Reversal of granulocyte adherence to nylon fibers using local anesthetic agents: possible application to filtration leukapheresis

The effects of the cationic anesthetic agents tetracaine and lidocaine on granulocyte function, morphology, and adherence to nylon fibers were studied in an attempt to improve current methods of granulocyte collection by filtration leukapheresis (FL). When dissolved in acid- citrate-dextrose (ACD) plasma, these drugs significantly increased granulocyte elution from the fibers in a dose-related fashion. Granulocytes exposed to tetracaine and lidocaine remained more than 95% viable, retained normal bactericidal capacity after the drugs were washed from the cells, and had preserved membrane integrity, as evidenced by the normal ultrastructural appearance of tetracaine- exposed cells and an absence of leakage of lysozyme or lactic dehydrogenase. Granulocytes eluted with the anesthetic agents were rounded in shape with a reduction in the number of filopodial cytoplasmic projections and a relative absence of cytoplasmic vacuolization when compared to granulocytes eluted with ACD plasma alone. Dose-related inhibition of phagocytosis and adherence, which was largely reversible after washing the granulocytes, was noted. Greater than 95% of the lidocaine could be removed from the eluate with a single centrifugation and resuspension, indicating that granulocytes prepared by FL with anesthetic-enhanced elution could be potentially transfusable.     

Platelets inhibit the induction of nitric oxide synthesis by interleukin-1 beta in vascular smooth muscle cells

We have investigated the role of platelets in regulating the hemostatic and vasomotor properties of vascular smooth muscle. Experiments were performed to examine the effect of the releasate from activated platelets on the production of nitric oxide from interleukin-1 beta (IL- 1 beta)-treated cultured rat aortic smooth muscle cells. Treatment of vascular smooth muscle cells with IL-1 beta resulted in significant accumulation of nitrite in the culture media and in marked elevation of intracellular cyclic guanosine monophosphate (GMP) levels. The releasate from collagen-aggregated platelets blocked the IL-1 beta- mediated production of nitrite and the accumulation of cyclic GMP in smooth muscle cells in a platelet number-dependent manner. In functional assays, the perfusates from columns containing IL-1 beta- treated smooth muscle cells relaxed detector blood vessels without endothelium and the addition of IL-1 beta-treated smooth muscle cells to suspensions of platelets inhibited their thrombin-induced aggregation. The simultaneous treatment of smooth muscle cells with IL- 1 beta and the platelet releasate abolished both the vasorelaxing activities of the perfusates and the inhibition of platelet aggregation. Platelet releasates treated with a neutralizing antibody to platelet-derived growth factor (PDGF) failed to block IL-1 beta- induced nitric oxide production by the smooth muscle cells, as measured by both biochemical and functional assays. The platelet releasate from a patient with gray platelet syndrome likewise failed to block IL-1 beta-induced nitrite release by smooth muscle cells. These results demonstrate that platelets downregulate the production of nitric oxide by IL-1 beta-treated vascular smooth muscle cells through the release of PDGF. This effect may represent a novel mechanism by which platelets regulate vasomotor tone and thrombus formation at sites of vascular injury.     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.     

Cetyl palmitate-based NLC for topical delivery of Coenzyme Q(10) - development, physicochemical characterization and in vitro release studies.

In the present study, nanostructured lipid carriers (NLC) composed of cetyl palmitate with various amounts of caprylic/capric triacylglycerols (as liquid lipid) were prepared and Coenzyme Q(10) (Q(10)) has been incorporated in such carriers due to its high lipophilic character. A nanoemulsion composed solely of liquid lipid was prepared for comparison studies. By photon correlation spectroscopy a mean particle size in the range of 180-240nm with a narrow polydispersity index (PI) lower than 0.2 was obtained for all developed formulations. The entrapment efficiency was 100% in all cases. The increase of oil loading did not affect the mean particle size of NLC formulations. NLC and nanoemulsion, stabilized by the same emulsifier, showed zeta potential values in the range -40/-50mV providing a good physical stability of the formulations. Scanning electron microscopy studies revealed NLC of disc-like shape. With respect to lipid polymorphism, a decrease in the ordered structure of NLC was observed with the increase of both oil and Q(10) loadings, allowing therefore high accommodation for Q(10) within the NLC. Using static Franz diffusion cells, the in vitro release studies demonstrated that Q(10)-loaded NLC possessed a biphasic release pattern, in comparison to Q(10)-loaded nanoemulsions comprising similar composition of which a nearly constant release was observed. The NLC release patterns were defined by an initial fast release in comparison to the release of NE followed by a prolonged release, which was dependent on the oil content.     

Angiotensin‐converting enzyme inhibition increases glucose‐induced insulin secretion in response to acute restraint

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Physicochemical properties and skin permeation of Span 60/Tween 60 niosomes of ellagic acid

Ellagic acid (EA) is a potent antioxidant phytochemical substance which has limitation to use due to its poor biopharmaceutical properties, low solubility and low permeability. The aim of the present study was to develop niosomal formulations obtained from the mixture of Span 60 and Tween 60 that could encapsulate EA for dermal delivery. The EA-loaded niosomes were prepared with 1:0, 2:1, 1:1, 0:1 Span 60 and Tween 60, using polyethylene glycol 400 (PEG 400), propylene glycol (PG) or methanol (MeOH) as a solubilizer. The influence of formulations on vesicle size, entrapment efficiency and stability of EA-loaded niosomes was investigated. It was found that all ratios of surfactants could produce EA-loaded niosomes when using 15% (v/v) PG, 15% (v/v) PEG 400 or 20% (v/v) MeOH. The niosomes were spherical multilamellar vesicles showing the localization of EA in the vesicles. The vesicle sizes of the niosomes after extrusion were 124-752 nm with PI less than 0.4. The percentages of entrapment efficiency (% E.E.) of all EA-loaded niosomes varied between 1.35% and 26.75% while PEG 400 niosomes gave the highest % E.E. The most stable and highest entrapped formulation was 2:1 Span 60 and Tween 60 niosomes. Additionally, the in vitro skin permeation revealed that penetration of EA from the niosomes depended on vesicle size, the amount of EA entrapped and the added solubilizers which could act as a permeation enhancer. From skin distribution study, the EA-loaded niosomes showed more efficiency in the delivery of EA through human epidermis and dermis than EA solution. The results indicated that the Span 60 and Tween 60 niosomes may be a potential carrier for dermal delivery of EA.     

GROWTH HORMONE ATTENUATES MYOCARDIAL FIBROSIS IN RATS WITH CHRONIC PRESSURE OVERLOAD-INDUCED LEFT VENTRICULAR HYPERTROPHY

• 1 The role of growth hormone (GH) in cardiac remodelling and function in chronic and persistent pressure overload‐induced left ventricular hypertrophy has not been defined. The aim of the present study was to assess short‐term GH treatment on left ventricular function and remodelling in rats with chronic pressure overload‐induced hypertrophy.
• 2 Twenty‐six weeks after induction of ascending aortic stenosis (AAS), rats were treated with daily subcutaneous injections of recombinant human GH (1 mg/kg per day; AAS‐GH group) or saline (AAS‐P group) for 14 days. Sham‐operated animals served as controls. Left ventricular function was assessed by echocardiography before and after GH treatment. Myocardial fibrosis was evaluated by histological analysis.
• 3 Before GH treatment, AAS rats presented similar left ventricular function and structure. Treatment of rats with GH after the AAS procedure did not change bodyweight or heart weight, both of which were higher in the AAS groups than in the controls. After GH treatment, posterior wall shortening velocity (PWSV) was lower in the AAS‐P group than in the control group. However, in the AAS‐GH group, PWSV was between that in the control and AAS‐P groups and did not differ significantly from either group. Fractional collagen (% of total area) was significantly higher in the AAS‐P and AAS‐GH groups compared with control (10.34 ± 1.29, 4.44 ± 1.37 and 1.88 ± 0.88%, respectively; P < 0.05) and was higher still in the AAS‐P group compared with the AAS‐GH group.
• 4 The present study has shown that short‐term administration of GH to rats with chronic pressure overload‐induced left ventricular hypertrophy induces cardioprotection by attenuating myocardial fibrosis.

     

Inhibitory effect of Thai plant extracts on P-glycoprotein mediated efflux

Curcuminoids from Curcuma longa L. and extracts of Psidium guajava L., Andrographis paniculata (Burm. f.) Nees, Phyllanthus emblica L. and Solanum trilobatum L. were investigated for their inhibitory effect on P-glycoprotein (P-gp) on the efflux transport of rhodamine 123 (Rho-123 ) in Caco-2 cells and rat ileum. Of the five tested samples, curcuminoids and an extract of P. guajava showed the highest inhibitory effect on P-gp mediated efflux of Rho-123 in Caco-2 cells. Additionally, they were found to have equal potential in inhibiting Rho-123 efflux transport from serosal to mucosal surfaces of the rat ileum.     

Peroral delivery of insulin using chitosan derivatives: a comparative study of polyelectrolyte nanocomplexes and nanoparticles

Polymeric delivery systems based on nanoparticles (NP) have emerged as a promising approach for peroral insulin delivery. Using a trimethyl chitosan (TMC) and a PEG-graft-TMC copolymer, polyelectrolyte complexes (PEC) and nanoparticles were prepared and their properties were compared. The amount of insulin was quantified by HPLC and the stability of PEC and NP upon exposure to simulated gastrointestinal (GI) fluid was monitored by dynamic laser light scattering. It was shown that polymer/insulin (+/-) charge ratio played an important role in PEC and NP formation. Stable, uniform, and spherical PEC/NP with high insulin association efficiency (AE) were formed at or close to optimized polymer/insulin (+/-) charge ratio, depending on polymer structure. All PEC were more stable in pH 6.8 simulated intestinal fluid (SIF) than NP. The PEC also appeared to play some role in protecting insulin from degradation at higher temperature and with proteolytic enzyme more efficiently than NP. On the basis of these results, polyelectrolyte complexation can be suggested as a potentially useful technique for generating insulin delivery systems for peroral administration.