Echocardiographic assessment of cardiac dysfunction in patients of end stage renal disease on haemodialysis.

OBJECTIVE: To assess the prevalence of systolic and diastolic dysfunction in patients of end stage renal disease (ESRD) on haemodialysis. METHODS: Seventy patients with ESRD were subjected to two-dimensional and M mode echocardiography for determination of systolic and diastolic dysfunction. All patients were evaluated clinically, biochemically and radiologically and were diagnosed as chronic kidney disease (CKD). The left ventricular ejection fraction (LVEF) and fractional shortening (FS) were taken as measures of left ventricular (LV) systolic function. Diastolic function was determined by measuring E/A ratio by spectral doppler LV inflow velocity. Echocardiographic findings of hypertensive and normotensive patients were compared. RESULTS: Out of 70 patients studied, there were 53 males (75.7%) and 17 females (24.3%). Hypertension (37.1%) was leading cause of ESRD. Echocardiography showed that left ventricular hypertrophy (LVH) was present in 74.3%. Systolic dysfunction as measured by reduced fractional shortening (<25%) and decreased LVEF (< 50%) was present in 8.6% and 24.3% respectively. Diastolic dysfunction as denoted by E/A ratio of less than 0.75 or more than 1.8 was present in 61.4% of patients. Regional wall motion abnormality (RWMA) was present in 12.9%. Pericardial effusion was noted in 14.3% of patients. Valvular calcification was noted in 7.1% of ESRD patients. Mean left ventricular internal diameter in diastole was 45.55 +/- 6.03 mm. Mean Interventricular septum diameters in systole was 12.2 +/- 1.71 mm. Mean left atrium diameter was 33.01 +/- 4.11 mm. Normotensive group was compared to hypertensive group. Statistically significant difference was noted in LVH and E/A ratio in hypertensive group as compared to normotensive group. CONCLUSION: Patients with hypertensive ESRD had higher prevalence of diastolic and systolic dysfunction as compared to normotensive counterparts.

Acyclovir skin depot characterization following in vivo iontophoretic delivery.

BACKGROUND/PURPOSE: Current Herpes labialis infection treatment by oral, parenteral or topical routes is inefficient. The objective of this study was to investigate the use of iontophoresis for improved topical delivery of acyclovir (ACV) in vivo in hairless rat. METHODS: Iontophoresis was performed for 10 min using a 5% ACV gel formulation. Tape stripping and skin extractions were performed at different time points following treatment for drug quantification in stratum corneum (SC) and underlying skin, respectively. RESULTS: Fourfold more ACV was detected in the SC immediately following 10-min iontophoresis as compared with passive delivery. Similarly, high ACV levels (29.27±3.52 µg/cm(2)) were achieved in the underlying skin following a single 10-min iontophoretic treatment while no drug detected following passive delivery (P<0.05). At 24-h post-iontophoresis, ACV levels in the SC decreased with a corresponding increase in the underlying skin due to drug migration. After 24-h post-iontophoresis, drug levels gradually decreased in both skin compartments until no ACV was detected at 72-h post-iontophoresis. CONCLUSION: Iontophoretic delivery of ACV resulted in high drug levels in skin layers to form a drug depot, which persisted over 2-3 days.

Influence of end groups on in vitro release and biological activity of lysozyme from a phase-sensitive smart polymer-based in situ gel forming controlled release drug delivery system.

Phase-sensitive in situ gel forming controlled release formulations of lysozyme were prepared using poly lactic acid (PLA) and/or poly glycolic acid (PGA) based polymers differing in end groups in addition to composition, and a solvent system consisting of various ratios of benzyl benzoate (BB) and benzyl alcohol (BA). The amount of lysozyme in the released samples was determined by measuring absorbance at 280 nm using suitable controls to nullify the effect of absorption of formulation degradation products. Biological activity of lysozyme was studied by an enzyme activity assay using Micrococcus lysodeikticus as substrate. Polymers bearing carboxylic acid end group were not soluble in 100% BB but polymers having ester end groups were soluble up to 27% (w/v) except polymer 4. A biphasic release profile consisting of slower first phase followed by faster second phase was observed. Formulations prepared from polymer with carboxylic acid groups showed significantly (p<0.05) lower burst release (4%) than those containing ester end groups (20-30%). However, formulations consisting of polymer with carboxylic acid end groups showed significantly (p<0.05) faster release rate of incorporated lysozyme, although the total amount released was less in comparison to the total amount released from formulations prepared using polymers containing ester end groups. The mean percentage specific enzyme activity (MPSEA) data were supported by the release profiles. In conclusion, polymer end groups may influence the release profiles of a protein from an in situ gel depot forming controlled release formulations.

Current and emerging lipid-based systems for transdermal drug delivery.

Developing a transdermal drug delivery system is a challenging task considering the selective permeability of the skin and the physicochemical properties the drug must possess to permeate through the skin. Lipid-based drug delivery systems have contributed a great deal in this direction in the last few decades, and thereby have helped to expand the range of therapeutic molecules that can be delivered through the skin in a safe and effective manner. Additionally, vesicular delivery systems such as nanoparticles and emulsions have also played important roles in providing alternative novel approaches for drug delivery. In this article, we will discuss some of the current and future lipid-based systems for transdermal drug delivery along with the associated challenges.

Transdermal delivery of proteins using a combination of iontophoresis and microporation.

AIM: This study aimed to investigate transdermal delivery of proteins using combination of microporation and iontophoresis (ITP). Materials & methods & results: Delivery of model protein, Alexa Fluor 555 bovine serum albumin conjugate (AF-BSA) using ITP alone, microneedle (MN) alone, and ITP plus MN combination was assessed using confocal microscopy. Compared to MN alone, combination of MN plus ITP significantly increased skin's penetration depth of AF-BSA (300 vs 110 µm) and achieved lateral distribution of the model protein. Average fluorescence intensity quantified around each microchannel was 23.7-fold (8.2-fold, in vivo) higher for combination treatment compared with MN alone, in vitro. After 1 h in vitro permeation study, the unlabeled BSA amount delivered across skin was found to be 0, 1.4, 0.63 and 14 µg by passive, MN alone, ITP alone and ITP plus MN combination delivery, respectively.

In vivo transdermal delivery of leuprolide using microneedles and iontophoresis.

The objective of this study was to investigate the use of iontophoresis and/or microneedles to enhance transdermal delivery of leuprolide acetate in vivo in hairless rats. Microporation was achieved using 500 µm long maltose microneedles and pore formation was confirmed using dye binding studies, histology studies, calcein imaging studies, pore permeability index calculation and trans-epidermal water loss measurement. Iontophoresis was performed using liquid reservoir patch with inbuilt silver wire electrode and a current density of 0.1 mA/cm2 was applied for 4 hours. Delivery studies were performed using microneedles and iontophoresis alone and in combination. Passive studies involving delivery through intact skin and injections of drug solution administered subcutaneously served as controls. Blood samples were collected at predetermined time points and plasma samples were analyzed for drug using ELISA. Significantly higher drug levels were detected at the end of 6 hours treatment by microneedles alone treatment (0.98 ± 0.08 ng/ml) as compared to passive (0.36 ± 0.22 ng/ml) delivery (p < 0.05). Further, three times more drug was found to be present systemically with iontophoresis alone (3.47 ± 0.03 ng/ml) or by combination (3.54 ± 0.08 ng/ml) treatments as compared to microneedles alone treatment (p < 0.05) at the end of treatment duration. When compared to iontophoresis alone treatment, combination treatment resulted in faster drug delivery due to propulsion of the drug through the preformed micropores. In conclusion, the use of microneedles and/or iontophoresis seems promising for the transdermal delivery of peptide like leuprolide acetate.

Formulation and optimization of desogestrel transdermal contraceptive patch using crystallization studies.

Levonorgestrel (LNG) is the most commonly used progestin in contraception. In this study, we report the use of an alternative progestin, desogestrel, for transdermal contraception. The drug was found to be significantly more permeable as compared to LNG (p<0.05). Crystallization studies were used to select the best adhesive among acrylate (Duro-Tak 87-4098 and Duro-Tak 87-202A) and polyisobutylene (PIB, Duro-Tak 87-608A) pressure sensitive adhesives by determining the drug's saturation solubility in them. The use of copovidone and mineral oil as formulation excipients was investigated to increase drug loading in the PIB adhesive. Physical characterization of the patches was performed using in vitro drug release, content analysis, patch weight and thickness variations and rolling ball tack and peel adhesion studies. Optimized patches were evaluated for in vitro transdermal delivery across hairless rat skin. The saturation solubility of desogestrel was found to be approximately 49.3% (w/w) and 55.6% (w/w) in Duro-Tak 87-4098 and Duro-Tak 87-202A acrylate adhesives, respectively. The saturation solubility of desogestrel was significantly lower (3-4%, w/w) in the PIB adhesive. Mineral oil (10%, w/w) and copovidone (30%, w/w) were found to be optimum for increasing drug loading and patch cosmetics. Results from the physical characterization studies suggest that a uniform and reproducible 7 day drug-in-adhesive patch could be developed.

Evaluation of acyclovir cream and gel formulations for transdermal iontophoretic delivery.

BACKGROUND: Efficient iontophoretic transdermal delivery of hydrophilic drug molecules requires selection of appropriate aqueous formulation. In this study, oil/water cream and gel formulations were investigated for iontophoretic transdermal delivery of acyclovir (ACV), a model hydrophilic small-drug molecule, across hairless rat skin on Franz diffusion cells. RESULTS: Iontophoresis (0.2 mA/cm2) enhanced ACV delivery from both 5% cream (pH 6.8) and 4% gel (pH II) formulations. However, sixfold higher drug levels were delivered across the skin using gel formulation (12.25 +/- 4.04 microg/cm2) as compared with cream formulation (2.03 +/- 0.05 microg/cm2). Significantly higher drug levels were delivered when iontophoresis was performed at higher current density (0.32 mA/cm2; p < 0.05). Influence of formulation co-solvents (glycerin and propylene glycol) on drug delivery was also investigated in vitro using Franz cells and in vivo in hairless rats using microdialysis. CONCLUSION: Iontophoretic transdermal delivery of ACV was feasible and dependent on the selection of formulation components and delivery parameters.

Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen.

The objective of this study was to test low frequency sonophoresis at 20 kHz for delivery of ketoprofen into and across the skin. Permeation studies were carried out in vitro on excised hairless rat skin over a period of 24h using Franz diffusion cells after which, skin samples were subjected to skin extraction to quantify the amount of drug present in skin. Parameters like ultrasound application time, duty cycle coupling medium and distance of ultrasound horn from skin were optimized. Transepidermal water loss (TEWL) was measured to indicate the extent of barrier disruption following sonophoresis. Confocal microscopy was used to visualize dye penetration through sonophoresis treated skin. Application of ultrasound significantly enhanced permeation of ketoprofen from 74.87 ± 5.27 µg/cm(2) for passive delivery to 491.37 ± 48.78 µg/cm(2) for sonophoresis. Drug levels in skin layers increased from 34.69 ± 7.25 µg following passive permeation to 212.62 ± 45.69 µg following sonophoresis. TEWL increased from 31.6 ± 0.02 (passive) to 69.5 ± 12.60 (sonophoresis) indicating disruption of barrier properties. Confocal microscopy images depicted enhanced dye penetration through sonophoresis treated skin confirming barrier disruption. Low frequency sonophoresis with optimized ultrasound parameters can be effectively used to actively enhance transdermal and topical delivery of ketoprofen.

Microneedles and their applications.

Microneedle mediated microporation has proved its potential to enhance the delivery of therapeutic drug molecules through skin over the last one decade. Several patents have been granted and cutting edge research is going on particularly for the delivery of biopharmaceuticals (macromolecules like protein or peptides). The technology involves use of micron sized needles made of diverse materials to form microchannels into the stratum corneum (or deeper), outermost barrier layer of the skin. These microchannels are deep enough to facilitate efficient drug delivery through disrupted stratum corneum but short enough to avoid bleeding or pain. So far, the microneedle technology has been explored for drug and vaccine delivery through transcutaneous route. However, the miniaturized nature of these microneedles and anticipated minimal invasiveness has led the scientists to explore and patent its possible use for several other applications.The use of this technology in combination with other enhancement techniques has also gained recent attention. This review article focuses on the latest developments in the field of microneedles as described in patent and research literature. Comprehensive review of several topics including device design/fabrication, formulation development, safety/regulatory issues, therapeutic applications and major challenges in the commercialization of microneedles as medical devices has been presented here.

Iontophoretic delivery of acyclovir: intradermal drug monitoring using microdialysis and quantification by skin extraction.

The objective of this study was to investigate the effect of iontophoresis on the intradermal and transdermal delivery of acyclovir using hairless rat skin on a vertical Franz diffusion cell. In this study, cathodal iontophoretic delivery of acyclovir from a pH 11 formulation was explored. The effects of time of iontophoresis (10 min, 1 h, and 4 h) and current density (0.2, 0.3, and 0.5 mA/cm(2)) on skin permeation were examined. In vitro dermal microdialysis was performed to identify the drug depot formed in the dermis during iontophoresis. Acyclovir delivery into the receptor compartment was not influenced by current density or duration of current application. However, greater drug levels were delivered into the skin as a function of time of current application to form a drug depot. These results were further confirmed by in vitro dermal microdialysis in which higher drug levels were observed in dialysate in the 4 h iontophoresis group due to higher drug levels delivered into the skin layers as compared to 1 h iontophoresis group. Short duration iontophoresis enhanced acyclovir delivery into the skin layers rapidly and thus may be beneficial to improve treatment for cold sores (herpes labialis infection). Microdialysis could be used as a tool to simultaneously monitor drug levels in the tissue's interstitial fluid in real time in an in vitro setting. LAY ABSTRACT: The objective of this study was to investigate the effect of current on the delivery of acyclovir into and across the skin using hairless rat skin mounted on glass diffusion cells. Acyclovir was delivered under negative polarity from a formulation with a very basic pH. The effect of current intensity and duration of application on delivery of acyclovir was investigated. The amount in the skin was also determined by inserting a probe into the skin with a semipermeable membrane that allows sampling of the drug that has entered the skin. When the current intensity or duration was increased, greater drug levels were seen in the skin but not across the skin. It was found that even short duration of current application can deliver acyclovir into the skin and this has potential use for treatment of cold sores.

Iontophoresis mediated in vivo intradermal delivery of terbinafine hydrochloride.

The objective of this study was to investigate the use of iontophoresis for the delivery of terbinafine hydrochloride (TH) into hairless rat skin in vivo. Drug formulation was applied to the abdominal skin and studies were performed using anodal iontophoresis. A current density of 250 microA/cm(2) was applied for 10, 15 and 20 min. Tape stripping and skin extraction were performed thereafter. For depot clearance studies, 20 min treatment was followed by tape stripping and skin extraction at 12, 24 and 48 h. Results indicated that iontophoresis delivered significantly more drug into the deeper skin as compared to controls (p<0.05). Drug levels in the stratum corneum (SC) and underlying skin increased with increasing duration of current application. Depot clearance studies suggested drug depletion within 24 h from SC. A redistribution of terbinafine from the SC to the underlying skin over time was observed. Drug was detectable in the underlying skin for at least 48 h suggesting that formation of a drug depot persisted for at least 2 days following iontophoretic treatment. Thus, iontophoresis of TH may be useful in delivering higher drug levels more rapidly into the superficial and deep seated skin infection sites to form a depot providing sustained release.

Transdermal iontophoretic delivery of terbinafine hydrochloride: quantitation of drug levels in stratum corneum and underlying skin.

The objective of this study was to determine the effect of iontophoresis on the delivery of terbinafine hydrochloride (4%, w/w) into and across hairless rat skin. In vitro skin uptake and permeation studies were performed using Franz diffusion cells. Anodal iontophoresis was applied for 1h at current densities of 0.2, 0.3 and 0.4mA/cm(2). In addition, iontophoresis was applied for 15, 30, 45 and 60min. Studies were conducted in which the formulation was either removed or left in contact with the skin following iontophoresis and then passive delivery was assessed 23h later. Tape stripping and skin extraction were performed to quantify drug levels in the stratum corneum and the underlying skin, respectively. The samples were analyzed using HPLC. The amount of drug delivered into the stratum corneum following iontophoresis was not significantly different from the amount delivered passively (p>0.05). However, drug levels in the underlying skin were significantly higher for the iontophoretic group. The amount of terbinafine delivered into the skin layers was influenced by current density and duration of current application. Leaving the drug formulation in contact with the skin during the post-iontophoretic period had a significant effect on drug levels delivered into skin layers. Iontophoresis enhanced the delivery of terbinafine hydrochloride into the skin layers and, therefore, may be used to improve the treatment of skin fungal infections.