Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: a randomised remote conditioning study

Aims: Remote ischemic conditioning (RIC) alleviates ischemia–reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. Methods and results: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p  15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. Conclusion: RIC evokes “vascular conditioning” likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling

Acute administration of the olive constituent, oleuropein, combined with ischemic postconditioning increases myocardial protection by modulating oxidative defense

Oleuropein, one of the main polyphenolic constituents of olive, is cardioprotective against ischemia reperfusion injury (IRI). We aimed to assess the cardioprotection afforded by acute administration of oleuropein and to evaluate the underlying mechanism. Importantly, since antioxidant therapies have yielded inconclusive results in attenuating IRI-induced damage on top of conditioning strategies, we investigated whether oleuropein could enhance or imbed the cardioprotective manifestation of ischemic postconditioning (PostC). Oleuropein, given during ischemia as a single intravenous bolus dose reduced the infarct size compared to the control group both in rabbits and mice subjected to myocardial IRI. None of the inhibitors of the cardioprotective pathways, l-NAME, wortmannin and AG490, influence its infarct size limiting effects. Combined oleuropein and PostC cause further limitation of infarct size in comparison with PostC alone in both animal models. Oleuropein did not inhibit the calcium induced mitochondrial permeability transition pore opening in isolated mitochondria and did not increase cGMP production. To provide further insights to the different cardioprotective mechanism of oleuropein, we sought to characterize its anti-inflammatory potential in vivo. Oleuropein, PostC and their combination reduce inflammatory monocytes infiltration into the heart and the circulating monocyte cell population. Oleuropein's mechanism of action involves a direct protective effect on cardiomyocytes since it significantly increased their viability following simulated IRI as compared to non-treated cells. Οleuropein confers additive cardioprotection on top of PostC, via increasing the expression of the transcription factor Nrf-2 and its downstream targets in vivo. In conclusion, acute oleuropein administration during ischemia in combination with PostC provides robust and synergistic cardioprotection in experimental models of IRI by inducing antioxidant defense genes through Nrf-2 axis and independently of the classic cardioprotective signaling pathways (RISK, cGMP/PKG, SAFE)

Oral Drug Delivery Systems Comprising Altered Geometric Configurations for Controlled Drug Delivery

Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix® multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise®, which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix® as well as “release modules assemblage”, which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6 ± 0.25% PB content, and zeta potential of −66 ± 1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p < 0.05). The microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85 ± 5 and 92 ± 2%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules

Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect

AIM: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi-organ metabolic adjustments to prevent dehydration. Here we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet. METHODS: We studied mice with keratinocyte-specific overexpression of IL-17A which develop severe psoriasis-like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure. RESULTS: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute-driven maximal anti-diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL. CONCLUSION: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation-like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen-dependency of the metabolic water conservation response explains their catabolic muscle wasting

Dizaj i statistička optimizacija liposfera s glipizidom pomoću metodologije odgovora površine

A 32 factorial design was employed to produce glipizide lipospheres by the emulsification phase separation technique using paraffin wax and stearic acid as retardants. The effect of critical formulation variables, namely levels of paraffin wax (X1) and proportion of stearic acid in the wax (X2) on geometric mean diameter (dg), percent encapsulation efficiency (% EE), release at the end of 12 h (rel12) and time taken for 50% of drug release (t50), were evaluated using the F-test. Mathematical models containing only the significant terms were generated for each response parameter using the multiple linear regression analysis (MLRA) and analysis of variance (ANOVA). Both formulation variables studied exerted a significant influence (p < 0.05) on the response parameters. Numerical optimization using the desirability approach was employed to develop an optimized formulation by setting constraints on the dependent and independent variables. The experimental values of dg, % EE, rel12 and t50 values for the optimized formulation were found to be 57.54 ± 1.38 µm, 86.28 ± 1.32 %, 77.23 ± 2.78 % and 5.60 ± 0.32 h, respectively, which were in close agreement with those predicted by the mathematical models. The drug release from lipospheres followed first-order kinetics and was characterized by the Higuchi diffusion model. The optimized liposphere formulation developed was found to produce sustained anti-diabetic activity following oral administration in rats.32 faktorijalni dizajn primijenjen je za pripravu liposfera s glipizidom metodom separacije pomoću emulzija koristeći parafinski vosak i starinsku kiselinu kao tvari za usporavanje. Pomoću F-testa praćen je učinak kritičnih varijabli tijekom formuliranja, tj. količina parafinskog voska (X1) i udio stearinske kiseline (X2) na srednji promjer liposfera (dg), postotak inkapsulirane ljekovite tvari (% EE), oslobađanje ljekovite tvari nakon 12 h (rel12) te vrijeme potrebno za oslobađanje 50% ljekovite tvari (t50). Pomoću multiple linearne regresijske analize (MLRA) i analize varijabli (ANOVA) za svaki su parametar načinjeni matematički modeli koji sadrže samo značajne varijable. Proučavanje varijabli na oba načina ukazalo je na njihov značajan utjecaj (p < 0,05) na parametre liposfera. Postavljanjem ograničenja na zavisne i nezavisne varijable provedena je numerička optimizacija na principu poželjnosti. Eksperimentalne vrijednosti dg, % EE, rel12 i t50 optimiziranih formulacija bile su 57,54 ± 1,38 µm, 86,28 ± 1,32%, 77,23 ± 2,78% i 5,60 ± 0,32 h. Dobivene eksperimentalne vrijednosti iznosile su vrlo slične vrijednostima predviđenim matematičkim modelima. Oslobađanje glipizida iz liposfera slijedio je kinetiku prvog reda i okarakterizirano je Higuchijevim difuzijskim modelom. Optimizirane liposfere su nakon peroralne primjene na štakorima pokazale produljeni antidijabetički učinak

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Evaluation of maltodextrins as excipients for direct compression tablets and their influence on the rate of dissolution

The maltodextrins Maltrin M700, M500 and M150 have been evaluated as excipients for direct tablets and their influence on the rate of dissolution was examined. The amount of lubricant appears to play an important role and significantly affects and rate of releasel of drug from the tablet, particularly when the drug is insoluble in water, while the release rate of a soluble drug remains unaffected. All the formulations prepared showed excellent flow and compressibility. Storage of the tablets for 90 days at 45°C was found to have almost no influence on their properties. © 1992

The formation of an inclusion complex of methocarbamol with hydroxypropyl-β-cyclodextrin: The effect on chemical stability, solubility and dissolution rate

The inclusion complex of the hydrophobic drug methocarbamol (ML) with hydroxypropyl-β-cyclodextrin (HPβCB) was prepared and characterized in the solid state and in aqueous solution. The prepared complex was studied by chromatographic, spectral and phase solubility methods to determine its structure, solubility, chemical stability and dissolution rate. Host-guest interactions in aqueous solution were studied by proton nuclear magnetic resonance spectroscopy (1H-NMR) and in the solid state by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). The stoichiometry of the isolated complex was determined by reversed phase high pressure liquid chromatography (RP-HPLC), 1H-NMR spectroscopy and elemental analysis. The solubility and dissolution rate of ML in free and complexed form were examined in aqueous solution. The stability constant of the complex was determined by the classical solubility techniques. The chemical stability of free and complexed ML, in buffered solution at pH 7.4 and at two different temperatures, 37 and 60°C, was monitored using an HPLC method and resulted in a 2-fold increase in the stability of complexed ML compared to free ML