scholarly journals Ultrasound-Induced Release of Nimodipine from Drug-Loaded Block Copolymer Micelles: In Vivo Analysis

Author(s):  
Katja Döring ◽  
Swetlana Sperling ◽  
Milena Ninkovic ◽  
Henning Schroeder ◽  
André Fischer ◽  
...  

AbstractNimodipine prevents cerebral vasospasm and improves functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). The beneficial effect is limited by low oral bioavailability of nimodipine, which resulted in an increasing use of nanocarriers with sustained intrathecal drug release in order to overcome this limitation. However, this approach facilitates only a continuous and not an on-demand nimodipine release during the peak time of vasospasm development. In this study, we aimed to assess the concept of controlled drug release from nimodipine-loaded copolymers by ultrasound application in the chicken chorioallantoic membrane (CAM) model. Nimodipine-loaded copolymers were produced with the direct dissolution method. Vasospasm of the CAM vessels was induced by means of ultrasound (Physiomed, continuous wave, 3 MHz, 1.0 W/cm2). The ultrasound-mediated nimodipine release (Physiomed, continuous wave, 1 MHz, 1.7 W/cm2) and its effect on the CAM vessels were evaluated. Measurements of vessel diameter before and after ultrasound-induced nimodipine release were performed using ImageJ. The CAM model could be successfully carried out in all 25 eggs. After vasospasm induction and before drug release, the mean vessel diameter was at 57% (range 44–61%) compared to the baseline diameter (set at 100%). After ultrasound-induced drug release, the mean vessel diameter of spastic vessels increased again to 89% (range 83–91%) of their baseline diameter, which was significant (p = 0.0002). We were able to provide a proof of concept for in vivo vasospasm induction by ultrasound application in the CAM model and subsequent resolution by ultrasound-mediated nimodipine release from nanocarriers. This concept merits further evaluation in a rat SAH model. Graphical abstract

1990 ◽  
Vol 258 (6) ◽  
pp. H1829-H1834 ◽  
Author(s):  
K. Fujii ◽  
D. D. Heistad ◽  
F. M. Faraci

Vasomotion is a rhythmic change in vascular caliber that has been described in vivo mainly in peripheral arterioles. In this study, we have characterized vasomotion in a large artery of the brain in vivo. In anesthetized rats, spontaneous vasomotion was observed in 38 of 47 basilar arteries visualized through a cranial window. Base-line arterial diameter was 259 +/- 9 (means +/- SE) microns. Under control conditions, the frequency of vasomotion was 4.8 +/- 0.2 cycles/min, and the amplitude was 19 +/- 2% of the mean diameter. Vasomotion usually occurred simultaneously along the entire length of the vessel, but in some arteries it propagated in either direction. Moderate hypertension (phenylephrine) or vasoconstriction induced by topical application of serotonin, vasopressin, or the thromboxane analogue U 46619 increased the frequency of vasomotion. Moderate hypotension or vasodilation induced by nitroglycerin, adenosine, or acetylcholine decreased the frequency. Marked hypertension, hypotension, or vasodilatation abolished vasomotion. Thus vasomotion of the basilar artery in vivo 1) is common and of relatively large amplitude, 2) does not seem to be driven by a single pacemaker, and 3) is dependent on vessel diameter or vasomotor tone.


1992 ◽  
Vol 262 (4) ◽  
pp. H1217-H1223 ◽  
Author(s):  
B. Woldhuis ◽  
G. J. Tangelder ◽  
D. W. Slaaf ◽  
R. S. Reneman

Platelet distribution was investigated in 21 venules (V) and 10 arterioles (A) of the rabbit mesentery (vessel diam 15-33 microns). Circulating platelets were labeled in vivo with the dye acridine red and observed with fluorescence video microscopy. Only platelets flowing in a thin (5-7 microns) optical section located about the median plane of the vessel were used. The relative position of each platelet, i.e., the distance of its centroid to the left vessel wall divided by the local vessel diameter, was determined. In addition, in 10 venules leukocyte margination was inhibited by intravenous injection of dextran sulfate (500,000 mol wt; 30 mg/kg body wt). The number of platelets per unit volume (i.e., platelet density) relative to the mean density was significantly higher in the vessel center of V (1.04) than of A (0.55; P less than 0.005). In contrast, near the wall this density was significantly higher in A compared with V. Mean values were as follows: at radial position (R) = 0.9-1.0, 0.30 in A and 0.11 in V (P greater than 0.05); at R = 0.8-0.9, 1.63 in A and 0.84 in V (P less than 0.002); at R = 0.7-0.8, 1.60 in A and 1.36 in V (P greater than 0.05); at R = 0.6-0.7, 1.16 in A and 1.60 in V (P less than 0.02); and at R = 0.5-0.6, 0.92 in A and 1.36 in V (P less than 0.02). These differences in platelet distribution between arterioles and venules are not caused by the presence of leukocyte margination in venules.


2001 ◽  
Vol 281 (3) ◽  
pp. H1353-H1363 ◽  
Author(s):  
Ute Lindauer ◽  
Alexander Kunz ◽  
Sigrid Schuh-Hofer ◽  
Johannes Vogt ◽  
Jens P. Dreier ◽  
...  

In the isolated rat middle cerebral artery (MCA) we investigated the role of nitric oxide (NO)/cGMP in the vasodilatory response to extraluminal acidosis. Acidosis increased vessel diameter from 140 ± 27 μm (pH 7.4) to 187 ± 30 μm (pH 7.0, P < 0.01). NO synthase (NOS) inhibition by N ω-nitro-l-arginine (l-NNA, 10 μM) reduced baseline diameter (103 ± 20 μm, P < 0.01) and attenuated response to acidosis (9 ± 8 μm). Application of the NO-donors 3-morpholinosydnonimine (1 μM) or S-nitroso- N-acetylpenicillamine (1 μM), or of 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP, 100 μM) reestablished pre-l-NNA diameter at pH 7.4 and reversedl-NNA-induced attenuation of the vessel response to acidosis. Restoration of pre-l-NNA diameter (pH 7.4) by papaverine (20 μM) or nimodipine (30 nM) had no effect on the attenuated response to acidosis. Guanylyl cyclase inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (5 μM) or NOS-inhibition with 7-nitroindazole (7-NI, 100 μM) reduced baseline vessel diameter (109 ± 8 or 127 ± 11 μm, respectively) and vasodilation to acidosis, and restoration of baseline diameter with 8-BrcGMP (30 μM) completely restored dilation to pH 7.0. Chronic denervation of NOS-containing perivascular nerves in vivo 14 days before artery isolation significantly reduced pH-dependent reactivity in vitro (diameter increase sham: 48 ± 14 μm, denervated: 14 ± 8 μm), and 8-BrcGMP (30 μM) restored dilation to pH 7.0 (denervated: 49 ± 31 μm). Removal of the endothelium did not change vasodilation to acidosis. We conclude that NO, produced by neuronal NOS of perivascular nerves, is a modulator in the pH-dependent vasoreactivity.


2021 ◽  
Vol 22 (13) ◽  
pp. 6659
Author(s):  
Yang Han ◽  
Jieyi Pan ◽  
Na Liang ◽  
Xianfeng Gong ◽  
Shaoping Sun

In this study, an amphiphilic conjugate based on mPEG and cholesterol-modified chitosan with hydrazone bonds in the molecules (mPEG-CS-Hz-CH) was successfully synthesized. Using the polymer as the carrier, the paclitaxel (PTX)-loaded mPEG-CS-Hz-CH micelles were prepared by an ultrasonic probe method. The mean particle size and zeta potential of the optimized PTX-loaded micelles were 146 ± 4 nm and +21.7 ± 0.7 mV, respectively. An in vitro drug release study indicated that the PTX-loaded mPEG-CS-Hz-CH micelles were stable under normal physiological conditions (pH 7.4), whereas rapid drug release was observed in the simulated tumor intracellular microenvironment (pH 5.0). An in vitro cytotoxicity study demonstrated the non-toxicity of the polymer itself, and the PTX-loaded micelles exhibited superior cytotoxicity and significant selectivity on tumor cells. An in vivo antitumor efficacy study further confirmed that the PTX-loaded micelles could improve the therapeutic efficacy of PTX and reduce the side effects. All these results suggested that the mPEG-CS-Hz-CH micelles might be promising pH-sensitive nanocarriers for PTX delivery.


1996 ◽  
Vol 76 (01) ◽  
pp. 111-117 ◽  
Author(s):  
Yasuto Sasaki ◽  
Junji Seki ◽  
John C Giddings ◽  
Junichiro Yamamoto

SummarySodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction


1993 ◽  
Vol 70 (04) ◽  
pp. 676-680 ◽  
Author(s):  
H F Kotzé ◽  
V van Wyk ◽  
P N Badenhorst ◽  
A du P Heyns ◽  
J P Roodt ◽  
...  

SummaryPlatelets were isolated from blood of baboons and treated with neuraminidase to remove platelet membrane sialic acid, a process which artificially ages the platelets. The platelets were then labelled with 111In and their mean life span, in vivo distribution and sites of Sequestration were measured. The effect of removal of sialic acid on the attachment of immunoglobulin to platelets were investigated and related to the Sequestration of the platelets by the spleen, liver, and bone marrow. Removal of sialic acid by neuraminidase did not affect the aggregation of platelets by agonists in vitro, nor their sites of Sequestration. The removal of 0.51 (median, range 0.01 to 2.10) nmol sialic acid/108 platelets shortened their life span by 75 h (median, range 0 to 132) h (n = 19, p <0.001), and there was an exponential correlation between the shortening of the mean platelet life span and the amount of sialic acid removed. The increase in platelet-associated IgG was 0.112 (median, range 0.007 to 0.309) fg/platelet (n = 25, p <0.001) after 0.79 (median, range 0.00 to 6.70) nmol sialic acid/108 platelets was removed (p <0.001). There was an exponential correlation between the shortening of mean platelet life span after the removal of sialic acid and the increase in platelet-associated IgG. The results suggest that platelet membrane sialic acid influences ageing of circulating platelets, and that the loss of sialic acid may have exposed a senescent cell antigen that binds IgG on the platelet membrane. The antibody-antigen complex may then provide a signal to the macrophages that the platelet is old, and can be phagocytosed and destroyed.


Author(s):  
EL- Assal I. A. ◽  
Retnowati .

Objective of the present investigation was enthused by the possibility to develop solid lipid nanoparticles (SLNs) of hydrophilic drug acyclovir. Also study vitro and vivo drug delivery. Methods: Drug loaded SLNs (ACV-SLNs) were prepared by high pressure homogenization of aqueous surfactant solutions containing the drug-loaded lipids in the melted or in the solid state with formula optimization study (Different lipid concentration, drug loaded, homogenization / stirring speed and compritol 888ATO: drug ratio). ACV - SLN incorporated in cream base. The pH was evaluated and rheological study. Drug release was evaluated and compared with simple cream- drug, ACV – SLN with compritol 888ATO and marketed cream. The potential of SLN as the carrier for dermal delivery was studied. Results: Particle size analysis of SLNs prove small, smooth, spherical shape particle ranged from 150 to 200 nm for unloaded and from 330 to 444 nm for ACV loaded particles. The EE% for optimal formula is 72% with suitable pH for skin application. Rheological behavior is shear thinning and thixotropic. Release study proved controlled drug release for SLNs especially in formula containing compritol88 ATO. Stability study emphasized an insignificant change in SLNs properties over 6 month. In-vivo study showed significantly higher accumulation of ACV in stratum corneum, dermal layer, and receptor compartment compared with blank skin. Conclusion: AVC-loaded SLNs might be beneficial in controlling drug release, stable and improving dermal delivery of antiviral agent(s).


Author(s):  
ShirishaG. Suddala ◽  
S. K. Sahoo ◽  
M. R. Yamsani

Objective: The objective of this research work was to develop and evaluate the floating– pulsatile drug delivery system (FPDDS) of meloxicam intended for Chrono pharmacotherapy of rheumatoid arthritis. Methods: The system consisting of drug containing core, coated with hydrophilic erodible polymer, which is responsible for a lag phase for pulsatile release, top cover buoyant layer was prepared with HPMC K4M and sodium bicarbonate, provides buoyancy to increase retention of the oral dosage form in the stomach. Meloxicam is a COX-2 inhibitor used to treat joint diseases such as osteoarthritis and rheumatoid arthritis. For rheumatoid arthritis Chrono pharmacotherapy has been recommended to ensure that the highest blood levels of the drug coincide with peak pain and stiffness. Result and discussion: The prepared tablets were characterized and found to exhibit satisfactory physico-chemical characteristics. Hence, the main objective of present work is to formulate FPDDS of meloxicam in order to achieve drug release after pre-determined lag phase. Developed formulations were evaluated for in vitro drug release studies, water uptake and erosion studies, floating behaviour and in vivo radiology studies. Results showed that a certain lag time before drug release which was due to the erosion of the hydrophilic erodible polymer. The lag time clearly depends on the type and amount of hydrophilic polymer which was applied on the inner cores. Floating time and floating lag time was controlled by quantity and composition of buoyant layer. In vivo radiology studies point out the capability of the system of longer residence time of the tablets in the gastric region and releasing the drug after a programmed lag time. Conclusion: The optimized formulation of the developed system provided a lag phase while showing the gastroretension followed by pulsatile drug release that would be beneficial for chronotherapy of rheumatoid arthritis and osteoarthritis.


Author(s):  
Anamika Saxena Saxena ◽  
Santosh Kitawat ◽  
Kalpesh Gaur ◽  
Virendra Singh

The main goal of any drug delivery system is to achieve desired concentration of the drug in blood or tissue, which is therapeutically effective and nontoxic for a prolonged period. Various attempts have been made to develop gastroretentive delivery systems such as high density system, swelling, floating system. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to design single-unit and multiple-unit floating systems, and their classification and formulation aspects are covered in detail. Gastric emptying is a complex process and makes in vivo performance of the drug delivery systems uncertain. In order to avoid this variability, efforts have been made to increase the retention time of the drug-delivery systems for more than 12 hours. The floating or hydrodynamically controlled drug delivery systems are useful in such application. Background of the research: Diltiazem HCL (DTZ), has short biological half life of 3-4 h, requires rather high frequency of administration. Due to repeated administration there may be chances of patient incompliance and toxicity problems. Objective: The objective of study was to develop sustained release alginate beads of DTZ for reduction in dosing frequency, high bioavailability and better patient compliance. Methodology: Five formulations prepared by using different drug to polymer ratios, were evaluated for relevant parameters and compared. Alginate beads were prepared by ionotropic external gelation technique using CaCl2 as cross linking agent. Prepared beads were evaluated for % yield, entrapment efficiency, swelling index in 0.1N HCL, drug release study and SEM analysis. In order to improve %EE and drug release, LMP and sunflower oil were used as copolymers along with sodium alginate.


Author(s):  
Bhikshapathi D. V. R. N. ◽  
Haarika B ◽  
Jyothi Sri S ◽  
K Abbulu

The purpose of present investigation was to develop floating matrix tablets of gemifloxacin mesylate, which after oral administration could prolong the gastric residence time, increase the drug bioavailability and diminish the side effects of irritating drugs. Tablets containing drug, various viscosity grades of hydroxypropyl methylcellulose such as HPMC K4M and HPMC K15M as matrix forming agent, Sodium bicarbonate as gas-forming agent and different additives were tested for their usefulness in formulating gastric floating tablets by direct compression method. The physical parameters, in vitro buoyancy, release characteristics and in vivo radiographic study were investigated in this study. The gemifloxacin mesylate floating tablets were prepared using HPMC K4M polymer giving more sustained drug release than the tablet containing HPMC K15M. All these formulations showed floating lag time of 30 to 47 sec and total floating time more than 12 h. The drug release was decreased when polymer concentration increases and gas generating agent decreases. Formulation that contains maximum concen-tration of both HPMC K15M and sodium bicarbonate (F9) showing sufficiently sustained with 99.2% of drug release at 12 h. The drug release from optimized formulation follows Higuchi model that indicates the diffusion controlled release. The best formulation (F9) was selected based on in vitro characteristics and used in vivo radiographic studies by incorporating barium sulphate as a radio-opaque agent and the tablet remained in the stomach for about 6 h.   


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