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1.
Drug Deliv ; 28(1): 894-905, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33960251

RESUMO

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120-130 nm with well-developed pore structure (SBET: 1009.94 m2/g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.


Assuntos
Nanopartículas/química , Nimodipina/farmacocinética , Polietilenoimina/química , Dióxido de Silício/química , Tartaratos/química , Administração Oral , Animais , Química Farmacêutica , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Masculino , Nimodipina/administração & dosagem , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Propriedades de Superfície
2.
Biomed Chromatogr ; 35(2): e4971, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32840898

RESUMO

Nimodipine is a dihydropyridine calcium channel blocker that exhibits higher selectivity toward cerebral blood vessels compared with other members of the same class. It has been shown to improve outcomes and prevent delayed cerebral ischemia in the setting of aneurysmal subarachnoid hemorrhage, a life-threatening brain bleed. Nimodipine is a chiral compound and it is marketed as a racemic mixture of (+)-R and (-)-S enantiomers. (-)-S-Nimodipine is approximately twice as potent a vasorelaxant as the racemic mixture and is more rapidly eliminated than the (+)-R counterpart following oral dosing. Few analytical procedures have been reported to determine nimodipine enantiomers in biological samples; however, the reported methods were time-consuming, involved multistep extraction procedures and required large sample volumes. Herein, we present an LC-MS/MS method for quantifying nimodipine enantiomers in human plasma using a small sample volume (0.3 ml) and a single liquid-liquid extraction step. The peak area ratios were linear over the tested concentration ranges (1.5-75 ng/ml) with r2 > 0.99. The intraday CV and percentage error were within ±14% while the interday values were within ±13%, making this analytical method feasible for research purposes and pharmacokinetic studies.


Assuntos
Cromatografia Líquida/métodos , Nimodipina/sangue , Nimodipina/química , Espectrometria de Massas em Tandem/métodos , Humanos , Modelos Lineares , Nimodipina/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estereoisomerismo , Hemorragia Subaracnóidea/tratamento farmacológico , Vasodilatadores/sangue , Vasodilatadores/química , Vasodilatadores/farmacocinética
3.
Bioanalysis ; 12(21): 1509-1519, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33078962

RESUMO

Aim: Nimodipine and 3-n-butylphthalide are co-administered to treat vascular dementia, but the pharmacokinetic interaction between the two drugs is still unknown. Therefore, a robust, high-throughput and economical supercritical fluid chromatography-ESI-MS/MS method has been initially developed to simultaneously determine nimodipine and 3-n-butylphthalide in beagle plasma, in order to study the safety of co-administration. Materials & methods: After a simple protein precipitation procedure, isocratic elution with mobile phase of CO2 and methanol (containing 0.3% formic acid and 2 mM ammonium acetate) was applied to minimize run time and facilitate sensitive and high-throughput bioanalysis. The method was fully validated according to US FDA Guidance. The validated method was then successfully applied in a pharmacokinetic interaction study. Results: The results indicated there is no significant pharmacokinetic interaction between the two drugs.


Assuntos
Benzofuranos/uso terapêutico , Nimodipina/uso terapêutico , Animais , Benzofuranos/sangue , Cromatografia com Fluido Supercrítico/métodos , Cães , Nimodipina/sangue , Nimodipina/farmacocinética , Espectrometria de Massas em Tandem/métodos
4.
Neurosurgery ; 88(1): E13-E26, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32985652

RESUMO

BACKGROUND: A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. METHODS: Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. RESULTS: The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups. CONCLUSION: Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.


Assuntos
Anti-Hipertensivos/administração & dosagem , Nimodipina/administração & dosagem , Hemorragia Subaracnóidea/tratamento farmacológico , Adulto , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Feminino , Humanos , Ácido Hialurônico , Injeções Intraventriculares/métodos , Pessoa de Meia-Idade , Nimodipina/efeitos adversos , Nimodipina/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Resultado do Tratamento
5.
Drugs R D ; 20(4): 307-318, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32902829

RESUMO

Nimodipine has been shown to improve outcomes following aneurysmal subarachnoid hemorrhage. Guidelines recommend that all patients receive a fixed dose of oral nimodipine for 21 days. However, pharmacokinetic studies have suggested variability of nimodipine pharmacokinetics in subarachnoid hemorrhage and in other patient populations. The clinical relevance of such variability is unknown. Therefore, the objective of the present review is, first, to conduct a literature review and summarize nimodipine pharmacokinetic data and sources of variability in various patient groups. Second, to determine if there is any evidence reporting an association between nimodipine exposure and clinical outcomes in patients with subarachnoid hemorrhage. A systematic literature search was performed in MEDLINE and EMBASE. The following keywords were used: ("nimodipine" OR "nymalize" OR "nimotop") AND ("pharmacokinetic*", OR "PK"). The search results were limited to English language and human studies. A large interpatient variability in nimodipine pharmacokinetics has been reported. Patient-specific factors that had an influence on pharmacokinetic parameters are age, comorbidities, variabilities in metabolism due to genetic polymorphism and co-administered medications, as well as nimodipine administration technique. The association between nimodipine exposure and clinical outcomes remains unclear and data available are too scarce to reach a firm conclusion. Here, we present a narrative review with a systematic literature search discussing nimodipine pharmacokinetic variability in various patient populations. It is not clear if minimal or lack of systemic exposure to nimodipine denies its benefit and contributes to worsening outcomes in patients with subarachnoid hemorrhage. Further studies are needed to determine if such an association exists.


Assuntos
Nimodipina/farmacocinética , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Vasodilatadores/farmacocinética , Animais , Variação Biológica da População , Interações Medicamentosas , Fatores Epidemiológicos , Humanos , Nimodipina/uso terapêutico , Resultado do Tratamento , Vasodilatadores/uso terapêutico
6.
AAPS PharmSciTech ; 21(6): 234, 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32794077

RESUMO

We investigated the pharmacokinetics of nimodipine (NMD) in rats plasma and tissues following intraocular (io), intragastric (ig), and intravenous (iv) administration at doses of 5.0 mg/kg io and iv and 10.0 mg/kg ig. After a single dose of NMD, plasma, heart, liver, spleen, lung, kidney, and brain samples were collected at the scheduled time points. The concentration of NMD in rat plasma and tissues was determined by high-performance liquid chromatography, and the main pharmacokinetic parameters were calculated and compared. NMD was rapidly absorbed and reached the maximum plasma concentration in approximately 5 min after io administration. The absolute bioavailability after io administration was higher than that after ig administration (40.05% vs. 5.67%). There were significant differences in the tissue distribution of NMD with different administration routes. After io administration, NMD was distributed more in the lung, spleen, and brain tissues, and less in the kidney. The maximum drug concentration after io administration in the heart, liver, spleen, lung, kidney, and brain was 1.00, 0.47, 2.02, 1.47, 0.22, and 5.79 times higher than that after via ig administration, and the area under the curve value was 0.59, 0.78, 1.71, 1.84, 0.25, and 4.59 times greater, respectively. Nimodipine appears to achieve systemic effects via io administration. Compared with ig, io administration could significantly increase NMD distribution in the brain tissue, indicating that NMD could be delivered to the brain via io administration.


Assuntos
Encéfalo/metabolismo , Injeções Intraoculares/métodos , Nimodipina/administração & dosagem , Nimodipina/sangue , Administração Intravenosa , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Injeções Intraperitoneais , Injeções Intravenosas , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Nimodipina/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
7.
Biomed Chromatogr ; 34(9): e4872, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32358897

RESUMO

Xuefu Zhuyu Decoction (XFZYD) is a traditional Chinese medicine prescription used for the clinical treatment of traumatic brain injury (TBI). The purpose of this work was to develop a sensitive and rapid UHPLC-MS/MS method to simultaneously study the pharmacokinetics of nimodipine and eight components of XFZYD, namely, amygdalin, hydroxysafflor yellow A, rutin, liquiritin, narirutin, naringin, neohesperidin and saikosaponin A, in rats with and without TBI. Multiple reaction monitoring was highly selective in the detection of nine analytes and the internal standard without obvious interference. The calibration curves displayed good linearity (r > 0.99) over a wide concentration range. The mean absolute recoveries of the nine analytes were 85-106%, and all matrix effects were in the range 80-120%. The intra- and inter-day precision and accuracy were acceptable (RSD, <15%; RE%, ±20%). The validated method was successfully applied to compare the pharmacokinetics in four experimental groups, including control rats orally administered XFZYD and TBI model rats orally administered XFZYD, XFZYD and nimodipine, or nimodipine alone. The results showed that herb-drug interactions occurred between XFZYD and nimodipine in the treatment of TBI, nimodipine affected the pharmacokinetics of XFZYD, and XFZYD affected the absorption, distribution and excretion of nimodipine in vivo.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Nimodipina , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Lesões Encefálicas Traumáticas , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/sangue , Flavonoides/química , Flavonoides/farmacocinética , Glicosídeos/sangue , Glicosídeos/química , Glicosídeos/farmacocinética , Modelos Lineares , Masculino , Nimodipina/administração & dosagem , Nimodipina/sangue , Nimodipina/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Mater Sci Eng C Mater Biol Appl ; 111: 110836, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279765

RESUMO

Solid dispersion is a widely used method to improve the dissolution and oral bioavailability of water-insoluble drugs. However, due to the strong hydrophobicity, the drug crystallization in the release media after drug dissolution and the resulted decreased drug absorption retards the use of solid dispersions. It is widely known that the amphiphilic copolymer can encapsulate the hydrophobic compounds and help form stable nano-dispersions in water. Inspired by this, we tried to formulate the solid dispersion of nimodipine by using amphipathic copolymer as one of the carriers. Concerning the solid dispersions, there are many important points involved in these formulations, such as the miscibility between the drug and the carriers, the storage stability of solid dispersions, the dissolution enhancement and so on. In this study, a systemic method is proposed. In details, the supersaturation test and the glass transition temperature (Tg) measurement to predict the crystallization inhibition, the ratios of different components and the storage stability, the interactions among the components were investigated in detail by nuclear magnetic resonance (1H NMR) and isothermal titration calorimetry (ITC) and, the final dissolution and oral bioavailability enhancement. It was found that the amphiphilic copolymer used in the solid dispersion encouraged the formation the drug loading micelles in the release media and, finally, the problem of drug crystallization in the dissolution process was successfully solved.


Assuntos
Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanopartículas/química , Nimodipina/farmacologia , Tensoativos/química , Administração Oral , Animais , Células CACO-2 , Cristalização , Composição de Medicamentos , Endocitose , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Camundongos , Micelas , Nanopartículas/ultraestrutura , Nimodipina/administração & dosagem , Nimodipina/sangue , Nimodipina/farmacocinética , Polietilenoglicóis/química , Polivinil/química , Povidona/análogos & derivados , Povidona/química , Soluções
9.
Int J Nanomedicine ; 15: 1161-1172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110014

RESUMO

PURPOSE: Nimodipine (NIMO) is used clinically to treat ischemic damage resulting from subarachnoid hemorrhage. However, clinical application of NIMO is limited by poor aqueous solubility and low safety. To overcome these limitations, a novel two-vial NIMO-loaded nanoemulsion (NIMO-TNE) was designed in this study. METHODS: NIMO-TNE was prepared by mixing a nimodipine-polyethylene glycol 400 (NIMO-PEG400) solution and a commercially available 20% injectable blank nanoemulsion (BNE). Drug distribution in NIMO-TNE, physical stability, and dilution stability were evaluated in vitro, and pharmacokinetics and pharmacodynamics were evaluated in vivo. Safety was assessed using the hemolysis test and the intravenous irritation test, and acute toxicity of NIMO-TNE was compared with that of commercial Nimotop injection. RESULTS: Drug loading (DL) in NIMO-TNE was enhanced 5-fold compared with that in Nimotop injection. The mean particle size of NIMO-TNE was 241.53 ± 1.48 nm. NIMO-TNE and NIMO-TNE diluted in 5% glucose injection and 0.9% sodium chloride was stable for a sufficient duration to allow for clinical use. In addition, NIMO-TNE exhibited a similar pharmacokinetic profile and similar brain ischemia reduction in a rat middle cerebral artery occlusion (MCAO) model compared to Nimotop injection. Furthermore, NIMO-TNE did not induce hemolysis at 37°C, and NIMO-TNE induced less intravenous irritation than Nimotop injection. Moreover, NIMO-TNE could be injected at a 23-fold higher dose than the LD50 of Nimotop injection with no obvious toxicity or side effects. CONCLUSION: NIMO-TNE is a promising formulation suitable for intravenous injection, is easy to prepare, and exhibits excellent safety.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Nimodipina/administração & dosagem , Animais , Portadores de Fármacos/administração & dosagem , Estabilidade de Medicamentos , Emulsões/química , Feminino , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Camundongos Endogâmicos ICR , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Nimodipina/farmacocinética , Tamanho da Partícula , Polietilenoglicóis , Coelhos , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual , Testes de Toxicidade Aguda
10.
Curr Drug Deliv ; 16(9): 862-871, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31633475

RESUMO

BACKGROUND: Nimodipine is a calcium channel blocker frequently used in critical care settings. It is mainly absorbed in the upper gastrointestinal tract. Accordingly, the development of gastroretentive formulation will be beneficial. The benefit would be maximized for critical care patients if the developed system was in liquid form to facilitate the administration through nasogastric tubing. OBJECTIVE: Development of gastro-retentive liquid oral controlled release formulation of nimodipine through in situ gellation. METHODS: Nimodipine dissolution was improved by solid dispersion (SD) using poloxamer 407. Sodium alginate solutions (1, 1.5 and 2%w/v) were loaded with the optimized SD microparticles. Carboxymethylcellulose was added to modulate the release and to augment mucoadhesion power. All in situ gelling alginate solutions were characterized regarding viscosity, gelling capacity and drug release. SD microparticles showed considerable improvement in nimodipine dissolution. RESULTS: All alginate systems were pourable. Increasing alginate concentration increased the gelling capacity and reduced drug release rate. The addition of carboxymethylcellulose produced greater control over drug release rate. X-ray radiography showed successful stomach-retention over 8 hours in rabbits, which correlates with the controlled release pattern of the developed systems. CONCLUSION: The study provides the formulator with a range of gastroretentive controlled release formulations of nimodipine while maintaining the convenience of administration through nasogastric tubing with the potential for enhanced bioavailability.


Assuntos
Bloqueadores dos Canais de Cálcio/administração & dosagem , Sistemas de Liberação de Medicamentos , Nimodipina/administração & dosagem , Adesividade , Administração Oral , Alginatos/administração & dosagem , Alginatos/química , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Carboximetilcelulose Sódica/administração & dosagem , Carboximetilcelulose Sódica/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Mucosa Gástrica/metabolismo , Masculino , Nimodipina/química , Nimodipina/farmacocinética , Poloxâmero/administração & dosagem , Poloxâmero/química , Coelhos
11.
J Sep Sci ; 42(12): 2179-2186, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30993887

RESUMO

A simple, sensitive, and efficient supercritical fluid chromatography with tandem mass spectrometry method was established for the determination of nimodipine in beagle plasma. One-step protein precipitation with acetone was used to extract the analytes from the plasma. Nitrendipine was used as the internal standard. The chromatographic separation was achieved on an ACQUITY UPC2 ™ BEH 2-EP column, and a gradient elution program was applied at a flow rate of 1.5 mL/min. The detection was carried out on a triple quadrupole tandem mass spectrometer with an electrospray ionization source operating in positive ion mode. Quantification was performed using multiple reaction monitoring of the transitions of m/z 419.3→301.3 for nimodipine and m/z 361.4→315.2 for nitrendipine. A satisfactory linearity was obtained over the concentration range of 0.5-800 ng/mL (r > 0.996). The intra- and interday precision and accuracy results were <9.1% across the quality control levels. The peak concentration and area under concentration-time curve (0-720 min) values of the test and reference formulations were 279.28 ± 211.46 and 265.13 ± 149.26 ng/mL, 25608.00 ± 17553.65 and 28553.67 ± 20207.92 ng·min/mL, respectively. The validated method was successfully applied to reveal the pharmacokinetic profiles of nimodipine in beagle dogs after oral administration. Moreover, the analytical method could be used for further bioequivalence studies.


Assuntos
Nimodipina/sangue , Administração Oral , Animais , Cromatografia com Fluido Supercrítico , Cães , Ensaios de Triagem em Larga Escala , Nimodipina/administração & dosagem , Nimodipina/farmacocinética , Espectrometria de Massas em Tandem
12.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(1): 57-62, 2019 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-30837043

RESUMO

Objective To explore the pharmacokinetics of nimodipine in plasma of rats after intraocular administration.Methods Totally 135 SD rats were randomly divided into three groups according to drug administration routes:intraocular(io group),intravenous (iv group),and intragastric (ig group). The doses were 5.0 mg/kg for IO and IV groups and 10.0 mg/kg for IG group. The serum nimodipine level was analyzed by high performance liquid chromatography. The main pharmacokinetic parameters were calculated and compared.Results The pharmacokinetic parameters in io group were as follows:Cmax:0.52 mg/ml;tmax:5.0 min;and AUC0-t:21.10 mg/(ml·min). The main pharmacokinetic parameters in iv group were as follows:Cmax:3.62 mg/ml;and AUC0-t:52.58 mg/(ml·min). The main pharmacokinetic parameters in ig group were as follows:Cmax:0.20 mg/ml;tmax:5.0 min;and AUC0-t:5.98 mg/(ml·min).Conclusions Nimodipine is rapidly absorbed after io administration,and the ophthalmic formulation has a higher bioavailability than the oral solution. Therefore,the io route may help to improve the treatment effectiveness of cardiovascular diseases.


Assuntos
Nimodipina/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Ratos , Ratos Sprague-Dawley
13.
Neurocrit Care ; 31(1): 32-39, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30725331

RESUMO

BACKGROUND: Oral nimodipine is used for prophylaxis and treatment of delayed cerebral ischemia in patients with aneurysmal or perimesencephalic subarachnoid hemorrhage (SAH). In cases of serious refractory cerebral vasospasm, a continuous intra-arterial (IA) infusion of nimodipine (CIAN) may be required to avoid cerebral ischemia. Nimodipine can cause arterial hypotension requiring either a dosage reduction or its discontinuation. Aim of the present study was to examine the effect of different nimodipine formulations on arterial blood pressure in aneurysmal or perimesencephalic SAH patients and to measure the plasma levels after both, peroral administration as tablet or solution and IA infusion. METHODS: In a prospective setting, over a 1-year observation period, data on the course of arterial blood pressure and nimodipine dosage were collected for 38 patients undergoing treatment for aneurysmal or perimesencephalic SAH in an intensive care unit. In addition, plasma concentrations of nimodipine were measured by liquid chromatography-tandem mass spectrometry. RESULTS: The intended full dose of 60 mg of nimodipine given orally every 4 h could only be administered on 57.2% of the examined days. Ninety-seven episodes of relevant arterial hypotension probably caused by the administration of nimodipine were observed within the first 14 days of treatment. Drops in blood pressure occurred about three times as often after administration of nimodipine as oral solution than as tablet. However, there were no differences in nimodipine plasma levels between the two formulations. In patients suffering from higher-grade SAH, arterial hypotension and consequent dosage reduction or discontinuation of nimodipine were more frequent than in patients with lower-grade SAH. Plasma concentrations of nimodipine during CIAN did not exceed those achieved by oral administration. CONCLUSIONS: Dosage reduction or discontinuation of oral nimodipine is often necessary in patients with higher-grade SAH. Oral nimodipine solutions cause drops in blood pressure more frequently than tablets. Intra-arterial infusion rates of less than 1 mg/h result in venous plasma concentrations of nimodipine similar to those observed after oral application of 60 mg every 4 h.


Assuntos
Anti-Hipertensivos/administração & dosagem , Hipotensão/epidemiologia , Nimodipina/administração & dosagem , Hemorragia Subaracnóidea/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Incidência , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Nimodipina/farmacocinética , Estudos Prospectivos , Hemorragia Subaracnóidea/sangue , Comprimidos
14.
Int J Nanomedicine ; 14: 119-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30613141

RESUMO

PURPOSE: Nimodipine (NMP) is a clinical dihydropyridine calcium antagonist. However, the clinical application of NMP is limited by poor water solubility and low oral bioavailability. To overcome these drawbacks, this study designed optimal NMP-incorporated nanostructured lipid carriers (NLCs). METHODS: High-pressure homogenization was successfully applied to prepare NMP-NLC, and the nanoparticle morphology was observed by a transmission electron microscope. The existence form of NMP in NMP-NLC was investigated by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy, respectively. The in vitro release study was performed by the dialysis method, and in vivo studies including in situ intestinal perfusion and pharmacokinetics were investigated in rats with NMP detected by high-performance liquid chromatography. RESULTS: The obtained NMP-NLC shared a spherical shape of ~70 nm with a smooth surface and high encapsulation efficiency of 86.8%±2.1%. Spectroscopy indicated that the drug was in an amorphous state. The NMP-NLC exhibited a sustained release and diverse release profiles under different release medium, which mimicked the physiological environment. Moreover, an in situ intestinal perfusion experiment revealed that NMP-NLC could be mainly absorbed by the small intestine. Remarkable improvements in Cmax and AUC0-∞ from NMP-NLC were obtained from pharmacokinetic experiments, and the relative bioavailability of NMP-loaded nanostructured lipid systems was 160.96% relative to NMP suspensions. CONCLUSION: Collectively, the NLCs significantly enhanced the oral bioavailability of NMP and might provide a promising nanoplatform for hydrophobic drug delivery.


Assuntos
Lipídeos/química , Nanoestruturas/química , Nimodipina/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Masculino , Nanoestruturas/ultraestrutura , Nimodipina/sangue , Nimodipina/química , Nimodipina/farmacocinética , Tamanho da Partícula , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X
15.
Colloids Surf B Biointerfaces ; 172: 118-126, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30144623

RESUMO

In current study, a novel nimodipine solid dispersion (NM-SD) was prepared by hot-melt extrusion (HME) with Hypromellose methylcellulose acetate succinate (H type and fine grades, HPMCAS-HF) for its excellent recrystallization inhibition effects. NM was confirmed to exist as an amorphous state in NM-SD by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), hot stage microscopy (HSM) and scanning electron micrographs (SEM). FT-IR analysis illustrated hydrogen bond interaction between drugs and excipients in NM-SD. The release behavior of NM-SD tablets was investigated in the dissolution medium of pH 6.8 for the in vitro study, which showed that the release of nimodipine could be realized in vitro without recrystallization within two hours. The in vivo pharmacokinetic profiles study in Sprague-Dawley rats was also determined. It was obvious that the Cmax value of NM-SD tablets made by dry granulation was slightly higher than Nimotop®, while the area under the curve, AUC(0-t) exhibited no significant difference between them. In conclusion, the solubility of NM and dissolution rate of NM-SD tablets were greatly improved by HME due to the recrystallization inhibition characteristic of HPMCAS-HF.


Assuntos
Composição de Medicamentos/métodos , Metilcelulose/análogos & derivados , Nimodipina/farmacologia , Animais , Varredura Diferencial de Calorimetria , Cristalização , Metilcelulose/química , Nimodipina/farmacocinética , Tamanho da Partícula , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Comprimidos , Temperatura , Termogravimetria , Difração de Raios X
16.
Mol Pharm ; 15(7): 2754-2763, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29782805

RESUMO

Amorphous solid dispersion (ASD) is one of the most versatile supersaturating drug delivery systems to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. PVP based ASD formulation of nimodipine (NMD) has been marketed and effectively used in clinic for nearly 30 years, yet the mechanism by which PVP maintains the supersaturation and subsequently improves the bioavailability of NMD was rarely investigated. In this research, we first studied the molecular interactions between NMD and PVP by solution NMR, using CDCl3 as the solvent, and the drug-polymer Flory-Huggins interaction parameter. No strong specific interaction between PVP and NMD was detected in the nonaqueous state. However, we observed that aqueous supersaturation of NMD could be significantly maintained by PVP, presumably due to the hydrophobic interactions between the hydrophobic moieties of PVP and NMD in aqueous medium. This hypothesis was supported by dynamic light scattering (DLS) and supersaturation experiments in the presence of different surfactants. DLS revealed the formation of NMD/PVP aggregates when NMD was supersaturated, suggesting the formation of hydrophobic interactions between the drug and polymer. The addition of surfactants, sodium lauryl sulfate (SLS) or sodium taurocholate (NaTC), into PVP maintained that NMD supersaturation demonstrated different effects: SLS could only improve NMD supersaturation with concentration above its critical aggregation concentration (CAC) value while not with lower concentration. Nevertheless, NaTC could prolong NMD supersaturation independent of concentration, with lower concentration outperformed higher concentration. We attribute these observations to PVP-surfactant interactions and the formation of PVP/surfactant complexes. In summary, despite the lack of specific interactions in the nonaqueous state, NMD aqueous supersaturation in the presence of PVP was attained by hydrophobic interactions between the hydrophobic moieties of NMD and PVP. This hydrophobic interaction could be disrupted by surfactants, which interact with PVP competitively, thus hindering the capability of PVP to maintain NMD supersaturation. Therefore, caution is needed when evaluating such ASDs in vitro and in vivo when various surfactants are present either in the formulation or in the surrounding medium.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Nimodipina/química , Tensoativos/química , Disponibilidade Biológica , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Nimodipina/administração & dosagem , Nimodipina/farmacocinética , Polivinil/química , Pirrolidinas/química , Dodecilsulfato de Sódio/química , Solubilidade , Ácido Taurocólico/química
17.
Int J Pharm ; 543(1-2): 245-256, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29604372

RESUMO

Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 µg/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments.


Assuntos
Bloqueadores dos Canais de Cálcio/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Nimodipina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Administração Oral , Animais , Ansiedade/sangue , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/sangue , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Cognição/efeitos dos fármacos , Corticosterona/sangue , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Nimodipina/sangue , Nimodipina/química , Nimodipina/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Ratos Wistar , Estresse Psicológico/sangue , Estresse Psicológico/tratamento farmacológico
18.
Eur J Pharm Sci ; 117: 321-330, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29530545

RESUMO

In this study, spherical shaped chiral mesoporous silica nanoparticles (CMS) was biomimetic synthesized using histidine derivatives (C16-L-histidine) as template via the sol-gel reaction and employed as poorly water-soluble drug nimodipine (NMP) carrier. Characteristics of CMS and its application as drug carrier were intensively investigated and compared with MCM41. Then NMP was respectively loaded into CMS and MCM41 with the drug: carrier weight ratio of 2:1. Structural features of NMP before and after drug loading were systemically characterized. The results demonstrated that hydrogen bonds were formed between NMP and carriers during the drug loading process. After drug loading, crystalline state of NMP effectively converted into modification L and amorphous state, and the first form turned out to be easily removed by washing. On the other hand, drug dissolution rate was significantly improved after drug loading, and the best result came from NMP-C3 sample. It was able to release 17.83% of drug within 60 min, which was 6.8-fold higher than the release amount of pure NMP. Undoubtedly, NMP-C3 presented the highest relative bioavailability (386.22%), and the best therapeutic effect. Meanwhile, CMS improved the brain distribution of NMP in vivo.


Assuntos
Materiais Biomiméticos , Biomimética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Portadores de Fármacos , Histidina/síntese química , Nimodipina/administração & dosagem , Dióxido de Silício/síntese química , Tecnologia Farmacêutica/métodos , Água/química , Administração Oral , Animais , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Preparações de Ação Retardada , Modelos Animais de Doenças , Composição de Medicamentos , Liberação Controlada de Fármacos , Histidina/análogos & derivados , Ligação de Hidrogênio , Hipóxia Encefálica/induzido quimicamente , Hipóxia Encefálica/prevenção & controle , Masculino , Camundongos , Estrutura Molecular , Nimodipina/química , Nimodipina/farmacocinética , Porosidade , Ratos Sprague-Dawley , Nitrito de Sódio , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual
19.
AAPS PharmSciTech ; 19(3): 1308-1319, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29340982

RESUMO

The present study was intended to develop a controlled released osmotic pump capsule based on Nimodipine (NM)-loaded self-microemulsifying drug delivery systems (SMEDDSs) in order to improve the low oral bioavailability of NM. To optimize the NM-loaded SMEDDS composition, the experiments of NM solubility in different oils, the pseudo-ternary phase diagram experiments and the different drug loading experiments were conducted in the preliminary screening studies. Controlled release of NM required an osmotic pump capsule comprising a coated semi-permeable capsule shell, plasticizer, and pore-forming agent. NM release follows zero-order kinetics after oral administration. Polyethylene glycol content, used as a pore-forming agent, coating mass, and drug release orifice size were key factors affecting drug release behavior according to the single methods and were optimized through response surface methodology. The NM-loaded SMEDDS droplet size and the 1H NMR mass spectrogram of the novel capsule were determined. The droplet size of the reconstituted microemulsion was 39.9 nm and 1H NMR analysis showed NM dissolution in the microemulsion. The dissolution test performed on three batches of NM-SMEDDS capsules-prepared using optimal preparation methods-indicated the capsule to deliver a qualified drug delivery with a zero-order release rate. The results demonstrated that NM-loaded SMEDDSs were successfully developed and displayed a qualified release rate in vitro.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Nimodipina/síntese química , Administração Oral , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Cápsulas , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Sistemas de Liberação de Medicamentos/instrumentação , Liberação Controlada de Fármacos/fisiologia , Emulsões/administração & dosagem , Emulsões/química , Emulsões/farmacocinética , Bombas de Infusão Implantáveis/tendências , Nimodipina/administração & dosagem , Nimodipina/farmacocinética , Osmose/fisiologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacocinética , Solubilidade
20.
J Int Med Res ; 46(1): 335-347, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28851258

RESUMO

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.


Assuntos
Anti-Hipertensivos/farmacocinética , Hepatócitos/efeitos dos fármacos , Hipotermia Induzida , Microssomos Hepáticos/efeitos dos fármacos , Nimodipina/farmacocinética , Vasodilatadores/farmacocinética , Animais , Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacologia , Proteínas Sanguíneas/metabolismo , Temperatura Corporal , Circulação Cerebrovascular/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hepatócitos/metabolismo , Injeções Intravenosas , Masculino , Microssomos Hepáticos/metabolismo , Nimodipina/sangue , Nimodipina/farmacologia , Cultura Primária de Células , Ligação Proteica , Coelhos , Ultrassonografia Doppler , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/sangue , Vasodilatadores/farmacologia
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