Bleeding and thrombotic risk in pregnant women with Fontan physiology

Background/objectives Pregnancy may potentiate the inherent hypercoagulability of the Fontan circulation, thereby amplifying adverse events. This study sought to evaluate thrombosis and bleeding risk in pregnant women with a Fontan.  Methods We performed a retrospective observational cohort study across 13 international centres and recorded data on thrombotic and bleeding events, antithrombotic therapies and pre-pregnancy thrombotic risk factors.  Results We analysed 84 women with Fontan physiology undergoing 108 pregnancies, average gestation 33 +/- 5 weeks. The most common antithrombotic therapy in pregnancy was aspirin (ASA, 47 pregnancies (43.5%)). Heparin (unfractionated (UFH) or low molecular weight (LMWH)) was prescribed in 32 pregnancies (30%) and vitamin K antagonist (VKA) in 10 pregnancies (9%). Three pregnancies were complicated by thrombotic events (2.8%). Thirty-eight pregnancies (35%) were complicated by bleeding, of which 5 (13%) were severe. Most bleeds were obstetric, occurring antepartum (45%) and postpartum (42%). The use of therapeutic heparin (OR 15.6, 95% CI 1.88 to 129, p=0.006), VKA (OR 11.7, 95% CI 1.06 to 130, p=0.032) or any combination of anticoagulation medication (OR 13.0, 95% CI 1.13 to 150, p=0.032) were significantly associated with bleeding events, while ASA (OR 5.41, 95% CI 0.73 to 40.4, p=0.067) and prophylactic heparin were not (OR 4.68, 95% CI 0.488 to 44.9, p=0.096). Conclusions Current antithrombotic strategies appear effective at attenuating thrombotic risk in pregnant women with a Fontan. However, this comes with high (>30%) bleeding risk, of which 13% are life threatening. Achieving haemostatic balance is challenging in pregnant women with a Fontan, necessitating individualised risk-adjusted counselling and therapeutic approaches that are monitored during the course of pregnancy

‘Portar esca ai fermenti perché lo scoppio anticipi’. Sovversivismo di Lucini sui periodici repubblicani

Recensione di: Pier Luigi Ferro, La penna d’oca e lo stocco d’acciaio: Gian Pietro Lucini, Arcangelo Ghisleri e i periodici repubblicani nella crisi di fine secolo, Milano-Udine, Mimesis, 2014, 430 p., ISBN: 9788857525136, € 32,00

Improvement of the dissolution behavior of gliclazide, a slightly soluble drug, using solid dispersions

Gliclazide is a second generation sulphonylurea used in the treatment of type 2 diabetes characterized by a low risk of hypoglycaemia and cardiovascular disorders. This drug shows poor water solubility, particularly at low pH values, that may cause reduced and variable absorption after oral administration, above all in fasted state. To improve gliclazide dissolution behavior, different drug carrier systems were prepared and tested using two different methods: co-mixing and co-milling. The samples produced were characterized by differential scanning calorimetry, powder X-ray diffraction, and scanning electron mi- croscopy. Their dissolution rate was tested and compared to an immediate release commercial product. Several approaches were effective for a rapid and complete dissolution of this drug: co-milling with suitable hydrophilic carriers such as cross-linked swellable polymers or amorphous silica and co-milling with a small amount of sodium lauryl sulphate (10 mg). In the case of the highest dose (80 mg) both approaches should be used at the same time to avoid saturation of the medium

I. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: Nanoparticles and co-mixing.

Nateglinide is a non-sulphonylurea insulinotropic oral antidiabetic agent. The main problem in formulating an oral dosage form is its low solubility in aqueous media. This problem is particularly critical for an anti-diabetic drug because it should be administered just before the meals and be quickly bioavailable to cover the post-prandial glycemic peak. In this work, some technological approaches have been studied to improve the dissolution rate of nateglinide. Furthermore, two different polymorphs of nateglinide (H and B) have been tested to evaluate the influence of the crystal habitus on the dissolution behavior of the drug. The results have clearly demonstrated that wettability plays a key role in the dissolution behavior of nateglinide. As a matter of fact the physical dispersion of the drug with colloidal silica or hydrophilic swellable polymers strongly enhances the dissolution rate of nateglinide. The two polymorphs tested did not show significant differences in terms of dissolution behavior

II. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: Co-milling.

Nateglinide is an oral antidiabetic agent that should be administered 10-30min before the meal, but it shows low and pH-dependent solubility that may reduce its oral bioavailability. To improve nateglinide dissolution rate, the active was co-milled with three different super-disintegrants or with some hydrophilic excipients, in 1:1, 1:2, and 1:4 drug to carrier ratio (w:w). The three super-disintegrants were crosslinked polyvinylpyrrolidone (PVPC), sodium starch glycolate (SSG) and crosslinked carboxymethyl cellulose (CMCC). The three hydrophilic excipient were amorphous silica (AS), mannitol (M) and Poloxamer (PO). A strong enhancement of drug dissolution rate was obtained from the nateglinide:super-disintegrant co-milled systems in 1:4 ratio, which can be explained by a combination of several factors: an increase in wettability, due to the hydrophilic nature of the carriers, a possible reduction of particle size and a more intimate dispersion of the drug onto the carrier, as a result of the mechanical treatment

Dietary supplementation of coenzyme Q10 plus multivitamins to hamper the ROS mediated cisplatin ototoxicity in humans: a pilot study

Oxidative stress exerts major role in the pathogenesis of side effects of many antineoplastic drugs, including ototoxicity of cisplatin. In particular, increased levels of reactive oxygen species (ROS) represent one of the molecular mechanisms underlying the apoptosis of different types of hearing cells. Antioxidants and ROS scavengers may thus represent potential therapeutic options to prevent platinum-associated ototoxicity. The aim of this preliminary case-control study was to explore the efficacy of a dietary antioxidant supplement, in order to hamper the occurrences of ototoxicity in patients undergoing cisplatin chemotherapy. As results, a significant protection against cochlear toxic damage was demonstrat-ed in patients who took the antioxidant supplement, which furthermore prevented the occurrence of hearing disorders and tinnitus. These clinical evidences were corroborated by the oxidative status of patients. After cisplatin chemotherapy, the plasma derivatives of reactive oxygen metabolites (d-ROMs) content rapidly increased in control patients, but it was maintained in those under dietary supplementation, likely because of a higher anti-ROMs potential. Indeed, an increment in rapid anti-ROMs was detected in supplemented patients, though no differences were highlighted in terms of slow anti-ROMs. In conclusion, in this preliminary report we demonstrated the feasibility of a dietary antioxidant supplementation in order to prevent the cisplatin induced hearing damage

Fabrication, Physico-Chemical, and Pharmaceutical Characterization of Budesonide-Loaded Electrospun Fibers for Drug Targeting to the Colon

The objective of this study was to fabricate and characterize electrospun fibers loaded with budesonide with the aim of controlling its release in the gastrointestinal tract. Budesonide is a nonhalogenated glucocorticosteroid drug, highly effective in the treatment of some inflammatory bowel diseases with local action throughout ileum and colon. At this aim, Eudragit® S 100, a polymer soluble at pH > 7, commonly used for enteric release of drugs, has been successfully spun into ultrafine fibers loaded with Budesonide (B) at 9% and 20% (w/w) using the electrospinning process. The physico-chemical characterization by scanning electron microscopy, X-ray diffraction, FTIR spectroscopy, and thermal analyses indicated the amorphous nature of budesonide in the electrospun systems. Dissolution rate measurements using a pH-change method showed negligible drug dissolved at pH 1.0 and sustained release at pH 7.2. Therefore, the pharmaceutical systems proposed, made of fibers, represent an effective method for drug targeting to terminal ileum and colon with the aim of improving the local efficacy of this drug. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci

Identification of colorants on XVIII century scientific hand-coloured print volumes

Two series of printed volumes, respectively, created in Parma and in Vienna at the end of XVIII century, were analysed in order to characterise the palettes used in the hand-coloured miniatures and to determine whether decoration had been carried out simultaneously to, or shortly after, the time of printing. The application of complementary non-invasive analytical techniques allowed to yield a thorough knowledge of the colorants present and to determine that artists used a mixing of ancient, traditional materials such as cinnabar, minium or indigo, and materials of recent introduction in late XVIII century such as gamboge, Prussian blue or blue verditer. There was no evidence of colorants created successively to the age of printing, so that it can be concluded that decoration could have been done at the time of printing. Interesting is the use of metal pigments in the Vienna volumes, either in powder form and in foil form as a basis to obtain iridescence effects, a clue to evaluate the great skillfulness of the artist. Among the colorants identified, particularly relevant is the identification of gamboge, a colorant almost exclusively used among Far Eastern Asian painters according to the literature; this fact suggests that information on the use of pictorial materials can be strongly updated by diagnostic analyses

Nongenomic effects of 17beta-estradiol in human platelets: potentiation of thrombin-induced aggregation through estrogen receptor beta and Src kinase

The impact of estrogens on the cardiovascular system and their ability to regulate platelet function are matters of controversy. The recent finding that estrogen receptors are expressed in human platelets renders these cells an excellent model for studying the nongenomic effects of these hormones. In this work, we investigated 17beta-estradiol-dependent signaling in platelets from adult healthy men. 17beta-estradiol caused the rapid phosphorylation of the tyrosine kinases Src and Pyk2 and the formation of a signaling complex, which included Src, Pyk2, and the phosphatidylinositol 3-kinase. Both these events were dependent on estrogen receptor beta engagement. We found that estrogen receptor beta was membrane-associated in platelets. On treatment with 17beta-estradiol, Src and Pyk2 activation occurred in the membrane fraction but not in the cytosol. In contrast, no significant activation of phosphatidylinositol 3-kinase was detected in estrogen-treated platelets. 17beta-estradiol did not induce any platelet response directly, but it strongly potentiated the activation of integrin alpha(IIb)beta3 and the platelet aggregation induced by subthreshold concentrations of thrombin. These effects were dependent on estrogen receptor beta recruitment and were associated with a strong synergistic effect with thrombin on Src activation. Taken together, these results indicate that 17beta-estradiol can modulate platelet function by exercising a proaggregating role