GPIIb/IIIa Receptor Antagonism Using Small Molecules Provides no Additive Long-Term Protection after Percutaneous Coronary Intervention as Compared to Clopidogrel Plus Aspirin

Background: There is some controversy as to whether tirofiban or eptifibatide, two small anti-aggregating drugs (AAD), may reduce the incidence of composite ischemic events within one year in patients undergoing percutaneous coronary intervention (PCI) in the real clinical world. Methods: We compared consecutive patients on oral double AAD (with clopidogrel and aspirin) who underwent PCI (n=207) and patients who were on single AAD and received a second AAD, just prior to PCI, and either high-dose tirofiban or double-bolus eptifibatide (double AAD plus small molecules group, n=666). The primary end point (incidence of composite ischemic events within one year) included death, acute myocardial infarction, unstable angina, stent thrombosis or repeat PCI or coronary bypass surgery (related to the target vessel PCI failure) and was modelled by Cox's regression. Results: There were 89 composite ischemic events: 24 (11.6%) in double AAD alone and 65 (9.8%) in double AAD plus small molecules groups (log-rank test: p=0.36). Incidences by type of ischemic events were similar between the 2 groups. Based on 21 potential covariates fitted simultaneously, adjusted hazard ratios (HR and 95% confidence intervals) showed that age (HR 1.03, 1.01-1.06, p=0.01), diabetes (HR 1.68, 1.01-2.79, p=0.05) and intra aortic balloon pump (HR 5.12, 2.36-11.10, p=0.0001) were significant risk factors whereas thrombolysis by tenecteplase (HR 0.35, 0.13-0.98, p=0.05) and having had hypertension or anti-hypertensive treatment (HR 0.58, 0.36-0.93, p=0.03) were significant protectors for events. Whether small molecules were present provided a non significant additional benefit as compared to double AAD alone (HR 0.83, 0.51-1.36, p=0.46). Pre-PCI CK-MB were not useful to predict events (HR 1.01, 0.99-1.01, p=0.17). Conclusions: In clinical world patients undergoing PCI (rescue plus primary <13%) while on double AAD, based on clopidogrel plus aspirin, small molecules (tirofiban or eptifibatide) provided no additive long-term protection against the occurrence of composite ischemic events whereas thrombolysis by tenecteplase did. © Schiariti et al

Kidney Dysfunction and Long-Term Outcome in Post-PCI Acute Coronary Syndrome Patients Treated by High-Dose Tirofiban: The Role of Creatinine Clearance

Aims: Few data exist on kidney dysfunction (KD) and glycoprotein IIb/IIIa inhibitors (GPI) in acute coronary syndrome (ACS) patients treated by percutaneous coronary intervention (PCI) and whether they impact on long-term outcome since most frequently patients with various degrees of KD are excluded. Study Design: Comparison of independent but concomitant arms of a randomized investigation on GPI. Place and Duration of Study: The Sant\u2019ANna TIrofiban Safety study (SANTISS www.clinicaltrials.gov Identifier: NCT00566891) was an open-label investigator-initiated single centre registry at Sant\u2019Anna Hospital, Catanzaro, during a 5-year enrollment period. Methodology: We considered 726 ACS patients with PCI under either triple (aspirin, clopidogrel including high-dose tirofiban) or double (aspirin and clopidogrel) antiaggregating drugs (AAD). Serum creatinine levels, creatinine clearance (CrCl, using the Cockcroft-Gault formula) and estimated glomerular filtration rate (eGFR, using both MDRD and CKD_EPI formulas) were used as continuous co-variables. Cox\u2019s proportional hazards model tested the multivariable contribution of covariates all fitted simultaneously (forced method) in order to predict the incidence of 1-year cumulative ischemic events (CIE). Results: There were 69 (9.5%) 1-year CIE. Incidences were 5.4, 9.8 and 13.4% (P=0.012) in CrCl tertiles 1 (96-216 ml/min), 2 (73-95 ml/min) and 3 (15-72 ml/min), respectively. Compared to CrCl, the percentile distributions of eGFR, by MDRD or CKD_EPI formulas were similar: all were comparable and significant predictors multivariately (p<0.001) of long-term CIE. The presence of diabetes (hazard ratios, HRs 1.84-1.91), intra aortic balloon pump (HRs 3.59-4.03), and thrombolysis (a protective factor) by tenecteplase (HRs 0.30-0.30) were further significant risk factors. With highdose tirofiban there was a 20% lower but not statistically different incidence of 1-year CIE. Conclusion: KD assessed by CrCl or eGFR in ACS patients treated by PCI equally predicted and similarly impacted on 1-year CIE, independent of the formula adopted for eGFR calculation and the presence of GPI with high-dose tirofiban

Development and characterization of chitosan/hyaluronan film for transdermal delivery of thiocolchicoside

none6noThe objective of this study was the development of chitosan/hyaluronan transdermal films to improve bioavailability of thiocolchicoside. This approach offers the possibility to elude the first-pass metabolism and at the same time is able to provide a predictable and extended duration of activity. Films were prepared by casting and drying of aqueous solutions containing different weight ratios of chitosan and hyaluronan and characterized for their physico-chemical and functional properties. In accordance with polymeric composition of films and therefore with the amount of the net charge after the complexation, films containing the same weight ratio of chitosan and hyaluronan showed lower water uptake ability with respect to films containing only one polymeric specie or an excess of chitosan or hyaluronan. Moreover, the lower the hydration of the polymeric network, the lower is the drug diffusion through the films and its permeation through the skin. This study clearly confirmed that the selection of a suitable polymeric weight ratio and appropriate preparative conditions allows the modulation of film functional properties, suggesting that these formulations could be used as a novel technological platform for transdermal drug delivery.mixedFederica Bigucci; Angela Abruzzo; Bruno Saladini; Maria Caterina Gallucci; Teresa Cerchiara; Barbara LuppiFederica Bigucci; Angela Abruzzo; Bruno Saladini; Maria Caterina Gallucci; Teresa Cerchiara; Barbara Lupp

Buccoadhesive films as a new dosage form for transmucosal delivery of ondansetron

Purpose The lack of appropriate pediatric formulations has been identified as a major obstacle for the study and use of drugs in children. In general, there is a need in pediatrics to develop flexible dosage forms able to allow minimal dosage and frequency, and characterized by minimal impact on lifestyle, and easy and reliable administration. The aim of this study was the development of buccoadhesive polymeric films for transmucosal delivery of ondansetron hydrochloride (ODS), a serotonin 5-HT3 receptor antagonist widely used in the management of nausea and vomiting. Methods An aqueous solution of hyaluronic acid (HA; MW 1800-2300 kDa), an aqueous solution of type B gelatine from bovine skin (GEL; MW 50 kDa) and an acid solution of chitosan (CH; MW 150 kDa) were separately added to an aqueous solution of hydroxypropylmethylcellulose (HPMC) at different weight ratios (10:0, 9:1, 7:3, 5:5, 0:10; HPMC:HA or HPMC:GEL or HPMC:CH). After addition of a child-appropriate dose of ODS, each mixture was stirred at room temperature for 24h, spreaded on a Petri-dish and dried at 50°C for 6h. The films were characterized for their morphology (SEM), physical state (DSC, XRPD), mucoadhesion potential (residence time), water uptake ability (gravimetric method) and drug release (modified “paddle over disk” method). Moreover, in vitro permeation studies will carry out to evaluate drug permeation throught biological membranes (Franz-type diffusion cell). Results All films exhibited a smooth surface and a dense and homogeneous cross-section. Characterization at the solid state indicated an amorphous molecular structure. The presence of HA, GEL and CH did not improve the mucoadhesive properties of HPMC film. The inclusion of GEL and CH in HPMC film enhanced in vitro drug release with respect to the inclusion of HA, although HPMC:HA films showed the highest water uptake. This behaviour could be attributed to the high viscosity of the HPMC:HA films in the gel state. Conclusions HPMC can be mixed with HA, GEL and CH to obtain buccal films for the administration of ODS in children. The selection of suitable polymeric mixture and appropriate weight ratio allowed the modulation of film functional properties, suggesting that these formulations could be used as a novel technological platform for pediatric medicines

Vaginal inserts based on chitosan and carboxymethylcellulose complexes for local delivery of chlorhexidine: preparation, characterization and antimicrobial activity.

The aim of this work was to prepare vaginal inserts based on chitosan/carboxymethylcellulose polyelectrolyte complexes for local delivery of chlorhexidine digluconate. Complexes were prepared with different chitosan/carboxymethylcellulose molar ratios at a pH value close to pKa interval of the polymers and were characterized in terms of physico-chemical properties, complexation yield and drug loading. Then complexes were used to prepare inserts as vaginal dosage forms and their physical handling, morphology, water-uptake ability and drug release properties as well as antimicrobial activity toward Candida albicans and Escherichia coli were evaluated. Results confirmed the ionic interaction between chitosan and carboxymethylcellulose and the influence of the charge amount on the complexation yield. Complexes were characterized by high values of drug loading and showed increasing water-uptake ability with the increase of carboxymethylcellulose amount. The selection of appropriate chitosan/carboxymethylcellulose molar ratios allowed to obtain cone-like shaped solid inserts, easy to handle and able to hydrate releasing the drug over time. Finally, the formulated inserts showed antimicrobial activity against common pathogens responsible for vaginal infections

Design and evaluation of buccal films as paediatric dosage form for transmucosal delivery of ondansetron

In the process of implementation and innovation of paediatric dosage forms, buccal films for transmucosal administration of drug represent one of the most interesting approach. In fact, films are able to provide an extended duration of activity allowing minimal dosage and frequency and offer an exact and flexible dose, associated with ease of handling. The objective of the present study was to develop polymeric films for the sustained release of ondansetron hydrochloride, a selective inhibitor of 5-HT3 receptors indicated in paediatrics for the prevention and treatment of nausea and vomiting caused by cytotoxic chemotherapy or radiotherapy and postoperatively. Films were prepared by casting and drying of aqueous solutions containing different weight ratios of hydroxypropylmethylcellulose (HPMC) with chitosan (CH) or sodium hyaluronate (HA) or gelatin (GEL) and characterized for their physico-chemical and functional properties. The presence of HA, GEL and CH did not improve the mucoadhesive properties of HPMC film. The inclusion of GEL and CH in HPMC film increased in vitro drug release with respect to the inclusion of HA, although films containing HA showed the highest water uptake. Moreover in agreement with the release behaviour, the inclusion of CH and GEL provided higher drug permeation through porcine buccal mucosa with respect to HPMC film and ensured linear permeation profiles of drug

Spanish Broom (Spartium junceum L.) fibers impregnated with vancomycin-loaded chitosan nanoparticles as new antibacterial wound dressing: Preparation, characterization and antibacterial activity

In this work, we propose as new wound dressing, the Spanish Broom fibers impregnated with vancomycin (VM) loaded chitosan nanoparticles. Spanish Broom fibers were extracted by patented method DiCoDe and the morphological, physical and mechanical properties were investigated. Chitosan nanoparticles were prepared by ionic gelation using different weight ratios between chitosan (CH) and tripolyphosphate (TPP). Nanoparticles were characterized in terms of size, zeta potential, yield, encapsulation efficiency, stability and drug release. Finally, the antibacterial activity against Staphylococcus aureus as well as in vitro cytotoxicity on HaCaT cells were evaluated. The best formulation CH/TPP 4:1 was selected based on the encapsulation efficiency and yield. Spanish Broom fibers impregnated with loaded nanoparticles showed an increased antibacterial activity against S. aureus compared to the same fibers containing VM without nanoparticles. Moreover, these fibers were not toxic to HaCaT keratinocytes cells. In conclusion, Spanish Broom fibers impregnated with VM loaded CH/TPP nanoparticles would appear to be a promising candidate for wound dressing application