32 research outputs found
Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles
Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture
Microneedle assisted transdermal delivery of zolmitriptan: effect of microneedle geometry, in vitro permeation experiments, scaling analyses and numerical simulations
Objective: The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of Zolmitriptan (ZMT).
Methods: Two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 0.9, 1.2 and 1.5mm lengths) and laboratory fabricated polymeric MNs (PM) of 0.6mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77cm2 skin area (PM-3) to maintain the MN density closer to 0.6mm ADM. Scaling analyses was done using dimensionless parameters like concentration of ZMT (Ct/Cs), thickness (h/L) and surface area of the skin (Sa/L2).
Results: Micro-injection moulding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper
microconduits when compared to ADM of similar length. Approximately 3.17 and 3.65 fold increase in ZMT flux values were observed with 1.5mm ADM and PM-3 applications when compared to the passive studies. Good correlations were observed between different dimensionless parameters with scaling analyses. Numerical simulations, using MATLAB and COMSOL software, based on experimental data and histological images provided information regarding the ZMT skin distribution after MN application.
Discussion: Both from experimental studies and simulations, it was inferred that PM were more effective in enhancing the transdermal delivery of ZMT when compared to ADM.
Conclusion: The study suggests that MN application enhances the ZMT transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement
Effect of microneedle type on transdermal permeation of rizatriptan
The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation of rizatriptan (RIZ). Studies were carried out using two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 0.9, 1.2 and 1.5 mm lengths) and laboratory-fabricated polymeric MNs (PMs) of 0.6 mm length. In the case of the PMs, arrays were applied three times at different places within a 1.77-cm2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Histological studies revealed that PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 4.9- and 4.2-fold increases in the RIZ steady-state flux values were observed with 1.5 mm ADM and PM-3 applications when compared to the passive studies. A good correlation between different dimensionless parameters like the amount of RIZ permeated (Ct/Cs), thickness (h/L) and surface area (Sa/L2) of the skin was observed with scaling analyses. Numerical simulations provided further information regarding the distribution of RIZ in MN-treated skin after application of different MNs. Overall, the study suggests that MN application enhances the RIZ transdermal permeation and the geometrical parameters of MNs play an important role in the degree enhancement
Application of microneedle arrays for enhancement of transdermal permeation of Insulin: in vitro experiments, scaling analyses and numerical simulations
The aim of this investigation is to study the effect of donor concentration and microneedle (MN) length on permeation of insulin and further evaluating the data using scaling analyses and numerical simulations. Histological evaluation of skin sections was carried to evaluate the skin disruption and depth of penetration by MNs. Scaling analyses was done using dimensionless parameters like concentration of drug (Ct/Cs), thickness (h/L) and surface area of the skin (Sa/L2). Simulation studies were carried out using MATLAB and COMSOL software to simulate the insulin permeation using histological sections of MN treated skin and experimental parameters like passive diffusion coefficient. A 1.6 fold increase in transdermal flux and 1.9 fold decrease in lag time values were observed with 1.5mm MN when compared with passive studies. Good correlation (R2>0.99) was observed between different parameters using scaling analyses. Also, the in vitro and simulated permeations profiles were found to be similar (f2≥50). Insulin permeation significantly increased with increase in donor concentration and MN length (p<0.05). The developed scaling correlations and numerical simulations were found to be accurate and would help researchers to predict the permeation of insulin with new dimensions of MN in optimizing insulin delivery. Overall, it can be inferred that the application of MNs can significantly enhance insulin permeation and may be an efficient alternative for injectable insulin therapy in humans
Consistency tests of AMPCALCULATOR and chiral amplitudes in SU(3) Chiral Perturbation Theory: A tutorial based approach
Ampcalculator is a Mathematica based program that was made publicly available
some time ago by Unterdorfer and Ecker. It enables the user to compute several
processes at one-loop (upto ) in SU(3) chiral perturbation theory. They
include computing matrix elements and form factors for strong and non-leptonic
weak processes with at most six external states. It was used to compute some
novel processes and was tested against well-known results by the original
authors. Here we present the results of several thorough checks of the package.
Exhaustive checks performed by the original authors are not publicly available,
and hence the present effort. Some new results are obtained from the software
especially in the kaon odd-intrinsic parity non-leptonic decay sector involving
the coupling . Another illustrative set of amplitudes at tree level we
provide is in the context of -decays with several mesons including quark
mass effects, of use to the BELLE experiment. All eight meson-meson scattering
amplitudes have been checked. Kaon-Compton amplitude has been checked and a
minor error in published results has been pointed out. This exercise is a
tutorial based one, wherein several input and output notebooks are also being
made available as ancillary files on the arXiv. Some of the additional
notebooks we provide contain explicit expressions that we have used for
comparison with established results. The purpose is to encourage users to apply
the software to suit their specific needs. An automatic amplitude generator of
this type can provide error-free outputs that could be used as inputs for
further simplification, and used in varied scenarios such as applications of
chiral perturbation theory at finite temperature, density and volume. This can
also be used by students as a learning aid in low-energy hadron dynamics.Comment: 25 pages, plain latex, corresponds to version to appear in EPJA,
additional ancillary files adde
Identification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes
This document is the Accepted Manuscript version of a Published Work that appeared in final form in
Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher.
To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx300103jTienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [14C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 non-redundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 additional proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2–4 identifiable proteins, many of which are known targets of other chemically reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approximately 16 previously reported protein targets of TA in rat liver (Methogo, R., Dansette, P. and Klarskov, K. (2007) Int. J. Mass Spectrom., 268, 284–295), only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e. rat vs. human), and still another may be the method of detection of adducted proteins (i.e. Western blot vs. C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from human and only 21 of these are known to be targets for more than one chemical. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future
Metabolism and Toxicity of Thioacetamide and Thioacetamide SOxide in Rat Hepatocytes
“This document is the Accepted Manuscript version of a Published Work that appeared in final form in
Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher.
To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx3002719The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrilobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects TA requires oxidative bioactivation leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO2) which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis, and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 hr. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole, and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [14C]-TASO is inhibited by unlabeled TA which acts as a “cold-trap” for [14C]-TA and prevents its re-oxidation to [14C]-TASO. This in turn increases the net consumption of [14C]-TASO despite the fact that its oxidation to TASO2 is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA may help explain phenomena previously interpreted as “saturation toxicokinetics” in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification
Isolation and Characterization of Intestinal Epithelial Cells from Normal and SIV-Infected Rhesus Macaques
Impairment of intestinal epithelial barriers contributes to the progression of HIV/SIV infection and leads to generalized HIV-induced immune-cell activation during chronic infection. Rhesus macaques are the major animal model for studying HIV pathogenesis. However, detailed characterization of isolated rhesus epithelial cells (ECs) from intestinal tissues is not well defined. It is also not well documented whether isolated ECs had any other cell contaminants from intestinal tissues during the time of processing that might hamper interpretation of EC preparations or cultures. In this study, we identify and characterize ECs based on flow cytometry and immunohistochemistry methods using various enzymatic and mechanical isolation techniques to enrich ECs from intestinal tissues. This study shows that normal healthy ECs differentially express HLA-DR, CD23, CD27, CD90, CD95 and IL-10R markers. Early apoptosis and upregulation of ICAM-1 and HLA-DR in intestinal ECs are thought to be the key features in SIV mediated enteropathy. The data suggest that intestinal ECs might be playing an important role in mucosal immune responses by regulating the expression of different important regulatory and adhesion molecules and their function
Geoelectrical characterisation of CO2–water systems in porous media: application to carbon sequestration
Carbon sequestration is a promising method for the reduction of carbon dioxide (CO2) emissions as it permits the storage of compressed CO2 in the subsurface. The carbon sequestration sites must be monitored to detect potential leaks; one possible method involves the monitoring of geoelectrical properties such as electrical conductivity (σb) and dielectric constant (εb). This investigation focuses on using a time domain reflectometry (TDR) sensor to determine the influence of different factors on the measurements of the electrical conductivity (σb) and dielectric constant (εb) of a porous rock reservoir in relation to the soil water saturation (Sw). The factors investigated were presence of surfactant, salt concentration, pH and rock type which are unique to a given storage site. A number of dynamic two-phase flow experiments were performed using gaseous CO2. It was found that salt concentration, rock type and presence of a surfactant had a notable effect on the σb-Sw and εb-Sw relationships. Higher salt concentrations were found to give higher values for σb and εb for given Sw values. Limestone was found to result in the highest values of both σb and εb for any given Sw, followed by silica and basalt samples. The presence of a surfactant resulted in higher values for σb at higher Sw values and lower values for σb at lower Sw values compared to the case when no surfactant was present. Surfactant presence also resulted in lower values for εb at given Sw values. Initial pH values (with silica sand) were found to have no significant effect on the σb-Sw and εb-Sw relationships. The measurements of σb and εb indicate that the use of TDR presents a viable monitoring option. Furthermore, statistical analysis using non-linear regression was carried out on the experimental results and the model shows a good reliability in the prediction of the monitoring process in geological carbon sequestration