divided into a nimodipine only group and a combination group (nimodipine + vitamin C). The two groups were given intragastric administration and nimodipine blood concentrations were determined using high-performance liquid chromatography-tandem mass spectrum at different time points. Blood pressure and heart rate were measured via carotid artery cannulation. Pharmacokinetic differences were observed between the nimodipine only group and the combination group at the same dose. Compared with the nimodipine only group, the combination group's main pharmacokinetic parameters of peak concentration and area under the curve increased significantly, and the difference was statistically significant (p < 0.05); furthermore, the combination group exhibited a significant reduction in average blood pressure, while no significant effects on heart rate were observed. Vitamin C did not affect the activity of CYP450 in rat liver. The pharmacokinetic characteristics and pharmacodynamics of nimodipine were changed by vitamin C administration in rats.
Assuntos
Ácido Ascórbico , Nimodipina , Ratos , Animais , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450RESUMO
BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating diagnosis. A poor outcome is known to be highly dependent on the initial neurological status. Our goal was to identify other parameters that favor the risk of complications and poor outcome in patients with aSAH and initially favorable neurologic status. METHODS: Consecutive aSAH cases treated at our hospital between 01/2003 and 06/2016 with the initial World Federation of Neurosurgical Societies grades I-III were included. Data on demographic characteristics, previous medical history, initial aSAH severity, and functional outcome after aSAH were collected. The study endpoints were the occurrence of cerebral infarcts, in-hospital mortality, and unfavorable outcome at 6 months after aSAH (modified Rankin scale > 3). RESULTS: In the final cohort (n= 582), the rate of cerebral infarction, in-hospital mortality, and unfavorable outcome was 35.1%, 8.1%, and 17.6% respectively. The risk of cerebral infarction was independently related to the presence of acute hydrocephalus (adjusted odds ratio [aOR]=2.33, p<0.0001), aneurysm clipping (aOR=1.78, p=0.003), and use of calcium channel blockers concomitant to nimodipine (aOR=2.63, p=0.002). Patients' age (>55 years, aOR=4.24, p<0.0001), acute hydrocephalus (aOR=2.43, p=0.036), and clipping (aOR=2.86, p=0.001) predicted in-hospital mortality. Baseline characteristics associated with unfavorable outcome at 6 months were age (aOR=2.77, p=<0.0001), Fisher grades III-IV (aOR=2.81, p=0.016), acute hydrocephalus (aOR=2.22, p=0.012), clipping (aOR=3.98, p<0.0001), admission C-reactive protein>1mg/dL (aOR=1.76, p=0.035), and treatment intervals (aOR=0.64 per-5-year-intervals, p=0.006). CONCLUSIONS: Although cerebral infarction is a common complication in aSAH individuals with favorable initial clinical condition, >80% of these patients show favorable long-term outcome. The knowledge of outcome-relevant baseline characteristics might help to reduce the burden of further complications and poor outcome in aSAH patients who tolerated the initial bleeding event well.
Assuntos
Hidrocefalia , Hemorragia Subaracnóidea , Humanos , Pessoa de Meia-Idade , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/cirurgia , Fatores de Risco , Nimodipina , Infarto Cerebral/epidemiologia , Infarto Cerebral/etiologiaRESUMO
BACKGROUND: Causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH) include early brain injury and delayed neurologic deterioration, which may result from delayed cerebral ischemia (DCI). Complex pathophysiological mechanisms underlie DCI, which often includes angiographic vasospasm (aVSP) of cerebral arteries. METHODS: Despite the study of many pharmacological therapies for the prevention of DCI in aSAH, nimodipine-a dihydropyridine calcium channel blocker-remains the only drug recommended universally in this patient population. A common theme in the research of preventative therapies is the use of promising drugs that have been shown to reduce the occurrence of aVSP but ultimately did not improve functional outcomes in large, randomized studies. An example of this is the endothelin antagonist clazosentan, although this agent was recently approved in Japan. RESULTS: The use of the only approved drug, nimodipine, is limited in practice by hypotension. The administration of nimodipine and its counterpart nicardipine by alternative routes, such as intrathecally or formulated as prolonged release implants, continues to be a rational area of study. Additional agents approved in other parts of the world include fasudil and tirilazad. CONCLUSIONS: We provide a brief overview of agents currently being studied for prevention of aVSP and DCI after aSAH. Future studies may need to identify subpopulations of patients who can benefit from these drugs and perhaps redefine acceptable outcomes to demonstrate impact.
Assuntos
Isquemia Encefálica , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/prevenção & controle , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Infarto Cerebral/complicações , Nimodipina/farmacologia , Nimodipina/uso terapêutico , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/prevenção & controleRESUMO
Sleep disorders are one of the most common acute reactions on the plateau, which can cause serious complications. However, there is no effective and safe treatment currently available. Nimodipine (NMD) is a dihydropyridine calcium channel blocker with neuroprotective and vasodilating activity, mainly used for the treatment of ischemic brain injury. Commercial oral or injectable NMD formulations are not a good option for central neuron diseases due to their poor brain delivery. In this study, nimodipine dissolving microneedles (NDMNs) were prepared for the prevention of sleep disorders caused by hypoxia. NDMNs were composed of NMD and polyvinyl pyrrolidone (PVP) K90 with a conical morphology and high rigidity. After administration of NDMNs on the back neck of mice, the concentration of NMD in the brain was significantly higher than that of oral medication as was confirmed by the fluorescent imaging on mouse models. NDMNs enhanced cognitive function, alleviated oxidative stress, and improved the sleep quality of mice with high-altitude sleep disorders. The blockage of calcium ion overloading may be an important modulation mechanism. NDMNs are a promising and user-friendly formulation for the prevention of high-altitude sleep disorders.
Assuntos
Bloqueadores dos Canais de Cálcio , Nimodipina , Transtornos do Sono-Vigília , Animais , Camundongos , Nimodipina/administração & dosagem , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/prevenção & controle , Masculino , Bloqueadores dos Canais de Cálcio/administração & dosagem , Altitude , Agulhas , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Estresse Oxidativo/efeitos dos fármacos , Povidona/química , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND AND OBJECTIVE: Cerebral small vessel disease (CSVD) often coexists with cognitive dysfunction in patients, leading to significant challenges in treatment and management. This study aimed to examine the efficacy of combined application of donepezil and nimodipine on patients with comorbid CSVD and cognitive dysfunction and the effects on patients' albumin and prealbumin levels. METHODS: The records of 112 patients with comorbid CSVD and cognitive dysfunction treated at the People's Hospital of Suzhou New District from January 2019 to December 2022 were analysed retrospectively. A total of 50 patients receiving donepezil were allocated to the control group, and 62 patients receiving both nimodipine and donepezil to the study group. Outcomes compared between the two groups included serum homocysteine (Hcy), high sensitivity C-reactive protein (hs-CRP), albumin, and prealbumin before and after therapy, efficacy, and adverse reactions. Additionally, logistic regression was performed to analyze the risk factors impacting patient prognosis. RESULTS: Prior to therapy, the two groups did not differ significantly in Hcy and hs-CRP levels (p > 0.05), whereas after therapy, the levels in both groups dropped significantly (p < 0.01), with more obvious lower levels in the study group (p < 0.05). After treatment, the study group presented significantly higher albumin and prealbumin levels than the control group (p < 0.001). An obvious higher overall response rate was observed in the study group compared to the control group (p = 0.012). No significant inter-group discrepancy was found regarding the total incidence of adverse reactions (p = 0.752). Univariate analysis identified age, course of disease, heart rate (HR), Montreal Cognitive Assessment (MoCA) score, diastolic blood pressure (DBP), systolic blood pressure (SBP), drinking history, as well as medication regimen as risk factors impacting patient prognosis. Multivariate logistic regression analysis identified SBP, DBP, and medication regimen as the independent risk factors. CONCLUSION: Combined application of donepezil and nimodipine can effectively treat patients with comorbid CSVD and cognitive dysfunction. It can significantly lower the Hcy and hs-CRP levels and improve the nutritional status without increasing the frequency of adverse reactions. In addition, for CSVD patients with cognitive dysfunction, age, course of disease, MoCA score, HR, SBP, DBP, drinking history, and medication regimen are risk factors impacting patient prognosis, while SBP, DBP, and medication regimen are independent risk factors.
Assuntos
Doenças de Pequenos Vasos Cerebrais , Disfunção Cognitiva , Donepezila , Quimioterapia Combinada , Nimodipina , Estado Nutricional , Humanos , Feminino , Masculino , Donepezila/administração & dosagem , Donepezila/uso terapêutico , Doenças de Pequenos Vasos Cerebrais/tratamento farmacológico , Doenças de Pequenos Vasos Cerebrais/complicações , Disfunção Cognitiva/tratamento farmacológico , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Nimodipina/administração & dosagem , Nimodipina/uso terapêutico , Resultado do Tratamento , Nootrópicos/administração & dosagem , Nootrópicos/uso terapêutico , Nootrópicos/efeitos adversos , Homocisteína/sangueRESUMO
Reversible cerebral vasoconstriction syndrome (RCVS) is a condition defined by severe sudden-onset headaches, typically ‘thunderclap’ headaches, caused by multifocal cerebral vasoconstriction. Various triggers have been described, including illegal substances, medication and infections. We observed a 27 year old man that suddenly developed severe headaches during admission to a psychiatric ward, where RCVS was diagnosed as most likely clinical cause. He was given nimodipine with rapid and full symptom remission. We aim to highlight this rare, but important, neurological syndrome and its various psychiatric risk factors.
Assuntos
COVID-19 , Psicotrópicos , Transtornos Relacionados ao Uso de Substâncias , Humanos , Masculino , Adulto , Psicotrópicos/uso terapêutico , Psicotrópicos/efeitos adversos , Nimodipina/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Cefaleia/induzido quimicamente , SARS-CoV-2RESUMO
BACKGROUND: The only established pharmacological treatment option improving outcomes for patients suffering from subarachnoid hemorrhage (SAH) is the L-type-calcium channel inhibitor nimodipine. However, the exact mechanisms of action of nimodipine conferring neuroprotection after SAH have yet to be determined. More recently, spasms of the cerebral microcirculation were suggested to play an important role in reduced cerebral perfusion after SAH and, ultimately, outcome. It is unclear whether nimodipine may influence microvasospasms and, thus, microcirculatory dysfunction. The aim of the current study was, therefore, to assess the effect of nimodipine on microvasospasms after experimental SAH. METHODS: Male C57Bl/6 N mice (n=3-5/group) were subjected to SAH using the middle cerebral artery perforation model. Six hours after SAH induction, a cranial window was prepared, and the diameter of cortical microvessels was assessed in vivo by 2-photon-microscopy before, during, and after nimodipine application. RESULTS: Nimodipine significantly reduced the number of posthemorrhagic microvasospasms. The diameters of nonspastic vessels were not affected. CONCLUSIONS: Our results show that nimodipine reduces the formation of microvasospasms, thus, shedding new light on the mode of action of a drug routinely used for the treatment of SAH for >3 decades. Furthermore, L-type Ca2+ channels may be involved in the pathophysiology of microvasospasm formation.
Assuntos
Nimodipina , Hemorragia Subaracnóidea , Humanos , Animais , Camundongos , Masculino , Nimodipina/farmacologia , Nimodipina/uso terapêutico , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Microcirculação , Camundongos Endogâmicos C57BL , MicrovasosRESUMO
The experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis was used in combination with a Cav1.2 conditional knock-out mouse (Cav1.2KO) to study the role of astrocytic voltage-gated Ca++ channels in autoimmune CNS inflammation and demyelination. Cav1.2 channels were specifically ablated in Glast-1-positive astrocytes by means of the Cre-lox system before EAE induction. After immunization, motor activity was assessed daily, and a clinical score was given based on the severity of EAE symptoms. Cav1.2 deletion in astrocytes significantly reduced the severity of the disease. While no changes were found in the day of onset and peak disease severity, EAE mean clinical score was lower in Cav1.2KO animals during the chronic phase of the disease. This corresponded to better performance on the rotarod and increased motor activity in Cav1.2KO mice. Furthermore, decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes were found in the lumbar section of the spinal cord of Cav1.2KO mice 40 days after immunization. The degree of myelin protein loss and size of demyelinated lesions were also attenuated in Cav1.2KO spinal cords. Similar results were found in EAE animals treated with nimodipine, a Cav1.2 Ca++ channel inhibitor with high affinity to the CNS. Mice injected with nimodipine during the acute and chronic phases of the disease exhibited lower numbers of reactive astrocytes, activated microglial, and infiltrating immune cells, as well as fewer demyelinated lesions in the spinal cord. These changes were correlated with improved clinical scores and motor performance. In summary, these data suggest that antagonizing Cav1.2 channels in astrocytes during EAE alleviates neuroinflammation and protects the spinal cord from autoimmune demyelination.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Esclerose Múltipla/patologia , Nimodipina/metabolismo , Doenças Neuroinflamatórias , Astrócitos/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Medula Espinal/patologia , Camundongos Knockout , Camundongos Endogâmicos C57BLRESUMO
Parenteral depot systems can provide a constant release of drugs over a few days to months. Most of the parenteral depot products on the market are based on poly(lactic acid) and poly(lactide-co-glycolide) (PLGA). Studies have shown that acidic monomers of these polymers can lead to nonlinear release profiles or even drug inactivation before release. Therefore, finding alternatives for these polymers is of great importance. Our previous study showed the potential of starch as a natural and biodegradable polymer to form a controlled release system. Subarachnoid hemorrhage (SAH) is a life-threatening type of stroke and a major cause of death and disability in patients. Nimotop® (nimodipine (NMD)) is an FDA-approved drug for treating SAH-induced vasospasms. In addition, NMD has, in contrast to other Ca antagonists, unique neuroprotective effects. The oral administration of NMD is linked to variable absorption and systemic side effects. Therefore, the development of a local parenteral depot formulation is desirable. To avoid the formation of an acidic microenvironment and autocatalytic polymer degradation, we avoided PLGA as a matrix and investigated starch as an alternative. Implants with drug loads of 20 and 40% NMD were prepared by hot melt extrusion (HME) and sterilized with an electron beam. The effects of HME and electron beam on NMD and starch were evaluated with NMR, IR, and Raman spectroscopy. The release profile of NMD from the systems was assessed by high-performance liquid chromatography. Different spectroscopy methods confirmed the stability of NMD during the sterilization process. The homogeneity of the produced system was proven by Raman spectroscopy and scanning electron microscopy images. In vitro release studies demonstrated the sustained release of NMD over more than 3 months from both NMD systems. In summary, homogeneous nimodipine-starch implants were produced and characterized, which can be used for therapeutic purposes in the brain.
Assuntos
Nimodipina , Parassimpatolíticos , Humanos , Nimodipina/química , Preparações de Ação Retardada , Amido , Portadores de Fármacos/química , Polímeros/química , EncéfaloRESUMO
Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four ARs (quadruple knockout, QKO). Alternatively, an adenosinergic effect was identified if a drug potentiated adenosine-induced hypothermia. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased the hypothermia caused by adenosine. Dipyridamole and nimodipine probably achieved this by inhibition of adenosine clearance via ENT1. Two drugs (cannabidiol, canrenoate) did not cause hypothermia in wild type mice. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia, but the hypothermia was unchanged in QKO mice indicating non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity; the hypoactivity was blunted in the QKO mice. Interestingly, the antidepressant amitriptyline caused hypothermia in wild type mice that was amplified in the QKO mice. Thus, we have identified adenosine-related effects for some drugs, while other candidates do not affect adenosine signaling by this in vivo assay. The adenosine-modulating drugs could be considered for repurposing based on predicted effects on AR activation.
Assuntos
Adenosina , Hipotermia , Camundongos , Animais , Adenosina/farmacologia , Hipotermia/induzido quimicamente , Nimodipina/efeitos adversos , Receptores Purinérgicos P1 , Dipiridamol/efeitos adversosRESUMO
PURPOSE: The treatment of vasospasms during endovascular stroke treatment (EST) with intra-arterial nimodipine (NM) is routinely performed. However, the efficacy of resolving iatrogenic vasospasms during the angiographic intervention and the infarct development in follow-up imaging after EST has not been studied yet. METHODS: Retrospective single-center analysis of patients receiving EST for anterior circulation vessel occlusion between 01/2015 and 12/2021. The primary endpoint was ASPECTS in follow-up imaging. Secondary endpoints were the clinical outcome (combined endpoint NIHSS 24 h after EST and difference between modified Rankin Scale (mRS) before stroke and at discharge (delta mRS)) and intracranial hemorrhage (ICH) in follow-up imaging. Patients with vasospasms receiving NM (NM+) or not (NM-) were compared in univariate analysis. RESULTS: Vasospasms occurred in 79/1283 patients (6.2%), who consecutively received intra-arterial NM during EST. The targeted vasospasm angiographically resolved in 84% (66/79) under NM therapy. ASPECTS was lower in follow-up imaging after vasospasms and NM-treatment (NM - 7 (6-9), NM + 6 (4.5-8), p = 0.013) and the clinical outcome was worse (NIHSS 24 h after EST was higher in patients treated with NM (median, IQR; NM+: 14, 5-21 vs. NM-: 9, 3-18; p = 0.004), delta-mRS was higher in the NM + group (median, IQR; NM+: 3, 1-4 vs. NM-: 2, 1-2; p = 0.011)). Any ICH (NM+: 27/79, 34.2% vs. NM-: 356/1204, 29.6%; p = 0.386) and symptomatic ICH (NM+: 2/79, 2.5% vs. NM-: 21/1204, 1.7%; p = 0.609) was equally distributed between groups. CONCLUSION: Intra-arterial nimodipine during EST resolves iatrogenic vasospasms efficiently during EST without increasing intracranial hemorrhage rates. However, patients with vasospasms and NM treatment show higher infarct growth resulting in lower ASPECTS in follow-up imaging.
Assuntos
Doenças do Sistema Nervoso Autônomo , Isquemia Encefálica , Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Nimodipina/uso terapêutico , Estudos Retrospectivos , Seguimentos , Resultado do Tratamento , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Hemorragias Intracranianas/etiologia , Trombectomia/métodos , Doenças do Sistema Nervoso Autônomo/etiologia , Infarto/etiologia , Doença Iatrogênica , Procedimentos Endovasculares/métodos , Isquemia Encefálica/tratamento farmacológicoRESUMO
Autoimmune uveitis (AU) is a sight-threatening ocular inflammatory disorder, characterized by massive retinal vascular leakage and inflamed lesions with infiltration of the uveitogenic T cells in the retina and disorders of the T cell-related immune response in the system. Stimulation of TCRs can trigger calcium release and influx via Ca2+ channels and then transmit signals from the surface to the nucleus, which are important for energy metabolism, proliferation, activation, and differentiation. Inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may suppress T cell function, representing a novel anti-inflammatory strategy in the treatment of AU. This study investigated the effects of the l-type voltage-gated calcium channel blocker nimodipine in experimental AU (EAU). Nimodipine was found to not only decrease the clinical and histopathological inflammation score of EAU (C57BL/6J mice) but also dwindle the infiltration of uveitogenic CD4+ T cells into the retina. Moreover, nimodipine decreased the effector T cells and increased the regulatory T cells in the immune system. In vitro, nimodipine reduced the effector T cell differentiation of the IRBP1-20-specific CD4+ T cells of EAU mice and LPS-stimulated PBMCs of uveitis patients. Meanwhile, nimodipine suppressed the energy metabolism, proliferation, activation, and Th1 cell differentiation of T cells. Further studies on RNA sequencing and molecular mechanisms have established that nimodipine alleviates EAU by regulating T cells response through the p38-MAPK pathway signaling. Taken together, our data reveal a novel therapeutic potential of the l-type Ca2+ channels antagonist nimodipine in AU by regulating the balance of T cell subsets.