Sustained EKR Inhibition by EGFR Targeting Therapies Is a Predictive Factor for Synergistic Cytotoxicity With PDT as Neoadjuvant Therapy.

Sustained EKR inhibition by EGFR targeting therapies is a predictive factor for synergistic cytotoxicity with PDT as neoadjuvant therapy.

Biochim Biophys Acta. 2013 Mar; 1830(3): 2659-70
Weyergang A, Selbo PK, Berg K

Tyrosin kinase inhibitors (TKIs) and monoclonal antibodies aimed to target epidermal growth factor receptor (EGFR) have shown limited effect as monotherapies and drug resistance is a major limitation for therapeutic success. Adjuvant therapies to EGFR targeting therapeutics are therefore of high clinical relevance.Three EGFR targeting drugs, Cetuximab, Erlotinib and Tyrphostin AG1478 were used in combination with photodynamic therapy (PDT) in two EGFR positive cell lines, A-431 epidermoid skin carcinoma and WiDr colorectal adenocarcinoma cells. The amphiphilic meso-tetraphenylporphine with 2 sulphonate groups on adjacent phenyl rings (TPPS(2a)) was utilized as a photosensitizer for PDT. The cytotoxic outcome of the combined treatments was evaluated by cell counting and MTT. Cellular signalling was explored by Western blotting.PDT as neoadjuvant to Tyrphostin in A-431 cells as well as to Tyrphostin or Erlotinib in WiDr cells revealed synergistic cytotoxicity. In contrast, Erlotinib or Cetuximab combined with neoadjuvant PDT induced an antagonistic effect on cell survival of A-431 cells. Neoadjuvant PDT and EGFR targeting therapies induced a synergistic inhibition of ERK as well as synergistic cytotoxicity only when the EGFR targeting monotherapies caused a prolonged ERK inhibition. There were no correlation between EGFR inhibition by the EGFR targeting monotherapies or the combined therapies and the cytotoxic outcome combination-therapies.The results suggest that sustained ERK inhibition by EGFR targeting monotherapies is a predictive factor for synergistic cytotoxicity when combined with neoadjuvant PDT.The present study provides a rationale for selecting anticancer drugs which may benefit from PDT as adjuvant therapy. HubMed – drug

[Allergen immunotherapy for allergic rhinitis.]

Rhinology. 2013 Jun 1; 51(2): 99-110
Petalas K, Durham SR

Allergic rhinitis, a risk factor for bronchial asthma, is a global health problem that impairs patients` physical and social activity and consequently their quality of life. Specific Immunotherapy (SIT) involves the administration, subcutaneously or sublin- gually, of increasing doses of the causative allergen, in order to induce clinical and immunologic tolerance. SIT has been shown to be effective in those with a poor response to conventional drug therapy. Immunotherapy has been shown to have disease-modifying effects and result in long term remission of allergic symptoms and reduces the risk of progression from rhinitis to asthma, as well as the chances of developing new sensitizations to allergens. Injection immunotherapy is a safe tre- atment for allergic rhinitis with/without mild controlled asthma, provided that it is performed in the context of a harmonious interaction between trained medical personnel and appropriately selected patients. Immunotherapy suppresses early and late responses to allergen exposure by modifying both T-cell and B-cell responses to inhaled allergens. Immune deviation of allergen-specific T cell responses in favour of Th1 and/or the induction of regulatory T cells is crucial in achieving immune to- lerance. Increased understanding of the mechanisms of immunotherapy has identified potential biomarkers of the response to treatment and highlighted new therapeutic pathways with potential for even more effective future standardized vaccines. HubMed – drug

Reduction of methylglyoxal-induced glycation by pyridoxamine improves adipose tissue microvascular lesions.

J Diabetes Res. 2013; 2013: 690650
Rodrigues T, Matafome P, Santos-Silva D, Sena C, Seiça R

Background and Aims. Adipose tissue dysfunction results from many factors, including glycation-induced microvascular damages. We tested the usefulness of inhibiting methylglyoxal-induced glycation to adipose tissue microvasculature in this work, using the antioxidant and dicarbonyl scavenger drug pyridoxamine. Methods. A group of Wistar rats was treated daily with methylglyoxal (MG, 75?mg/Kg/day, 8 weeks). Half of this group was treated with pyridoxamine in the following 4 weeks (Pyr) (100?mg/Kg/day) and the other half did not have any further treatment (MG). A group of Wistar rats without MG treatment was used as control (C). Results. MG group showed decreased HDL cholesterol and increased plasma free fatty acids levels, what was reverted by pyridoxamine. MG also caused an increase of tissue CEL levels (glycation marker), as well as increased staining of PAS and Masson Trichrome-positive components. Pyridoxamine led to CEL and TGF- ? levels similar to those observed in control rats and inhibited the accumulation of PAS and Masson Trichrome-positive components. MG caused a decrease of Bcl-2/Bax ratio (marker of apoptosis) and vWF staining (microvascular marker), what was partially reverted by the treatment with pyridoxamine. Conclusions. Preventing methylglyoxal-induced accumulation of glycated and fibrotic materials using pyridoxamine improves the microvascular lesions of the adipose tissue. HubMed – drug

Deoxycholic Acid as a Modifier of the Permeation of Gliclazide through the Blood Brain Barrier of a Rat.

J Diabetes Res. 2013; 2013: 598603
Lali?-Popovi? M, Vasovi? V, Milijaševi? B, Golo?orbin-Kon S, Al-Salami H, Mikov M

Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as promoters of drug penetration across biological membranes. Accordingly, the aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Twenty-four male Wistar rats were randomly allocated to four groups, of which, two were given alloxan intraperitoneally (100?mg/kg) to induce diabetes. One diabetic group and one healthy group were given a bolus gliclazide intra-arterially (20?mg/kg), while the other two groups apart from gliclazide got deoxycholic acid (4?mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised and blood glucose and gliclazide concentrations were measured. Penetration of gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared to healthy animals. Also in both, the healthy and diabetic animals, deoxycholic acid increased the permeation of gliclazide through that in BBB. HubMed – drug

Ethyl pyruvate prevents methyglyoxal-induced retinal vascular injury in rats.

J Diabetes Res. 2013; 2013: 460820
Kim J, Lee YM, Kim CS, Sohn E, Jo K, Shin SD, Kim JS

Pyruvate is an endogenous antioxidant substance. The aim of this study was to investigate the protective effects of ethyl pyruvate (EP) on retinal vascular injury in diabetic retinopathy. To investigate the protective effect of EP on vascular cell apoptosis and blood-retinal barrier (BRB) breakage, we have used intravitreally methylglyoxal-(MGO-) injected rat eyes. Apoptosis of the retinal vascular cell that was stimulated by the intravitreal injection of MGO was evidently attenuated by the EP treatment. EP exerts inhibitory effect on MGO-induced vascular cell apoptosis by blocking oxidative injury. In addition, EP treatment prevented MGO-induced BRB breakage and the degradation of occludin, an important tight junction protein. These observations suggest that EP acts through an antioxidant mechanism to protect against oxidative stress-induced apoptosis in retinal vessels. HubMed – drug