Effect of Zendium toothpaste on recurrent aphthous stomatitis

Abstract – A Double-blind clinical trial with cross-over was conducted for a period of 12 months in 25 patients with recurrent aphthous stomatitis (RAS). The effect of the amyloglucosidase and glucoseoxidase containing Zendium toothpaste on the discomfort, number of exacerbations, duration of exacerbation, number of ulcers and number of days with pain caused by RAS was studied. The use of Zendium significantly reduced the sensation of discomfort from RAS as compared to the use of placebo toothpaste (0.025>p>0.01). However, the patients were unable to discriminate significantly between Zendium and placebo when asked to choose one of the toothpastes (0.10>p>0.05) and no significant differences were demonstrated as far as the above mentioned parameters of disease serverity were concerned. Therefore, it is concluded that the reducing effect of Zendium containing amyloglucosidase and glucoseoxidase on RAS is weak as compared to a similar toothpaste without these enzymes.     

Permeation of WIN 55,212-2, a potent cannabinoid receptor agonist, across human tracheo-bronchial tissue in vitro and rat nasal epithelium in vivo

The aim of this study was to investigate the intranasal absorption of R-(+)-WIN 55,212-2 mesylate in vivo and in vitro. Permeation experiments of R-(+)-WIN 55,212-2 formulations with 2% dimethyl-beta-cyclodextrin (DMbetaCD), 2% trimethyl-beta-cyclodextrin (TMbetaCD) or 2% randomly methylated-beta-cyclodextrin (RAMbetaCD) in 1:1 propylene glycol/saline and 1.5% propylene glycol +3% Tween 80 in saline were conducted using EpiAirway tissue and an anesthetized rat nasal absorption model, respectively. Samples were analysed by liquid chromatography-mass spectrometry. Mucosal tolerance was screened using paracellular marker permeation and tissue viability as indices. Nasal absorption of WIN 55,212-2 was rapid, with a t(max) (time of peak concentration) of 0.17 to 0.35 h in vivo. Relative to 1.5% propylene glycol +3% Tween 80 (control), 1:1 propylene glycol/saline, RAMbetaCD, DMbetaCD and TMbetaCD resulted in 24-, 20-, 17- and 10-fold WIN 55,212-2 permeation increases in vitro, respectively. The in vivo absolute bioavailabilities were also increased with 1:1 propylene glycol/saline, RAMbetaCD, DMbetaCD and TMbetaCD compared to 1.5% propylene glycol +3% Tween 80 (0.15 vs. 0.66-0.77). The viability of the EpiAirway tissues was significantly reduced by DMbetaCD and TMbetaCD formulations. This study showed that WIN 55,212-2 mesylate can be delivered via the nasal route. Absorption of R-(+)-WIN 55,212-2 was rapid and bioavailability was significantly improved using methylated cyclodextrins and propylene glycol-based cosolvent.     

Inhibition of calpain-mediated cell death by a novel peptide inhibitor

Calpains are calcium- and thiol-dependent proteases whose overactivation and degradation of various substrates have been implicated in a number of diseases and conditions such as cardiovascular dysfunction and ischemic stroke. With increasing evidence for calpain's role in cellular damage, the development of calpain inhibitors continues to be an important objective. Previously, we identified a highly specific calcium-dependent, calpain interacting peptide L-S-E-A-L, that showed homology to domains A and C of the only known endogenous inhibitor of calpains, calpastatin. This suggested that LSEAL had a calpain inhibitory function and synthetic LSEAL inhibited calpain I and II proteolysis of two calpain substrates, tau and alpha-synuclein. In the present study, we demonstrate that synthetic LSEAL is membrane permeable and is a potent inhibitor in two established models of calpain-mediated cell death using primary rat cortical neurons and SH-SY5Y neuroblastoma cells. In addition, we show that LSEAL inhibits calpain activity towards protein substrates as detected by an antibody to a calpain-specific breakdown product of spectrin. Taken together, these results suggest that LSEAL may represent a novel calpastatin mimetic with the potential for benefit in conditions of increased calpain activity such as stroke, traumatic brain injury or heart attack.     

Development of In Vivo Impedance Spectroscopy Techniques for Measurement of Micropore Formation Following Microneedle Insertion

Microneedles (MNs) provide a minimally invasive means to enhance skin permeability by creating micron-scale channels (micropores) that provide a drug delivery pathway. Adequate formation of the micropores is critical to the success of this unique drug delivery technique. The objective of the current work was to develop sensitive and reproducible impedance spectroscopy techniques to monitor micropore formation in animal models and human subjects. Hairless guinea pigs, a Yucatan miniature pig, and human volunteers were treated with 100 MN insertions per site following an overnight prehydration period. Repeated measurements were made pre- and post-MN treatment using dry and gel Ag/AgCl electrodes applied with light verses direct pressure to hold the electrode to the skin surface. Impedance measurements dropped significantly post-MN application at all sites (p < 0.05, irrespective of electrode type or gel application), confirming micropore formation. In the Yucatan pig and human subjects, gel electrodes with direct pressure yielded the lowest variability (demonstrated by lower %relative standard deviation), whereas dry electrodes with direct pressure were superior in the guinea pigs. These studies confirm that impedance measurements are suitable for use in both clinical and animal research environments to monitor the formation of new micropores that will allow for drug delivery through the impermeable skin layers.     

Diclofenac Enables Unprecedented Week-Long Microneedle-Enhanced Delivery of a Skin Impermeable Medication in Humans

Purpose

Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals. The purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans.

Methods

Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application.

Results

Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n?=?6), vs. 72 h in Group 2 (placebo + naltrexone, n?=?2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores).

Conclusion

This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases.     

Development of DENVax: a chimeric dengue-2 PDK-53-based tetravalent vaccine for protection against dengue fever

Dengue. virus infection is the leading arboviral cause of disease worldwide. A vaccine is being developed based on the attenuated DEN-2 virus, DEN-2 PDK-53. In this review, we summarize the characteristics of the parent DEN-2 PDK-53 strain as well as the chimeric viruses containing the prM and E genes of DEN-1, DEN-3 or DEN-4 virus in the genetic backbone of the DEN-2 PDK-53 virus (termed DENVax). Tetravalent DENVax formulations containing cloned, fully sequenced isolates of the DEN-2 PDK-53 virus and the three chimeras have been evaluated for safety and efficacy in preclinical animal models. Based on the safety, immunogenicity and efficacy in preclinical studies, Phase 1 clinical testing of DENVax has been initiated.     

Naltrexone salt selection for enhanced transdermal permeation through microneedle-treated skin

The passive delivery rate of naltrexone (NTX) through intact skin is too slow to achieve therapeutic plasma levels in humans from a reasonably sized transdermal patch. A physical enhancement method--microneedles (MNs)--has been shown to afford a substantial increase in the percutaneous flux of NTX hydrochloride in vitro. However, for better therapeutic effect and decrease in the transdermal patch area, further enhancement is desired. The purpose of this study was to identify a NTX salt that would (1) provide elevated in vitro percutaneous drug transport across MN-treated skin as compared with that of the NTX hydrochloride and (2) prove nonirritating to the skin in vivo. The pH-solubility profiles of NTX salts were investigated with three drug salts showing improved solubility at physiologically relevant skin surface pH of 5.0. The skin-irritation potential of NTX glycolate and lactate gels was not greater than that of placebo gel in the guinea pig model. Additionally, in vitro diffusion studies indicated that NTX glycolate provides around 50% enhancement in the flux through MN-treated skin at the cost of doubling the drug concentration in the donor solution. Overall, a new NTX glycolate salt appears to be a promising candidate for MN-assisted transdermal drug delivery system.     

Coinfection with hepatitis C virus,oxidative stress and antioxidant status in HIV‐positive drug users in Miami*

Background

The pathogenesis of HIV/hepatitis C virus (HCV) coinfection is poorly understood. We examined markers of oxidative stress, plasma antioxidants and liver disease in HIV/HCV‐coinfected and HIV‐monoinfected adults.

Methods

Demographics, medical history, and proof of infection with HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) and HCV were obtained. HIV viral load, CD4 cell count, complete blood count (CBC), complete metabolic panel, lipid profile, and plasma concentrations of zinc, selenium, and vitamins A and E were determined. Malondialdehyde (MDA) and glutathione peroxidase concentrations were obtained as measures of oxidative stress. Aminotransferase to platelet ratio index (APRI) and fibrosis index (FIB‐4) markers were calculated.

Results

Significant differences were found between HIV/HCV‐coinfected and HIV‐monoinfected participants in levels of alanine aminotransferase (ALT) (mean±standard deviation: 51.4±50.6 vs. 31.9±43.1 U/L, respectively; P=0.014), aspartate aminotransferase (AST) (56.2±40.9 vs. 34.4±30.2 U/L; P<0.001), APRI (0.52±0.37 vs. 0.255±0.145; P=0.0001), FIB‐4 (1.64±.0.91 vs. 1.03±0.11; P=0.0015) and plasma albumin (3.74±0.65 vs. 3.94±0.52 g/dL; P=0.038). There were no significant differences in CD4 cell count, HIV viral load or antiretroviral therapy (ART) between groups. Mean MDA was significantly higher (1.897±0.835 vs. 1.344± 0.223 nmol/mL, respectively; P=0.006) and plasma antioxidant concentrations were significantly lower [vitamin A, 39.5 ± 14.1 vs. 52.4±16.2 μg/dL, respectively (P=0.0004); vitamin E, 8.29±2.1 vs. 9.89±4.5 μg/mL (P=0.043); zinc, 0.61±0.14 vs. 0.67±0.15 mg/L (P=0.016)] in the HIV/HCV‐coinfected participants than in the HIV‐monoinfected participants, and these differences remained significant after adjusting for age, gender, CD4 cell count, HIV viral load, injecting drug use and race. There were no significant differences in glutathione peroxidase concentration, selenium concentration, body mass index (BMI), alcohol use or tobacco use between groups. Glutathione peroxidase concentration significantly increased as liver disease advanced, as measured by APRI (β=0.00118; P=0.0082) and FIB‐4 (β=0.0029; P=0.0177). Vitamin A concentration significantly decreased (β=?0.00581; P=0.0417) as APRI increased.

Conclusion

HIV/HCV coinfection is associated with increased oxidative stress and decreased plasma antioxidant concentrations compared with HIV monoinfection. Research is needed to determine whether antioxidant supplementation delays liver disease in HIV/HCV coinfection.

     

Aortic dissection associated with cogans's syndrome: deleterious loss of vascular structural integrity is associated with GM-CSF overstimulation in macrophages and smooth muscle cells

Background  

Cogan's syndrome is a rare disorder of unknown origin characterized by inflammatory ocular disease and vestibuloauditory symptoms. Systemic vasculitis is found in about 10% of cases.