Picc Line Associated Brachiocephalic Vein Rupture with Consequent Mediastinal Placement Causing Pneumomediastinum and Large Total Parenteral Nutrition Bilateral Effusion.

We present a rare case of large bilateral pleural effusion, pericardial effusion and pneumomediastinum caused by a peripherally inserted central catheter (PICC) line rupturing the left brachiocephalic vein, causing severe respiratory failure. The PICC line had been inserted with the aim of providing total parenteral nutrition (TPN). The patient developed symptoms within a day with effusions diagnosed on computer tomography pulmonary angiogram (CTPA). Bilateral pleural drains were inserted with a white milk-like substance drained consistent with TPN, prompting a further review of the CTPA revealing the mediastinal-positioned PICC line. The patient was transferred to the thoracic unit and was successfully managed with conservative measures. We propose some ideas such as the use of intracavitary electrocardiogram (IC-ECG) guidance as an adjuvant to obtain a correct and safe position. LEARNING POINTS: PICC lines, although seen as safer, have potential for catastrophic adverse effects.The use of intracavitary electrocardiogram may be a safe adjunct and even an alternative to the use of a chest X-ray.Aspirating blood from all lumens with particular emphasis on the distal most lumen is very important.

ISCHAEMIC STROKE, PREVENTABLE WITH TISSUE ADHESIVE.

Many cases of gas embolism-related stroke are preventable by following guidelines.Sealing the tract where central venous catheters have been removed with tissue glue prevents air entrainment into the vascular system.Early hyperbaric treatment is essential, and the location of the nearest hyperbaric unit should be known whenever invasive procedures are undertaken.

Essential and non-essential elements, and volatile organic compounds for the discrimination of twenty-three sweet cherry cultivars from Fundão, Portugal.

The mineral contents and volatile profiles of 23 sweet cherry cultivars were determined. A total of 27 minerals were determined by ICP-MS and flame atomic absorption spectrometry, including 12 essential and 15 non-essential elements. K was the most abundant in all cultivars, while Tl was the one found in the smallest amounts. A total of 66 volatiles were identified using SPME/GC-MS, including 16 aldehydes, 23 alcohols, 6 ketones, 6 esters, 8 monoterpenes, 3 norisoprenoids, 2 hydrocarbons and 2 acids. Benzaldehyde, hexanal, nonanal, benzyl alcohol, (E)-2-hexen-1-ol, 1-hexanol, (Z)-2-hexen-1-ol, 2-ethyl-1-hexanol, linalool, α-terpineol and α-ionone were the major ones. Qualitative and quantitative differences were observed among the cultivars, which influenced nutritional potential and aroma. Cherries from Fundão region contain high concentrations of phytochemicals and nutritional components. 4-84, Burlat and Celeste might be considered some of the most interesting cultivars, since they are rich in essential minerals and present high diversity in volatiles.

Sweet cherry phenolics revealed to be promising agents in inhibiting P-glycoprotein activity and increasing cellular viability under oxidative stress conditions: in vitro and in silico study.

This study aimed to explore the total phenolic and anthocyanin content (TPC and TAC, respectively), and the biological potential of Portuguese sweet cherry cultivars. The TPC and TAC values ranged between 72.9 and 493.6 gallic acid equivalents per 100 g fresh weight (fw), and from 1.0 to 179.1 cyanidin 3-O-rutinoside equivalents per 100 g fw, respectively. Cristalina total extract was the most effective in capturing DPPH reactive species, whereas the colored fraction and the total extract of Saco cultivar were the most efficient in scavenging ferric and peroxide species. Celeste total extract was the most effective in inhibiting α-glucosidase enzyme. Phenolic-rich extracts and standard phenolics also revealed ability to interfere with the P-gp activity on MDCK-II and MDCK-MDR1 cells and to increase cellular viability under conditions of oxidative stress. Computational studies were performed to evaluate the interaction between phenolics and the P-gp activity. This study revealed that cherry extracts and their phenolic compounds present notable biological properties, encouraging the development of cherry-based dietary and medicinal supplements. PRACTICAL APPLICATION: The interest in phenolic-rich sources has increased significantly in recent years, given their capacity to prevent the development of chronic disorders, such as cancer. Recent evidence suggests that phenolic compounds can act as P-glycoprotein (P-gp) inhibitors, an important drug efflux transporter, preventing multidrug resistance, and thus, enhancing the therapeutic efficacy of some drugs in certain target cells. Our results indicate that enriched-fractions from sweet cherries can effectively interfere with the P-gp activity on MDCK-II and MDCK-MDR1 cells and protect against oxidative damage.

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval.

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

Physical and phytochemical composition of 23 Portuguese sweet cherries as conditioned by variety (or genotype).

This study aimed to analyze physicochemical characteristics and phenolic profile of twenty-three sweet cherry cultivars from Fundão region, Portugal. The average length and width ranged between 1.9 and 2.6 and 2.1-2.8 cm, respectively. Weight varied between 4.9 and 11.8 g, firmness ranged from 7.3 to 20.1 N, moisture and ash contents ranged from 75.1 to 88.6% and 0.4 to 2.9%, respectively. Sunburst and Sweetheart presented high values of CIEL∗, a∗ and b∗, and low values regarding total soluble solids and maturity index. A total of 46 phenolic compounds were identified by HPLC-DAD-ESI/MSn and quantified by HPLC-DAD, namely 19 hydroxycinnamic acids, 2 hydroxybenzoic acids, 13 flavonols, 5 flavan-3-ols, 2 flavanones, 1 flavanonol and 4 anthocyanins. Sunburst and Brook's were the richest in non-colored phenolics, while Garnet and Tavora were the richest ones in anthocyanins. Therefore, our results revealed that sweet cherries represent a supply of high-value bioactive compounds, being greatly influenced by the cultivar.

Salting-out assisted liquid-liquid extraction method optimized by design of experiments for the simultaneous high-performance liquid chromatography analysis of perampanel and stiripentol in mouse matrices.

We report a high-performance liquid chromatography method development able to simultaneously determine perampanel and stiripentol, two third-generation antiepileptics whose therapeutic spectrum can potentially be extended, in several mouse matrices. A salting-out assisted liquid-liquid extraction optimized by a design of experiments approach was adopted for sample preparations. Isopropanol and magnesium sulfate were the extraction solvent and salting-out agent, respectively. Both drugs and internal standard (terbinafine) were separated using a LiChroCART® Purospher Star column (C18 , 55 × 4 mm; 3 µm) isocratically pumped with mobile phase [1% triethylamine in water (pH 2.5) and acetonitrile (53:47, v/v)] at 1 mL/min. Stiripentol and terbinafine were detected by fluorescence at 254/372 nm and perampanel at 275/430 nm. Good linearity was demonstrated for perampanel at 1-500 ng/mL range in brain, 2-2000 ng/mL in liver and 1-2000 ng/mL in plasma and kidney (r2  ≥ 0.9922), and for stiripentol between 10 and 2000 ng/mL in brain and 10 and 20 000 ng/mL in the remaining matrices (r2  ≥ 0.9917). Precision (CV ≤ 15%) and accuracy (bias ±15%) were also verified, with obtained recovery values consistent with those predicted by the experimental design. This method was applied in preliminary pharmacokinetic studies to quantify perampanel or stiripentol after oral administration to mice, showing to be a promising bioanalytical tool to support future nonclinical in vivo pharmacokinetic studies.

In vitro and in vivo experimental models employed in the discovery and development of antiepileptic drugs for pharmacoresistant epilepsy.

Epilepsy is one of the most common chronic, recurrent and progressive neurological diseases. In spite of the large number of antiepileptic drugs currently available for the suppression of seizures, about one-third of patients develop drug-resistant epilepsy, even when they are administered the most appropriate treatment available. Thus, nonclinical models can be valuable tools for the elucidation of the mechanisms underlying the development of pharmacoresistance and also for the development of new therapeutic agents that may be promising therapeutic approaches for this unmet medical need. Up today, several epilepsy and seizure models have been developed, exhibiting similar physiopathological features of human drug-resistant epilepsy; moreover, pharmacological response to antiepileptic drugs clinically available tends to be similar in animal models and humans. Therefore, they should be more intensively used in the preclinical discovery and development of new candidates to antiepileptic drugs. Although useful, in vitro models cannot completely replicate the complexity of a living being and their potential for a systematic use in antiepileptic drug screening is limited. The whole-animal models are the most commonly employed and they can be classified as per se drug-resistant due to an inherent poor drug response or be based on the selection of subgroups of epileptic animals that respond or not to a specific antiepileptic drug. Although more expensive and time-consuming, the latter are chronic models of epilepsy that better exhibit the disease-associated alterations found in human epilepsy. Several antiepileptic drugs in development or already marketed have been already tested and shown to be effective in these models of drug-resistant epilepsy, constituting a new hope for the treatment of drug-resistant epilepsy. This review will provide epilepsy researchers with detailed information on the in vitro and in vivo nonclinical models of interest in drug-resistant epilepsy, which may enable a refined selection of most relevant models for understanding the mechanisms of the disease and developing novel antiepileptic drugs.

Early preclinical evaluation of dihydropyrimidin(thi)ones as potential anticonvulsant drug candidates.

Although significant advances are occurring in epilepsy research, about 30% of epileptic patients are still inadequately controlled by standard drug therapy. For this reason, it continues to be important to develop new chemical entities through which epilepsy could be effectively controlled. In this study, the anticonvulsant activity of forty-two dihydropyrimidin(thi)ones was explored and their efficacy was evaluated in rodents against the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole tests. The results of preliminary pharmacological screening after intraperitoneal injection in mice revealed that twenty-four compounds showed protection in half or more of the animals tested in the MES seizure model, being nine of them active at the lowest dose tested (30mg/kg). Structurally, the most promising compounds (both urea and thiourea derivatives) presented smaller lateral chains and unsubstituted or para-substituted phenyl ring with a methyl group. Compounds 4, 5 and 11 also protected against MES-induced seizures in 50-75% of rats after oral administration at 30mg/kg. Moreover, the minimal motor and/or neurological impairment evaluated through the rotarod assay showed that around 52% of the compounds presented lower toxicity than the antiepileptic drugs lamotrigine, carbamazepine and phenytoin. In addition, the most active compounds did not show notable cytotoxicity in in vitro experiments conducted in several cell lines (relative cell proliferation higher than 50% at 30µM), which can be relevant due to the fact that the toxicity is a common problem of the available antiepileptic drugs. Furthermore, additional computational studies indicated that all compounds respected the Lipinski's rule of five, which, together with the data of efficacy and toxicity, make them attractive compounds to be developed in the future as potential anticonvulsant agents.

First liquid chromatography method for the simultaneous determination of levofloxacin, pazufloxacin, gatifloxacin, moxifloxacin and trovafloxacin in human plasma.

For the first time a simple, selective and sensitive liquid chromatography method was developed and validated for the simultaneous determination of levofloxacin (LEV), pazufloxacin (PAZ), gatifloxacin (GAT), moxifloxacin (MOX) and trovafloxacin (TRO) in human plasma. Samples were pre-treated with acetonitrile for precipitation of plasma proteins followed by evaporation and reconstitution steps. Chromatographic separation of the analytes and norfloxacin, used as internal standard (IS), was performed under gradient elution on a LiChroCART(®) Purospher Star C18 column (55mm×4mm, 3µm). The mobile phase comprised a mixture of 0.1% aqueous formic acid adjusted to pH 3.0 with triethylamine, acetonitrile and methanol pumped at a flow rate of 1.0mL/min. The detector was set at excitation/emission wavelengths of 260/455nm. Calibration curves were linear (r(2)≥0.9923) in the ranges of 0.005-5µg/mL for GAT, 0.02-5µg/mL for LEV, PAZ and MOX and 0.04-5µg/mL for TRO. The intra and interday precision did not exceed 7.32% and the intra and interday accuracy ranged from -11.73 to 8.92%. The limits of quantification were established at 0.005µg/mL for GAT, 0.02µg/mL for LEV, PAZ and MOX and 0.04µg/mL for TRO. No endogenous or tested exogenous compounds were found to interfere at the retention times of the analytes and IS. Since the proposed method proved to be reliable for the quantitative determination of LEV, PAZ, GAT, MOX and TRO it may be a useful tool for routine analysis and to support clinical pharmacokinetic and toxicological studies involving these antibiotics.