Nimodipine Research Articles

HSA induced HCPT nanocrystal for high-performance antitumor therapy

The aim of this study was to prepare solid dispersion of nimodipine (NMD) by solvent evaporation method to overcome the poor water solubility of NMD, and to formulate controlled-release (CR) tablets containing the NMD solid dispersion. NMD is a dihydropyridine calcium-channel antagonist that is practically insoluble in water. Owing to the short half-life of the drug in the plasma, NMD immediate-release tablets should be administered frequently for the treatment and prevention of ischemic disorders following aneurysmal subarachnoid hemorrhage. In this study, solid dispersion technique was applied to increase the low solubility of NMD. Carriers for solid dispersions were prepared with different kinds of hydrophilic polymers. Kinetic solubility studies were performed for the prepared solid dispersions, using sodium acetate buffer (pH 4.5). Solid dispersions were then characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectrometry (FT-IR). CR tablets containing the NMD-PVP K30 solid dispersions were designed to reduce the dosing interval and increase patient compliance. Hydroxypropyl methylcelluloses (HPMC) were used as release-modifiers, and lactose anhydrous as a diluent.

Development of an RP-HPLC-UV Method for Simultaneous Detection of Nimodipine and its Metabolite in Cerebrospinal Fluid of Rat.

A rapid, simple and reproducible HPLC method was developed and validated for the analysis of nimodipine (NM) and/or its metabolite, oxidized nimodipine (OX-NM) in rat cerebrospinal fluid (CSF) and artificial CSF. The NM and OX-NM were eluted in less than 10 min with no interferences from the endogenous CSF peaks. Analysis was carried out on a Eurospher Performance (RP-C18, 250 × 4.6 mm) column and UV detection at 236 nm. The mobile phase consisted of acetonitrile and water (70:30 v/v, respectively) with a flow rate of 1 mL/min. Limit of detection was 0.1 μg/mL for OX-NM. The calibration curve was linear over the concentration range of 0.5-10 µg/mL and analytical recovery was more than 95%. The coefficients of variation for intra-day and inter-day assays were less than 5%.

Effect of nimodipine combined with 7.5% hypertonic saline on postoperative cognitive function in aged rats

Objective To evaluate the effect of nimodipine combined with 7.5% hypertonic saline(HS)on postoperative cognitive function in aged rats. Methods Ninety-six healthy male Wistar rats, aged 18 months, weighing 450-500 g, were assigned into 4 groups(n=24 each)using a random number table: splenectomy group(group S), nimodipine group(group N), group HS and nimodipine plus HS group(group N+ HS). Nimodipine 1 mg/kg was intraperitoneally injected in group N. In group HS, 7.5% HS 4 ml/kg was injected via the caudal vein.The equal volume of normal saline was injected intraperitoneally or via the caudal vein in group S. Splenectomy was performed under sevoflurane anesthesia at 30 min after the end of administration.On 1 day before operation and 3 and 7 days after operation, Morris water maze test was performed, and blood samples from the caudal vein were simultaneously collected for determination of the concentrations of serum S100β protein and neuron-specific enolase(NSE)by enzyme-linked immunosorbent assay. Results Compared with group S, the frequency of crossing the original platform was significantly increased, the escape latency was shortened, and the concentrations of serum S100β protein and NSE were decreased at each time point after operation in N, HS and N+ HS groups(P<0.05). Compared with group N or group HS, the frequency of crossing the original platform was significantly increased, the escape latency was shortened, and the concentrations of serum S100β protein and NSE were decreased at each time point after operation in group N+ HS(P<0.05). Conclusion Nimodipine combined with 7.5% HS exerts better efficacy than either alone in improving postoperative cognitive function in aged rats. Key words: Nimodipine; Hypertonic saline; Aged; Cognition disorders

Impact of nimodipine on the neurologic impairment score, cerebral hemodynamic parameters and clinical efficacy of hypertensive cerebral hemorrhage in acute phase

Objective To compare the impact of nimodipine combined with mannitol and mannitol only on the neurologic impairment score, cerebral hemodynamic parameters and clinical efficacy of hypertensive cerebral hemorrhage in acute phase. Methods 68 patients with hypertensive cerebral hemorrhage in acute phase were selected, and they were randomly divided into control group(34 cases) and study group(34 cases) by digital table method.The control group was treated with mannitol only, while the study group was treated with nimodipine combined with mannitol.The clinical efficacy, hematoma volume, area of cerebral edema, cerebral hemodynamic parameters, neurologic impairment score, Barthel score of the two groups were compared, and the adverse drug reaction of the study group was observed. Results The total effective rate(82.4% vs.94.1%) and efficiency rate(44.1% vs.61.8%) of the two groups had statistically significant differences(χ2=5.688, 4.956, all P<0.05). The neurologic impairment score[post-treatment of the control group (10.2±9.3) points vs.pre-treatment (14.9±11.6) points, t=4.607, P<0.05; post-treatment of the study group (6.0±4.7) points vs.pre-treatment (14.4±10.8) points, t=8.379, P<0.05], area of cerebral edema[post-treatment of the control group (3.7±0.6)cm2 vs.pre-treatment (4.8±0.9)cm2, t=5.262, P<0.05; post-treatment of the study group (2.2±0.8)points vs.pre-treatment (5.1±1.2)points, t=9.193, P<0.05], hematoma volume[post-treatment of the control group (12.5±7.4)mL vs.pre-treatment (18.9±7.1)mL, t=6.033, P<0.05; post-treatment of the study group (8.6±8.2)points vs.pre-treatment (18.4±7.3)points, t=10.437, P<0.05]and Barthel score[post-treatment of the control group (73.6±40.4)points vs.pre-treatment (32.8±27.1)mL, t=7.827, P<0.05; post-treatment of the study group (85.6±46.8)points vs.pre-treatment (36.7±28.6)points, t=10.966, P<0.05]of the two groups had statistically significant differences.The neurologic impairment score of the study group after treatment was much lower than that of the control group[(6.0±4.7)points vs.(10.2±9.3)points, t=3.955, P<0.05]. There were statistically significant differences between after and before treatment of the control group in critical pressure[(9.3±2.2)kPa vs.(9.6±2.1)kPa, t=5.046, P<0.05], peripheral resistance[(1 788.2±209.4)kPa·s-1·mL-1 vs. (1 659.2±219.3)kPa·s-1·mL-1, t=6.146, P<0.05]and mean blood flow velocity[(6.4±1.1) mL/s vs. (7.9±1.2)mL/s, t=6.266, P<0.05]. The cerebral hemodynamic parameters of the study group after treatment had statistical differences compared with before treatment in critical pressure[(8.9±2.3)kPa vs.(8.2±1.1)kPa, t=5.292, P<0.05], peripheral resistance[(1 794.3±188.6)kPa·s-1·mL-1 vs. (1 469.5±161.8)kPa·s-1·mL-1, t=4.693, P<0.05], mean blood flow velocity[(6.4±1.3)mL/s vs. (8.6±1.5)mL/s, t=4.069, P<0.05], mean blood flow volume[(13.3±3.0) cm/s vs.(14.5±3.3)cm/s, t=5.633, P<0.05]. There were statistically significant differences between the two groups in critical pressure, peripheral resistance, mean blood flow velocity, mean blood flow volume(t=4.664, 4.563, 5.532, 5.327, all P<0.05). There were 4 cases of facial flushing, 2 cases of pulsatile headache, 3 cases of blood pressure drop, and the symptoms were gradually relieved after slowing down. Conclusion In the acute phase of hypertensive cerebral hemorrhage, nimodipine can reduce the scope of hematoma in a timely manner, significantly improve the efficacy and the quality of life of patients, it is worthy of clinical promotion. Key words: Hypertension; Cerebral hemorrhage; Nimodipine; Neurologic impairment score

Clinical efficacy and adverse effects of nimodipine combined with rivastigmine in the treatment of senile vascular dementia

Objective To learn the clinical efficacy and adverse effects of nimodipine combined with rivastigmine in the treatment of senile vascular dementia, and to provide effective treatment for the disease. Methods 151 elderly patients with senile vascular dementia were randomly divided into observation group (78 cases) and control group (73 cases) by using the random number table method.The control group was given nimodipine, and the observation group was given nimodipine combined with rivastigmine.The cognitive function was assessed by mini mental state examination(MMSE) scale, clinical dementia rating (CDR) scale was used to evaluate the degree of dementia, and activity of daily living (ADL) scale was used to evaluate the ability of daily activities.P300 test was performed before and after treatment for 12 weeks, and latency period (P300-PL) and amplitude (P300-A) of P300 were determined.The adverse drug reactions of the two groups were observed during the treatment period. Results After 12 weeks of treatment, the MMSE scores of the two groups were higher than before treatment, the CDR, ADL scores of the two groups were significantly lower than before treatment(t=8.353, 18.289, 6.627, 2.463, 10.681, 5.201, all P 0.05). Conclusion Nimodipine combined with rivastigmine can effectively treat senile vascular dementia, improve cognitive function, degree of dementia and daily activity ability of patients, the incidence rate of adverse drug reaction is low, and the therapeutic method is well tolerated with good clinical application value. Key words: Dementia, Vascular; Event-Related Potentials, P300; Rivastigmine; Nimodipine; Aged

Observation of the efficacy of Toutongning capsule combined with nimodipine in the treatment of 76 patients with primary vascular headache

Objective To explore the clinical efficacy of Toutongning capsule combined with nimodipine in the treatment of 76 patients with primary vascular headache. Methods 76 patients with primary vascular headache were selected as the research subjects.According to the different surgery, the patients were randomly divided into control group(n=38) and observation group(n=38). The control group was given compound Danshen injection, while the observation group was given Toutongning capsule combined with nimodipine.The efficacy, the peak systolic velocity(Vs) and pulsatility index(PI) of each vessel, the time of stopping pain, recurrence rate and adverse reaction were compared between the two groups. Results The total effective rate of the observation group was 94.74%, which was higher than 84.21% of the control group, the difference was statistically significant (χ2=4.785, P<0.05). The MCA, ACA, BA, VA value of Vs and PI, the time of stopping pain and recurrence rate in the observation group were better than those in the control group(t=5.385, 6.834, 7.407, 6.651, 4.032, 5.716, 6.203, 5.016, 4.785, χ2=5.473, all P<0.05). There were no significant differences between the two groups in PCA value of Vs and PI and adverse reaction(t=0.283, 0.037, χ2=0.314, all P<0.05). Conclusion Toutongning capsule combined with nimodipine in the treatment of primary vascular headache has high application value and significant effect, and it can promote cerebral circulation, blood flow, time of stopping pain and recurrence rate, so it is worthy of clinical popularization and application. Key words: Primary vascular headache; Toutongning capsule; Nimodipine; Clinical efficacy

Methodological assessment of the reduction of the content of impurities in nimodipine emulsion via the use of 21 amino acid protection

PurposeThe present study examined the factors affecting the content of impurities of nimodipine (NMP) emulsion and the associated methods of compound protection.MethodsDestructive testing of NMP emulsion and its active pharmaceutical ingredient (API) were conducted, and ultracentrifugation was used to study the content of impurities in two phases. The impurity of NMP was measured under different potential of hydrogen (pH) conditions, antioxidants and pH-adjusting agents.ResultsFollowing destruction, the degradation of NMP notably occurred in the basic environment. The consumption of the pH-adjusting agent NaOH was proportional to the production of impurities since the inorganic base and/or acid promoted the degradation of NMP. The organic antioxidants, notably amino acids with an appropriate length of intermediate chain and electron-donating side group, exhibited improved antioxidant effects compared with inorganic antioxidants. The minimal amount of impurities was produced following addition of 0.04% lysine and 0.06% leucine in the aqueous phase and adjustment of the pH to a range of 7.5–8.0 in the presence of acetic acid solution.ConclusionNMP was more prone to degradation in an oxidative environment, in an aqueous phase and/or in the presence of inorganic pH-adjusting agents and antioxidants. The appropriate antioxidant and pH-adjusting agent should be selected according to the chemical structure, while destructive testing of the drug is considered to play the optimal protective effect.

Effect of Intra-Arterial and Intravenous Nimodipine Therapy of Cerebral Vasospasm After Subarachnoid Hemorrhage on Cerebrovascular Reactivity and Oxygenation.

For the treatment and prevention of delayed cerebral ischemia after subarachnoid hemorrhage, the vasodilating agent nimodipine (NDP) is widely employed. This study investigates the effect of NDP on cerebrovascular autoregulation, assessed by pressure reactivity index (PRx), and brain tissue oxygenation (pbrO2) when given continuously intravenously as an intra-arterial bolus or during continuous intra-arterial therapy. Computerized continuous neuromonitoring data (intracranial pressure, mean arterial pressure, cerebral perfusion pressure [CPP], pbrO2, PRx) of 105 patients with aneurysmal SAH were retrospectively evaluated. The effect of NDP on all parameters was compared when applied intra-arterially for the treatment of severe macrovasospasm leading to perfusion deficits as either bolus treatment (n= 111 in 37 patients) or continuous infusion (n= 20 patients) to patients without or with only mild macrovasospasm who received either intravenous NDP or no NDP at all. Compared with patients without treatment, the intravenous application of NDP was associated with a significantly higher PRx. Autoregulation was strongly and long lastingly affected (high PRx) in continuous intra-arterial NDP infusion, accompanied by a sustained improvement of pbrO2. Intra-arterial bolus NDP application resulted as well in a significant increase of pbrO2 and PRx; the induced effect, however, was transient and subsided within 6 hours. Intracranial pressure, mean arterial pressure, and CPP were not affected during the monitoring period. The pharmacologically induced alteration of the cerebrovascular autoregulation by NDP correlates with changes of pbrO2 and indicates a beneficial effect on cerebral blood flow if CPP is maintained. This effect is limited to a few hours after bolus treatment and milder for intravenous compared with intra-arterial application.

Combining nanoscale magnetic nimodipine liposomes with magnetic resonance image for Parkinson's disease targeting therapy.

To enhance drug targeting and blood-brain barrier penetration for Parkinson's disease (PD), a novel nanoscale magnetic nimodipine (NMD) delivery system was designed and prepared. The PD rats were established and treated with free NMD or Fe3O4-modified NMD liposomes (Fe3O4-NMD-lips). Then, factional anisotropy values were measured by MRI to evaluate therapy efficacy. Fe3O4-NMD-lips showed the best neuroprotective effect, and the NMD concentration of lesions was 2.5-fold higher in Fe3O4-NMD-lips group than that of free NMD group. These results demonstrated that the magnetic drug system had a great potential to cross the blood-brain barrier and provided a noninvasive and effective therapeutic strategy for PD.

Contribution of both olfactory and systemic pathways for brain targeting of nimodipine-loaded lipo-pluronics micelles: in vitro characterization and in vivo biodistribution study after intranasal and intravenous delivery

Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5–13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NM-loaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with 99mTc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NM-loaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/g) in the heart of mice following administration of 99mTc-NM loaded LPM were lower compared with that following administration of 99mTc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of 99mTc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of 99mTc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM.

Controlled-release oral dosage forms containing nimodipine solid dispersion and hydrophilic carriers

The aim of this study was to prepare solid dispersion of nimodipine (NMD) by solvent evaporation method to overcome the poor water solubility of NMD, and to formulate controlled-release (CR) tablets containing the NMD solid dispersion. NMD is a dihydropyridine calcium-channel antagonist that is practically insoluble in water. Owing to the short half-life of the drug in the plasma, NMD immediate-release tablets should be administered frequently for the treatment and prevention of ischemic disorders following aneurysmal subarachnoid hemorrhage. In this study, solid dispersion technique was applied to increase the low solubility of NMD. Carriers for solid dispersions were prepared with different kinds of hydrophilic polymers. Kinetic solubility studies were performed for the prepared solid dispersions, using sodium acetate buffer (pH 4.5). Solid dispersions were then characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectrometry (FT-IR). CR tablets containing the NMD-PVP K30 solid dispersions were designed to reduce the dosing interval and increase patient compliance. Hydroxypropyl methylcelluloses (HPMC) were used as release-modifiers, and lactose anhydrous as a diluent.

Protective effects of nimodipine and lithium against aluminum-induced cell death and oxidative stress in PC12 cells.

The role of aluminum (Al) in the pathogenesis of neurodegenerative diseases has been implicated in several studies. However, the exact mechanisms of cytotoxic effects of Al have not been elucidated yet. The aim of this study was to investigate the effect of L-type calcium channel antagonist, nimodipine (NM), and lithium chloride (LiCl) on Al-induced toxicity in PC12 cells. PC12 cells were treated with Al-maltolate (Almal) in the presence and absence of different concentrations of NM (50-150 μm) and/or LiCl (0.5-1.0 mM) for 48 hr. Cell viability, apoptosis, and catalase (CAT) activity, a marker of oxidative stress, were then measured using MTT, flow cytometry and enzyme assay, respectively. The results showed that Almal, dose dependently induced cell death, apoptosis and CAT activity in the PC12 cells. NM significantly increased cell viability and decreased apoptosis and CAT activity of Almal-treated cells in a dose dependent mode. LiCl reduced CAT activity and increased cell viability in Almal-treated cells, without significant effect on apoptosis (P=0.74). These findings suggest that NM and Li may have benefits in the prevention of Al-induced cytotoxicity through decreasing oxidative stress.

Rare Cause of Severe Neurological Impairment in a Young Patient With Lupus

Systemic lupus erythematous (SLE) is a chronic autoimmune disease that frequently leads to kidney involvement. Hypertension in lupus nephritis (LN) is common, but malignant hypertension (MH) is a rare condition. MH in LN is associated with severe clinical manifestations and intrarenal vascular lesions. A 19-year-old woman with a history of SLE, class VI LN and MH presented with sudden drop in general status, confusion, diplopia, bradypsychia, and bradylalia. Physical exam showed cold extremities, cyanosis, high blood pressure (260/100 mm Hg) and tachycardia. Neurological exam showed impairment of the cerebellum, left central facial palsy and left-sided hemiparesis. Laboratory work showed thrombocytopenia, hyperuricemia, hypoalbuminemia and an estimated glomerular filtration rate of 66.1 mL/min/1.73 m 2 . A cerebral computed tomography (CT) showed no hemorrhagic lesions, but a diffuse hypodense edematous area in the pons, midbrain and bilateral thalamic nuclei. She was started on antihypertensive therapy, dexamethasone and mannitol. After 5 days in intensive care unit, a brain magnetic resonance angiogram (MRA) showed petechial hemorrhage and swelling in deep thalamic regions, left internal capsule, pons, and midbrain. Nimodipine was added to the regimen. Workup for JC virus and Listeria monocytogenes was negative. Evolution was favorable with complete remission of neurological symptoms. Repeated brain MRA confirmed regression of swelling and hemorrhagic lesions. The diagnosis of hypertensive encephalopathy was sustained by improved clinical evolution under anti-edema measures, antihypertensives and by CT/magnetic resonance imaging (MRI). Differential diagnosis was made with central nervous system vasculitis and infections due to immunosuppression therapy (tuberculosis, HIV, and JC virus). This case describes the evolution of a young woman with lupus and recurrent MH, complicated with neurological manifestations. J Med Cases. 2016;7(11):488-490 doi: http://dx.doi.org/10.14740/jmc2676w

P.3.c.008 - Brexpiprazole improves negative-like behaviours in the nest building and social interaction assays in a mouse model of schizophrenia

Previous studies have shown that intracellular calcium ion dysfunction may be an etiological factor in affective illness. Nimodipine (NMD) is a Ca2+ channel blocker that has been extensively investigated for therapy of central nervous system (CNS) disorders. In this work, we have evaluated the antidepressant-like activity of nimodipine encapsulated into liposomes (NMD-Lipo) in mice through tail suspension and forced swim assays, as well as MAOB activity. During the tail suspension test, the administration of NMD-Lipo at 0.1, 1 and 10 mg/kg was able to promote a reduction in the immobility time of animals greater than the positive control (imipramine). In the forced swim test, the immobility time of mice treated with NMD-Lipo was reduced. This reduction was significantly greater than that found in the animals treated with imipramine and paroxetine. This may suggest that NMD-Lipo provides more antidepressant-like activity than in positive controls. The groups that received a combination of liposomal NMD and antidepressant drugs showed lower immobility time than the groups, which were treated only with imipramine or paroxetine. The mice treated with the combination of NMD-Lipo and reserpine presented an increase in the time of immobility compared with animals treated only with NMD-Lipo. There was a significant decrease in MAOB activity in animals treated with NMD-Lipo compared with untreated animals. The results of the tail suspension test, forced swim test and MAOB activity suggested that the antidepressant activity of NMD-Lipo may be related to an increase in the cerebral monoamine concentrations.

Differential Regulation of Human Paired Associative Stimulation-Induced and Theta-Burst Stimulation-Induced Plasticity by L-type and T-type Ca2+ Channels.

Activity-dependent changes of postsynaptic Ca2+-concentration are influenced by a variety of different Ca2+-channels and play an important role in synaptic plasticity. Paired associative stimulation (PAS) and theta-burst stimulation (TBS) are noninvasive magnetic stimulation protocols used in human subjects to induce lasting corticospinal excitability changes that have been likened to synaptic long-term potentiation and long-term depression. To better characterize the Ca2+-related physiological mechanisms underlying PAS- and TBS-induced plasticity, we examined the impact of different Ca2+-sources. PAS-induced facilitation of corticospinal excitability was blocked by NMDA-receptor blocker dextromethorphan (DXM) and L-type voltage gated Ca2+ channels (VGCC) blocker nimodipine (NDP), but turned into depression by T-type VGCC blocker ethosuximide (ESM). Although, surprisingly, static corticospinal excitability was increased by the combination of DXM and NDP, PAS-induced facilitation was blocked. TBS-induced facilitation of corticospinal excitability, which has previously been shown to be turned into depression by L-type VGCC blocker NDP (Wankerl K, Weise D, Gentner R, Rumpf J, Classen J. 2010. L-type voltage-gated Ca2+ channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans. J Neurosci. 30(18):6197-6204.), was blocked, but not reverted, by T-type VGCC blocker ESM. The different patterns of Ca2+-channel modulation of PAS- and TBS-induced plasticity may point to an important role of backpropagating action potentials in PAS-induced plasticity, similar as in spike-timing dependent synaptic plasticity, and to a requirement of dendritic Ca2+-dependent spikes in TBS-induced plasticity.

The effect of neropeptide substance P receptor antagonist can relieve the current of reverse-mode NCX in airway smooth muscle cells

Objective Investigate the effect of substance P and receptor antagonist on the current of NCX in ASMC. Methods Primary rat ASMC cultures were established.Immunofluorescence was used to identify ASMCs.Patch clamp exam was used to assess NCX currents in ASMC before and after intervented by Ach, substance P, NK-1R receptor antagonist and nimodiping, Voltage-current curves were drawn according to variation of voltage and current.PA indicates current amplitude, PF indicates cell area, and PA/PF indicates current density. Results As the voltage increased, the current density increased.When voltage up to-40mV the reverse current appeard.When the voltage is 60mV the current density in the Ach intervention group was highest, but lowest in the nimodipine intervention group; the current density in the substance P intervention group is more than in control group but lower than in Ach interevention group.The current density in the substance P receptor antagonist intervention group higher than nimodipine interevention goup, but lower than the other group(P<0.05). Conclusion In asthma airways, Ca2+ overload is related to the appearance of reverse-mode NCX.NK-1R antagonist plays a role in decreasing the Ca2+ concentration, which can relieve the current of reverse-mode NCX, and may benefit alleviating airway inflammation and responsiveness.As a result, NK-1R antagonist may be an attractive target for therapeutic approaches to asthma. Key words: Substance P; Receptor antagonist; Asthma; Airway smooth muscle cell; Sodium-calcium exchang

Antidepressant-like activity of liposomal formulation containing nimodipine treatment in the tail suspension test, forced swim test and MAOB activity in mice

Previous studies have shown that intracellular calcium ion dysfunction may be an etiological factor in affective illness. Nimodipine (NMD) is a Ca2+ channel blocker that has been extensively investigated for therapy of central nervous system (CNS) disorders. In this work, we have evaluated the antidepressant-like activity of nimodipine encapsulated into liposomes (NMD-Lipo) in mice through tail suspension and forced swim assays, as well as MAOB activity. During the tail suspension test, the administration of NMD-Lipo at 0.1, 1 and 10mg/kg was able to promote a reduction in the immobility time of animals greater than the positive control (imipramine). In the forced swim test, the immobility time of mice treated with NMD-Lipo was reduced. This reduction was significantly greater than that found in the animals treated with imipramine and paroxetine. This may suggest that NMD-Lipo provides more antidepressant-like activity than in positive controls. The groups that received a combination of liposomal NMD and antidepressant drugs showed lower immobility time than the groups, which were treated only with imipramine or paroxetine. The mice treated with the combination of NMD-Lipo and reserpine presented an increase in the time of immobility compared with animals treated only with NMD-Lipo. There was a significant decrease in MAOB activity in animals treated with NMD-Lipo compared with untreated animals. The results of the tail suspension test, forced swim test and MAOB activity suggested that the antidepressant activity of NMD-Lipo may be related to an increase in the cerebral monoamine concentrations.

The effect of neuropeptide substance P on airway smooth muscle cell contraction amplitude

Objective To investigate the effect of neuropeptide substance P on airway smooth muscle cell contraction amplitude. Methods According to random method, 10 Wistar rats were divided into normal group and asthmatic group.By inhaled OVA to make asthmatic rat model; primary culture ASMC; confocal microscopy were used to observe the morphological changes and measure the length before and after different intervention.The percent of contraction length come from different group ASMC were used for statistical analysis. Results The ASMCs volume in acetylcholine intervented group and substance P intervented group decreased significantly, cell diameters shorten, cytoplasm reduction and cell arranged densely.The ASMCs volume in substance P receptor antagonist intervented group and nimodipine intervented group are about the same size as the ones in normal control group, were spindle-shaped, abundant cytoplasm and arrangement regularly.The contraction length percent of Ach intervened group is the biggest(19.60±3.47)%, contraction length percent of nimodiping intervented group is the shortest(3.25±1.14)%, the contraction length percent in substance P recepter antagonist intervented group is bigger than the one in control group(3.54±1.26)%, but less than the one in Ach intervented group, asthmatic(14.36±2.37)% and substance P intervened group(17.79±3.19)%. Conclusion Substance P can increase the amplitude of airway smooth muscle cell contraction, but the effect less than Ach; substance P receptor antagonists can inhibit smooth muscle cell contractility, but the effect less than nimodipine.Substance P participates in acute attack of asthma, increases airway reactivity by increasing airway smooth muscle contraction intensity. Key words: Neuropeptide; Airway smooth muscle cell; Contraction amplitude; Asthma

One-step self-assembled nanomicelles for improving the oral bioavailability of nimodipine.

Our study aimed to develop a self-assembled nanomicelle for oral administration of nimodipine (NIM) with poor water solubility. Using Solutol® HS15, the NIM-loaded self-assembled nanomicelles displayed a near-spherical morphology with a narrow size distribution of 12.57±0.21 nm (polydispersity index =0.071±0.011). Compared with Nimotop® (NIM tablets), the intestinal absorption of NIM from NIM nanomicelle in rats was improved by 3.13- and 2.25-fold in duodenum and jejunum at 1 hour after oral administration. The cellular transport of NIM nanomicelle in Caco-2 cell monolayers was significantly enhanced compared to that of Nimotop®. Regarding the transport pathways, clathrin, lipid raft/caveolae, and macropinocytosis mediated the cell uptake of NIM nanomicelles, while P-glycoprotein and endoplasmic reticulum/Golgi complex (ER/Golgi) pathways were involved in exocytosis. Pharmacokinetic studies in our research laboratory have showed that the area under the plasma concentration–time curve (AUC0–∞) of NIM nanomicelles was 3.72-fold that of Nimotop® via oral administration in rats. Moreover, the NIM concentration in the brain from NIM nanomicelles was dramatically improved. Therefore, Solutol® HS15-based self-assembled nanomicelles represent a promising delivery system to enhance the oral bioavailability of NIM.

Nimodipine-Loaded Pluronic® Block Copolymer Micelles: Preparation, Characterization, In-vitro and In-vivo Studies.

Nimodipine (NM), as a lipophilic calcium channel blocker indicated for the prevention and treatment of neurological disorders, suffers from an extensive first pass metabolism, resulting in low oral bioavailability. Polymeric micelles, self-assembled from amphiphilic polymers, have a core-shell structure which makes them unique nano-carriers with excellent performance as drug delivery. This investigation was aimed to develop NM-loaded polymeric micelles and evaluate their potential to cross the blood brain barrier (BBB). Micelles from Pluronics®P85, F127 and F68 were fabricated for the delivery of NM, using thin film hydration and direct dissolution techniques. Critical micelle concentration of the drug-free micelles was determined by pyrene fluorescence spectroscopy. Dynamic light scattering showed that in most cases, micelles less than 100 nm and low polydispersity indices were successfully developed. Transmission electron microscopy demonstrated spherical shape of micelles. The NM-loaded micelles were also characterized for particle size, morphology, entrapment efficiency, drug loading , in vitro drug release in phosphate buffer and artificial cerebrospinal fluid (CSF). Stability was assessed from size analysis, clarity of dispersion on standing and EE(%), following 3 months storage at room temperature. The in-vitro release of NM from polymeric micelles presented the sustained-release profile. Animal studies revealed the existence of fluorescein 5-isothiocyanate-labeled micelles in rat CSF following intraperitoneal administration, proving that the micelles crossed the BBB. Anticonvulsant effect of NM was shown to be significantly greater than that of NM solution. Our results confirmed that Pluronic micelles might serve as a potential nanocarrier to improve the activity of NM in brain.