Low in‑hospital mortality rate in patients with COVID‑19 receiving thromboprophylaxis: data from the multicentre observational START‑COVID Register

Abstract COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease,and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years

Hydroxyapatite Nanorods Based Drug Delivery Systems for Bumetanide and Meloxicam, Poorly Water Soluble Active Principles

Poorly water-soluble drugs represent a challenge for the pharmaceutical industry because it is necessary to find properly tuned and efficient systems for their release. In this framework, organic–inorganic hybrid systems could represent a promising strategy. A largely diffused inorganic host is hydroxyapatite (HAP, Ca10(PO4)6(OH)2), which is easily synthesized with different external forms and can adsorb different kinds of molecules, thereby allowing rapid drug release. Hybrid nanocomposites of HAP nanorods, obtained through hydrothermal synthesis, were prepared with two model pharmaceutical molecules characterized by low and pH-dependent solubility: meloxicam, a non-steroidal anti-inflammatory drug, and bumetanide, a diuretic drug. Both hybrids were physically and chemically characterized through the combined use of X-ray powder diffraction, scanning electron microscopy with energy-dispersive spectroscopy, differential scanning calorimetry, and infrared spectroscopy measurements. Then, their dissolution profiles and hydrophilicity (contact angles) in different media as well as their solubility were determined and compared to the pure drugs. This hybrid system seems particularly suitable as a drug carrier for bumetanide, as it shows higher drug loading and good dissolution profiles, while is less suitable for meloxicam, an acid molecule

Dosage variability of veterinary drug products, containing furosemide, linked to tablet splitting

Background: Furosemide is a potent diuretic drug widely used to treat congestive heart failure in dogs and cats,but it shows remarkable variability in bioavailability and efficacy when administered orally. In particular, a differentdiuretic effect can be detected after repeated administrations of the same medicinal product in the same animal. For this reason, we investigate the possible reasons for this peculiar behavior. Drug products for veterinary andhuman use are compared in terms of variability for tablet splitting, in vitro dissolution profiles (in different fluids that could simulate the gastrointestinal environment of pets), and drug distribution uniformity.Aim: To study the in vitro performances of drug products in terms of variability.Methods: Five veterinary products and five products for human use, containing different furosemide doses, arecharacterized. Tablets splitting uniformity, in vitro dissolution profiles in different fluids that could simulate thegastrointestinal environment of the different species, and drug content distribution, were tested.Results: The in vitro dissolution profiles of the different medicines are comparable but confirm a different dissolution rate as a function of the medium pH and volume. Many of the products considered show wide variability in the division performances of the scored tablets, and this problem could lead to the detected fluctuations in the diuretic effect. The four-leaf clover shape of a veterinary product appears to give rise to more uniform fractions. A uniform distribution of the drug in the tablets and their fractions is confirmed for all the products considered.Conclusion: The possibility of tablets splitting allows considerable dosage flexibility, but a non-uniform break of the tablets to obtain the dosage suitable for the pet’s weight, can cause dangerous over-or sub-dosing condition, especially in critical pathologies and in small breed pets

Hybrid Nanocomposites of Tenoxicam: Layered Double Hydroxides (LDHs) vs. Hydroxyapatite (HAP) Inorganic Carriers

The search for effective systems to facilitate the release of poorly bioavailable drugs is a forefront topic for the pharmaceutical market. Materials constituted by inorganic matrices and drugs represent one of the latest research strategies in the development of new drug alternatives. Our aim was to obtain hybrid nanocomposites of Tenoxicam, an insoluble nonsteroidal anti-inflammatory drug, with both layered double hydroxides (LDHs) and hydroxyapatite (HAP). The physicochemical characterization on the base of X-ray powder diffraction, SEM/EDS, DSC and FT-IR measurements was useful to verify the possible hybrids formation. In both cases, the hybrids formed, but it seemed that the drug intercalation in LDH was low and, in fact, the hybrid was not effective in improving the pharmacokinetic properties of the drug alone. On the contrary, the HAP-Tenoxicam hybrid, compared to the drug alone and to a simple physical mixture, showed an excellent improvement in wettability and solubility and a very significant increase in the release rate in all the tested biorelevant fluids. It delivers the entire daily dose of 20 mg in about 10 min

Tablet Formulations of Polymeric Electrospun Fibers for the Controlled Release of Drugs with pH-Dependent Solubility

A challenge in the pharmaceutical sector is the development of controlled release dosage forms for oral administration of poorly soluble drugs, in particular, drugs characterized by pH-dependent solubility through the gastrointestinal tract, which itself shows wide variability in terms of environmental pHs. The best approach is to increase the dissolution rate of the drugs at the different pHs and only then modify its release behavior from the pharmaceutical form. This work aims to demonstrate the ability of properly designed polymeric nanofibers in enhancing the release rate of model drugs with different pH-dependent solubility in the different physiological pHs of the gastrointestinal tract. Polymeric nanofibers loaded with meloxicam and carvedilol were prepared using the electrospinning technique and were then included in properly designed tablet formulations to obtain fast or sustained release dosage forms. The nanofibers and the tablets were characterized for their morphological, physico-chemical and dissolution properties. The tablets are able to deliver the dose according to the expected release behavior, and zero-order, first-order, Higuchi, Korsmeyer–Peppas and Hixon–Crowell kinetics models were used to analyze the prevailing release mechanism of the tablets. This study shows that the electrospun fibers can be advantageously included in oral dosage forms to improve their release performances

N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A Review

N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have been discovered over the years, making it a promising drug for diseases such as cystic fibrosis (CF). Its antioxidant activity plays a key role in CF airway inflammation and redox imbalance. Furthermore, this molecule appears to play an important role in the prevention and eradication of biofilms resulting from CF airway infections, in particular that of Pseudomonas aeruginosa. The aim of this review is to provide an overview of CF and the role that NAC could play in preventing and eliminating biofilms, as a modulator of inflammation and as an antioxidant, restoring the redox balance within the airways in CF patients. To do this, NAC can act alone, but it can also be used as an adjuvant molecule to known drugs (antibiotics/anti-inflammatories) to increase their activity

Improving the Carprofen Solubility: Synthesis of the Zn2Al-LDH Hybrid Compound

The development of efficient strategies for drug delivery is considerably desired. Indeed, often several issues such as the drug solubility, the control of the drug release rate, the targeted delivery of drugs, the drug bioavailability, and the minimization of secondary effects still present great obstacles. Different methodologies have been proposed, but the use of nano-hybrids compounds that combine organic and inorganic substances seems particularly promising. An interesting inorganic host is the layered double hydroxide (LDH) with a sheets structure and formula [M2þ 1x M3þ x (OH)2](An)x/n yH2O (M2þ ¼ Zn, Mg; M3þ ¼ Al; An ¼ nitrates, carbonates, chlorides). The possibility to exchange these counterions with drug molecules makes these systems ideal candidates for the drug delivery. In this article, we synthesize by co-precipitation method the hybrid compound Carprofen-Zn2Al-LDH. Carprofen, a poorly soluble antiinflammatory drug, could also benefit of the association with a natural antacid such as LDH, to reduce the gastric irritation after its administration. Through X-ray diffraction and Fourier-transformed infrared spectroscopy (FT-IR), we could verify the effective drug intercalation into LDH. The dissolution tests clearly demonstrate a significant improvement of the drug release rate when carprofen is in the form of hybrid compoun

Hybrid compounds for improving drugs solubility: Synthesis, physicochemical and pharmaceutical characterization of Nimesulide-LDH

Layered double hydroxides (LDHs) with their sheets structure are undoubtedly interesting inorganic hosts for different applications, in particular for drug delivery. Nimesulide, a poorly soluble anti-inflammatory drug, could benefit of the association with LDH to improve its low dissolution rate and thanks to natural antacid properties of LDH to reduce the gastric irritation after its administration. In this paper, we synthesize by coprecipitation and reconstruction methods the hybrid compound Nimesulide-Mg3Al-LDH, as demonstrated by X-ray powder diffraction (from hydroxide layers expansion with respect to pure LDH), thermal analysis (from the absence of drug melting point in the hybrids) and infrared spectroscopy (from the absence of stretching of NO2 and SO2 in the hybrid, suggesting the loose of its rotational freedom into the LDH). In addition, SEM microscopy/EDS microanalysis supported the formation of new entities. The dissolution tests demonstrate an improvement of two times in terms of percentage of drug dissolved when nimesulide is in the form of a hybrid compound, compared to the drug alone or a reference commercial product

Synthesis and Characterization of Carvedilol-Etched Halloysite Nanotubes Composites with Enhanced Drug Solubility and Dissolution Rate

Carvedilol is a poorly water-soluble drug employed to treat chronic heart failure. In this study, we synthesize new carvedilol-etched halloysite nanotubes (HNTs) composites to enhance solubility and dissolution rate. The simple and feasible impregnation method is used for carvedilol loading (30–37% weight). Both the etched HNTs (acidic HCl and H2SO4 and alkaline NaOH treatments) and the carvedilol-loaded samples are characterized by various techniques (XRPD, FT-IR, solid-state NMR, SEM, TEM, DSC, and specific surface area). The etching and loading processes do not induce structural changes. The drug and carrier particles are in intimate contact and their morphology is preserved, as demonstrated by TEM images. The 27Al and 13C solid-state NMR and FT-IR findings show that carvedilol interactions involve the external siloxane surface, especially the aliphatic carbons, the functional groups, and, by inductive effect, the adjacent aromatic carbons. All the carvedilol–halloysite composites display enhanced dissolution rate, wettability, and solubility, as compared to carvedilol. The best performances are obtained for the carvedilol–halloysite system based on HNTs etched with HCl 8M, which exhibits the highest value of specific surface area (91 m2 g−1). The composites make the drug dissolution independent of the environmental conditions of the gastrointestinal tract and its absorption less variable, more predictable, and independent from the pH of the medium

Improvement of firocoxib dissolution performance through electrospun fibers obtained from different polymer/surfactant associations

An electrospinning process was optimized to produce fibers of micrometric size with dierent combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Dierential scanning calorimetry (DSC) and X-ray powder diraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed