The safety profile of sustained release paracetamol during therapeutic use and following overdose.

Sustained release (SR) formulations of paracetamol (acetaminophen) have been introduced in several countries to provide lasting pain relief and reduced risk of rebound pain. However, few studies have evaluated the safety of paracetamol SR formulations.To assess the available published safety data regarding SR formulations of paracetamol, the EMBASE and MEDLINE databases were searched from 1980 to June 2003 for published worldwide human experience with paracetamol SR formulations. All publications that included any information about ingestion of any paracetamol SR formulation were systematically reviewed and abstracted by trained staff. The literature searches returned a total of 14 references containing safety data on paracetamol SR. In addition, the Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers (AAPCC) database was searched for human exposure cases. The TESS database yielded 3003 cases from 1994 to 2002 that involved a paracetamol SR product.The available information indicates that the adverse event and safety profile of paracetamol SR is very similar to immediate release (IR) formulations of paracetamol. During therapeutic use, minor effects such as gastrointestinal upset and headache may occur. The rate of these effects varies substantially among studies but overall does not appear to be different between the SR and IR formulations of paracetamol. Overdose with paracetamol SR is expected to cause liver injury similar to overdose with IR formulations. The number of human exposure cases has increased since introduction of the SR formulation; however, sales of the SR formulation amounted to 7.5% of all paracetamol sales but accounted for 2.5% of the cases reported to poison centres. There were two deaths recorded in the TESS database: both were the result of multiple drug ingestion. No cases of death or unusual types of toxicity have been described from an overdose of paracetamol SR alone.     

Marine and Agro-Industrial By-Products Valorization Intended for Topical Formulations in Wound Healing Applications

Over the past years, research attention has been focusing more on waste-derived, naturally derived, and renewable materials, in the view of a more sustainable economy. In this work, different topical formulations were obtained from the valorization of marine and agro-industrial by-products and the use of Carbopol 940 as gelling agent. In particular, the combination of extracts obtained from the marine snail, Rapanosa venosa, with Cladophora vagabunda and grape pomace extracts, was investigated for wound healing purposes. Rapana venosa has demonstrated wound healing properties and antioxidant activity. Similarly, grape pomace extracts have been shown to accelerate the healing process. However, their synergic use has not been explored yet. To this aim, four different formulations were produced. Three formulations differed for the presence of a different extract of Rapana venosa: marine collagen, marine gelatin, and collagen hydrolysate, while another formulation used mammalian gelatin as further control. Physico-chemical properties of the extracts as well as of the formulations were analyzed. Furthermore, thermal stability was evaluated by thermogravimetric analysis. Antioxidant capacity and biological behavior, in terms of cytocompatibility, wound healing, and antimicrobial potential, were assessed. The results highlighted for all the formulations (i) a good conservation and thermal stability in time, (ii) a neutralizing activity against free radicals, (iii) and high degree of cytocompatibility and tissue regeneration potential. In particular, collagen, gelatin, and collagen hydrolysate obtained from the Rapana venosa marine snail represent an important, valuable alternative to mammalian products.     

New alternatives for erythropoietin therapy in chronic renal failure

Erythropoietin (EPO) is one of the main cytokines involved in the regulation of erythropoiesis. The main site of EPO production are the kidneys. An altered EPO production leads to pathological conditions such as anemia and polycythaemia. Due to the progressive loss of renal peritubular cells, patients with chronic kidney disease (CKD) have low EPO plasma levels. This decreases erythron stimulation with the direct consequence of developing anemia. Before the introduction in the clinical practice of rHuEpo, in the late 1980s, the only solution for treating this type of anemia were blood transfusions and anabolic steroids. Even rHuEpo has proven to be safe and effective for treatment of anemias, there are some concerns about its cost, the need for frequent parenteral administration, and development of anti-EPO antibodies. These inconveniences prompted the search for novel erythropoiesis stimulating agents. Different strategies lead to isolation or chemical synthesis of such agents as darbepoetin alfa and EPO mimetics. In this review, we present some general aspects of EPO biology, with emphasis on chronic renal failure, and expose some of the alternatives to EPO used for anemia correction.     

Pharmacokinetics and comparative bioavailability of two vinpocetine tablet formulations in healthy volunteers by using the metabolite apovincaminic acid as pharmacokinetic parameter

The objective of this study was to evaluate the pharmacokinetics of apovincaminic acid, the main metabolite of vinpocetine ((3alpha, 16alpha) -eburnamenine-14-carboxylic acid ethyl ester, CAS 42971-09-5), and to assess the average bioequivalence of two immediate release formulations of 10 mg vinpocetine tablets in 24 healthy male volunteers. The relative bioavailability of the test (generic) product (Vimpocetina) with respect to the reference product was determined in a single dose, randomized, crossover study. A simple, rapid specific and reliable high performance liquid chromatographic method coupled with mass spectrometry detection has been developed and validated for vinpocetine and apovincaminic acid. However, only the concentrations of the metabolite could be used for bioequivalence determinations because the concentrations of the parent drug were too low to be accurately measured in the biological matrix. The compartmental analysis of the metabolite's appearance-disappearance in blood shows similarity with first-order kinetics of a drug extravascularly administered. The apparent pharmacokinetic constants were determined. The mean values for the Cmax were 49.5 (+/- 16) ng/ml for test and 51.4 (+/- 14) ng/ml for the reference product. The mean values for the AUC0-infinity were 95 (+/- 29) ng/ml x h for test and 96.9 (+/- 26) ng/ml x h for reference, respectively. The 90 % confidence intervals for test/reference mean ratios of the plasma pharmacokinetic variables Cmax and AUC0-infinity lie between 0.83-1.08 and 0.88-1.08, respectively, which is within the conventional bioequivalence range of 80-125 % (Schuirman test). The difference between Tmax of the test and reference products was statistically non-significant (Friedman test). The test product is therefore bioequivalent to the reference product with respect to the rate and extent of apovincaminic acid pharmacokinetics.     

Design and Evaluation of Orally Dispersible Tablets Containing Amlodipine Inclusion Complexes in Hydroxypropyl-β-cyclodextrin and Methyl-β-cyclodextrin

The development of new orally dispersible tablets containing amlodipine (AML) inclusion complexes in hydroxypropyl-β-cyclodextrin (HP-β-CD) and in methyl-β-cyclodextrin (Me-β-CD) was studied. The methods of obtaining amlodipine and the physical and chemical properties of the inclusion complexes using the two cyclodextrins was investigated separately. Solid inclusion complexes were obtained by three methods: kneading, coprecipitation, and lyophilization, at a molar ratio of 1:1. For comparison, a physical mixture in the same molar ratio was prepared. The aim of the complexation process was to improve the drug solubility. As the lyophilization method leads to a complete inclusion of the drug in the guest molecule cavity, for both used cyclodextrins, these types of compounds were selected as active ingredients for the design of orally dispersible tablets. Subsequently, the formulation of the orodispersible tablets containing AML-HP-β-CD and AML-Me-β-CD inclusion complexes and quality parameters of the final formulation were evaluated. The results prove that F1 and F4 formulations, based on silicified microcrystalline cellulose, which contains insignificant proportions of very small or very large particles, had the lowest moisture degree (3.52% for F1 and 4.03% for F4). All of these demonstrate their porous structure, which led to good flowability and compressibility performances. F1 and F4 formulations were found to be better to manufacture orally dispersible tablets.     

Value of the intraoperative assessment of the depth of myometrial invasion in endometrial carcinoma

OBJECTIVES: The aim of the study was to evaluate the value of intraoperative assessment of depth of myometrial invasion in patients with FIGO stage I of the endometrial carcinoma. MATERIAL AND METHODS: A total number of 112 patients with FIGO stage I of the endometrial carcinoma undergoing surgery were enrolled in the study. All patients had undergone intraoperative assessment of the depth of myometrial invasion performed by a surgeon. The depth was determined as more or less than 50% of myometrial thickness according to FIGO classification. Gross visual estimation of the depth of myometrial invasion at the time of the operation was compared with the final histopathological report. Sensitivity, specificity and positive and negative predictive values of the method were determined by means of statistical analyses. RESULTS: The depth of the myometrial invasion was accurately determined by the surgeon in 82.1% of cases. Sensitivity and specificity were 68% and 82.1%, respectively. The accurate prediction rate of the myometrial invasion in the group of patients with well differentiated (G1) endometrial carcinoma was higher (88.4%) than in group with moderately and low differentiated tumour (78.3%). CONCLUSIONS: The accuracy of macroscopic evaluation of myometrial invasion is high and reaches up to 82.1%. The accurate determination rate increases if the differentiation of tumour is higher.     

Assessment of Woodcrete Using Destructive and Non-Destructive Test Methods

Utilizing solid wastes and industrial by-products as a partial replacement for raw materials has become an acceptable practice among researchers and scientists in the civil engineering field. Sawdust and wood shavings are not an exception; they are being used in concrete as a partial or total replacement for some of its constituents. The main goal of this research is to establish a relation between destructive and non-destructive testing for concrete containing wood shavings as a partial replacement of sand (woodcrete). With this type of material existing, thus the need to understand the behavior of such material becomes urgent and evokes the need to ease the process of the assessment and the evaluation of such materials and therefore provide more understanding of its behavior. In addition to the conventional concrete mix, five mixes of woodcrete were made by replacing fine aggregate by volume with wood shavings at different replacement levels varied from 5% to 50%. Cubic samples were tested at the age of 90 days using nondestructive tests (NDT), namely, rebound hammer test and ultrasonic pulse velocity test. Then, the specimens were tested using a conventional compressive test using a universal compression testing machine. Statistical analysis was performed to establish empirical relations between destructive and non-destructive results. The dynamic modulus of elasticity was calculated, and some formulas to estimate the (compressive) strength of woodcrete using NDT results were proposed and tested against experimental results and showed acceptable results.     

XPS Study on Calcining Mixtures of Brucite with Titania

In this work, we studied the phases in a Mg-Ti-O system using a 1:1 formulation of MgO:TiO₂, mixing synthetic brucite of Mexican origin with TiO₂ microparticles of high purity, with a heat treatment at 1100 °C for 1 h. Due to its valence electrons, TiO₂ can contribute to the sintering process to improve density in MgO products. The raw materials and formulation by XPS and X-RD techniques were characterized. The results demonstrate the presence of different oxidation states in titania and the formation of different oxides in the Mg-Ti-O system when mixed and calcined at 1100 °C; additionally, we estimated the formation of vacancies in the crystal lattice during the transformation from hexagonal brucite to magnesia with a cubic structure centered on the faces. Its thermal behavior is indicated by the MgO-TiO₂ phase diagram.     

Static and Fatigue Behaviour of Double-Lap Adhesive Joints and Notched Metal Samples Reinforced by Composite Overlays

The use of composite overlays to increase the fatigue life of notched steel samples is discussed in this paper. For such purposes, in the first set of studies, static and fatigue tests as well as the detailed analytical and numerical analyses for samples with double-lap joints were performed. Based on such studies, the shapes of the composite overlays were set. For a better understanding of the failure forms of the investigated adhesive joints, the experimental studies were monitored with the use of digital image correlation. In the second set of experimental studies, the static and fatigue tensile tests were performed for steel samples with a rectangular opening with rounded corners reinforced by composite overlays. The different shapes (square 45 × 45 mm and long stripes 180 × 15 mm) and composite materials (GFRP and CFRP) were used as overlays. The obtained improvement of fatigue life was in the range of 180–270% in the case of the rectangular overlays and 710% in the case of application of the overlays in the form of the long stripes. This was also confirmed by numerical analyses in which a reduction in the stress concentration factor from 2.508 (bare sample) through 2.014–2.183 (square 45 × 45 mm overlays) to 1.366 (overlays in the form of long stripes 180 × 15 mm) was observed.