Blood Drug Concentration Research Articles

Co-amorphous systems of sinomenine with nonsteroidal anti-inflammatory drugs: A strategy for solubility improvement, sustained release, and drug combination therapy against rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune joint disorder that affects about 1% of the world population and may lead to severe disability and comorbidity. Despite breakthroughs in past decades to understand its pathogenesis and the development of transforming disease-modifying antirheumatic drugs, the symptoms of many patients are not substantially improved. Sinomenine (SIN), a natural alkaloid with poor solubility, has been used to treat RA in China for years because of its unique immunoregulative activity. However, its commercial hydrochloride form has a short half-time, which may cause huge fluctuations of blood drug concentration leading to severe adverse reactions. In this study, co-amorphous systems of SIN with three nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin, naproxen, and sulindac, were prepared for the combination therapy, as well as the improvement of its aqueous solubility and controlled release. Each co-amorphous sample was characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), and Fourier transform infrared spectroscopy (FTIR). The CO2– and N+H stretching vibration in the three co-amorphous samples appears in FTIR spectra, suggesting the formation of salts between SIN and NSAIDs. SIN also exhibits sustained release rates in all three co-amorphous samples. These co-amorphous systems show excellent physicochemical stability because no recrystallization was observed at 25 °C and 75% relative humidity (RH) after four months. Our study suggests that SIN-NSAIDs co-amorphous systems represent an affordable and promising treatment against RA.

Factors associated with blood carnitine levels in adult epilepsy patients with chronic valproic acid therapy

AimsValproic acid (VPA) is a widely used antiepileptic drug for the treatment of epilepsy, seizures, and bipolar and psychiatric disorders. A deficiency of carnitine, a compound involved in energy production, is associated with chronic VPA use. However, the clinical factors affecting blood carnitine levels and their pathophysiology remain unclear. Hence, we aimed to identify the factors that correlated with serum carnitine levels in epilepsy patients receiving chronic VPA therapy. MethodsThis observational study included 138 epilepsy patients receiving chronic VPA therapy. Serum total and free carnitine levels, routine blood tests and drug concentrations were assessed. The correlation between carnitine levels and other factors were calculated using Spearman's rank correlation coefficients, and a principal component analysis (PCA) and a multiple linear regression analysis were performed. ResultsOverall, serum free carnitine levels showed significant negative correlations with epilepsy duration, VPA treatment duration, daily VPA dose, and blood VPA concentration. A significant positive correlation was observed with erythrocyte count, hemoglobin levels, and creatinine levels. Of the 138 patients, 21 (15.2 %) with serum free carnitine levels of <20 μmol/L had significantly longer disease duration, a higher daily VPA dose, and lower blood clobazam concentrations. In the 48 VPA monotherapy patients, serum free carnitine levels showed a significant negative correlation with disease duration and duration of VPA therapy. Furthermore, in the 2.1 % patients receiving VPA monotherapy, serum free carnitine levels were <20 μmol/L. PCA resulted in seven factor solution (eigenvalue >1; 71.67 % explained variance). Component 1 clearly revealed the maximal loading for serum free carnitine level (.792) and the most negative loading for disease duration of epilepsy (−.595). A linear regression analysis revealed that the duration of epilepsy, serum creatinine level, and daily dose of VPA were significant (p < .01) factors that affected serum free carnitine levels. ConclusionsThe effects of combination therapy with VPA and other anti-epileptic drug(s) on carnitine levels are higher than that of VPA monotherapy. Additionally, epilepsy duration may affect serum free carnitine level.

FORMULATION AND IN VIVO EVALUATION OF SELF-NANOEMULSIFYING DRUG DELIVERY SYSTEM OF RAMIPRIL IN WISTAR RATS

Objective: The aim was to formulate and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) of ramipril, an antihypertensive drug to improve the solubility and bioavailability.&#x0D; Methods: Based on solubility studies oil phase (Sefsol 218), surfactant (Acrysol EL135), and cosurfactant (Transcutol P), respectively, were selected to prepare SNEDDS. Ramipril SNEDDS optimized employing box-Behnken design through the study of factors. All formulations were evaluated for particle size, zeta potential (ZP), polydispersity index (PDI), entrapment efficiency (EE), drug content, and in vitro drug release. The optimized formulation was characterized for Fourier transform infrared (FTIR), scanning electron microscopy (SEM), stability studies, and pharmacokinetic study.&#x0D; Results: The mean particle size, PDI, ZP, EE, content uniformity, and in vitro drug release profile of optimized ramipril-loaded SNEDDS (RF14) were found to be 75.3±2.21nm, 0.126±0.05, −24.4±5.78mV, 98.74±1.97%, 99.52±1.67%, and 98.65±1.73%, respectively. FTIR studies revealed that there is no incompatibility between drug and excipients, SEM images exhibited nanoparticles to be more porous and in spherical shape. Stability studies indicated formulation was stable for 6 months. In vivo studies were conducted for optimized formulation RF14, the Tmax was found to be 0.5±0.62 and 0.5±0.95 h for the optimized and commercial formulations respectively, while Cmax was 25.16±1.73 ng/mL was significant (p&lt;0.05) as compared to the ramipril pure drug 8.02±0.086 ng/mL. AUC0-t of the SNEDDS formulation was higher 355.49±1.76ng h/ml compared to pure drug 116.57±1.64 ng h/ml indicated higher amount of drug concentration in blood proving better systemic absorption of ramipril from SNEDDS formulation as compared to the pure drug.&#x0D; Conclusion: It is concluded from the results that ramipril was successfully formulated into SNEDDS with higher concentration with fast action.

MO977POTENTIAL INTERACTIONS BETWEEN UREMIC TOXINS AND DRUGS: AN APPLICATION IN KIDNEY TRANSPLANT RECIPIENTS TREATED WITH CALCINEURIN INHIBITORS*

Abstract Background and Aims In addition to affecting glomerular filtration rate, chronic kidney disease (CKD) changes the absorption, distribution and nonrenal clearance of a number of drugs. The uremic toxins that accumulate with as renal function deteriorates can potentially affect drug pharmacokinetics. Given the requirement for therapeutic drug monitoring (TDM) with most immunosuppressants, the latter are good models for understanding the potential impact of uremic toxins on blood concentrations of drugs. We focused on two calcineurin inhibitors (tacrolimus and cyclosporine) with similar pharmacological properties: low but variable oral bioavailability, strong binding to plasma proteins (albumin for tacrolimus and lipoproteins for cyclosporine), metabolism by cytochrome P450 3A4/5, and excretion in the bile. Our starting hypothesis was that uremic toxins influence the exposure of immunosuppressants. The study’s objective was to determine whether plasma concentrations of certain uremic toxins were correlated with blood concentrations of the two immunosuppressants. Method DRUGTOX was a cross-sectional study of 403 adult patients followed up after kidney transplantation at Amiens University Medical Center (Amiens, France) and who had undergone TDM of calcineurin inhibitors between August 4th, 2019, and March 11th, 2020. The patients had been treated daily with oral tacrolimus or cyclosporine. Two groups were constituted: 203 patients with low uremic toxin levels (estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease equation &amp;gt;40 mL/min/1.73m2) and 200 patients with high uremic toxin levels (eGFR &amp;lt;40 mL/min/1.73m2). For each patient, immunosuppressant trough concentrations (C0) were measured in whole-blood samples and then normalized against the total daily dose: C0/D ratio. After centrifugation, the sample was assayed for five uremic toxins (urea, trimethylamine N-oxide (TMAO), indole acetic acid (IAA), para-cresylsulfate (PCS), and indoxylsulfate (IxS)) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Univariate and multivariate logistic regressions were used to evaluate the associations between plasma uremic toxin levels and the blood tacrolimus or cyclosporine C0/D ratio. Results The median [interquartile range] age was 56 [48-66] and the median eGFR was 41 [30-57] ml/min/1.73 m2. The majority of the patients (56.5%) were at CKD stage 3. A total of 248 (61.5%) patients were being treated with tacrolimus and 155 (38.5%) were being treated with cyclosporine. The median time between transplantation and study inclusion was 6.5 years. Plasma urea, TMAO, IAA, PCS and IxS levels rose progressively with the CKD stage. In a univariate logistic analysis, age, sex, BMI, urea, IxS and PCS were significantly associated with an increment in the tacrolimus C0/D ratio. A multivariate analysis revealed an independent association with IxS (odds ratio [95% confidence interval]: 1.36 [1.00; 1.85], after adjustment for sex, age and BMI, whereas adjustment for age weakened the association for PCS (OR: 1.22 (0.99; 1.55)) and urea (OR: 1.71 (0.93; 3.16)). In a univariate logistic analysis, age, sex, BMI, and the TMAO level (but neither PCS, IxS, IAA nor urea) were significantly associated with an increment in the cyclosporine C0/D ratio. Conclusion Even though TDM and dose adaptation of immunosuppressants keeps levels within the therapeutic window, elevated exposure to tacrolimus (but not cyclosporine) is associated with an accumulation of PCS, IxS and urea. This might be explained by an interaction between tacrolimus and highly albumin-bound uremic toxins. Our findings may have implications for other drugs that bind with high affinity to albumin (since an elevated free fraction might lead to unexpected exposures, which can alter their efficacy and/or tolerance).

Pediatric opioid fatalities: What can we learn for prevention?

The aim of this study was to highlight 19 cases investigated by the North Carolina Office of the Chief Medical Examiner over the last 12years involving accidental or undetermined manner of death opioid ingestions leading to fatalities in young children. These pediatric ingestions have closely mirrored the opioid epidemic in adults transitioning from prescription medications to illicit drugs including fentanyl and fentanyl analogues. Unlike a typical adult ingestion for purposes of self-harm or pleasure, poisonings in toddlers and infants are usually the result of curiosity, exploration, a decreased sense of danger, or imitation of adult or older sibling behavior. Eleven of the decedents were between the ages of 8 and 24months. Among the cases were 12 prescription opioid exposure deaths and 7 illicit drug poisonings. A majority of the decedents were found unresponsive in an unkept home and/or in unsafe sleeping spaces with easy access to drugs or drug materials, which stresses the importance of safe pediatric sleeping conditions. After a complete pathological investigation, several of the cases had physical or scene evidence demonstrating that foil, plastic, or paper small enough to be ingested can contain enough potent opioid to cause death. Details from the toxicological investigation are included for each case to provide postmortem whole blood drug concentrations for forensic practitioners. Accidental pediatric poisonings are preventable. Risk reduction through improving awareness and education of the dangers of opioids is a key factor in mitigating these tragedies.

The interactions between COVID-19 drugs and psychotropic agents

Coronavirus disease (COVID-19) is a systemic infection targeting multiple organs. Interstitial pneumonia is the landmark feature of this condition. Severe acute respiratory symptoms requiring intensive care support arises for about one out of twenty symptomatic cases. Aminochinolone, antiviral, antibiotic, corticoid, anticoagulant and immunobiological drugs are used, mostly to treat symptoms. Only remdesivir exhibiting weak antiviral activity is approved for COVID-19. Psychotropic medications may interact with medical treatments for COVID-19. The aim of this presentation is to highlight pharmacokinetic and pharmacodynamic drug-drug interactions to be expected for medical treatments of COVID-19. Remdesivir and favipiravir exhibit hepatotoxic properties which may be enhanced under combinations with tricyclic antidepressants or agomelatine. Favipiravir, hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir have QT interval prolongation potential and must be considered for combinations with antidepressant and antipsychotic drugs. For hydroxychloroquine, hypoglycemic activity may give rise to endocrine disturbances. Pharmacokinetic drug-drug interactions can be expected for lopinavir/ritonavir which inhibit cytochrome P-450 (CYP) 3A4 and induce CYP2C9 and CYP2C19. Combinations with psychotropic drugs that are substrates of these enzymes (victim drugs) will affect drug concentrations in blood and lead to supra- or subtherapeutic levels. Moreover, it must be assumed that the COVID-19 infection is associated with an enhanced production of cytokines which has a known impact on CYP enzyme activities. Though studies on interactions between psychotropic medications and medical treatments for COVID-19 are lacking, multiple drug interactions can be predicted and expected considering the side effect profiles and CYP inhibitory, inducing and substrate properties of combined drugs.DisclosureNo significant relationships.

Relevancia de la anfotericina B liposomal en el tratamiento de las infecciones fúngicas invasoras en pacientes oncohematológicos

Liposomal amphotericin B (L-AmB) has been a key cornerstone for the management of invasive fungal infections (IFI) caused by a wide array of molds and yeasts during the last three decades. Multiple studies performed over this period have generated a large body of evidence on its efficacy and safety, becoming the main antifungal agent in the management of IFI in patients with hematologic malignancies in several not mutually exclusive clinical settings. First, L-AmB is the most commonly used antifungal agent in patients undergoing intensive chemotherapy for acute leukemia and high-risk myelodysplastic syndrome, as well as in hematopoietic stem cell transplant recipients. Additionally, due to the administration of newer targeted therapies (such as monoclonal antibodies or small molecule inhibitors), opportunistic mold infections are increasingly being reported in patients with hematologic malignancies usually considered low-risk for IFI. These agents usually have a high drug-drug interaction potential, being triazoles, commonly used for antifungal prophylaxis, included. Finally, patients developing breakthrough IFI because of either subtherapeutic concentrations of antifungal prophylactic drugs in blood or selection of resistant strains, require broad spectrum antifungal therapy, usually with an antifungal of a different class. In both situations, L-AmB remains as the best option for early antifungal therapy.

Pharmacokinetics and pulmonary distribution of Draxxin® (tulathromycin) in healthy adult horses.

The objective of this study was to determine the pharmacokinetics and tolerability of tulathromycin (Draxxin® ; 2.5mg/kg once) after intramuscular (IM), subcutaneous (SC), and slow intravenous (IV) administration to six adult horses. A three-phase design and 4-week washout period were used. Drug concentrations in blood and bronchoalveolar lavage (BAL) samples were determined by ultra-performance liquid chromatography tandem mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Following SC and IM administration, all horses exhibited sweating, discomfort, and periods of recumbency. As signs were more severe after SC administration this route was only used in 3/6 horses. Intravenous administration of tulathromycin was well tolerated in all horses. Mean bioavailability was 99.4% IM and 115% SC. Mean maximum plasma concentration was 645ng/ml IM and 373ng/ml SC. Mean half-life was 59.8h, 54.8h, and 57.9h for IV, IM, and SC administration, respectively. Mean clearance was 3.25ml/kg/min, and mean volume of distribution was 16.8L/kg following IV administration. Drug was detectable in plasma and BAL samples for 120h following all routes; however, adverse effects may prevent IM use and SC use is not recommended. Tulathromycin may be a practical and affordable antimicrobial for use in adult equine patients.

Autopsy findings in drivers and passengers from fatal motor vehicle collisions: limited differences in injury patterns and toxicological test results

We performed a retrospective study of the injuries and characteristics of occupant fatalities in motor vehicle collisions in southeast Norway. The goal was to provide updated knowledge of injuries sustained in modern vehicles and detect possible differences in injury pattern between drivers and passengers. Forensic autopsy reports, police, and collision investigation reports from 2000 to 2014 were studied, data extracted and analyzed.A total of 284 drivers, 80 front-seat passengers, and 37 rear-seat passengers were included, of which 67.3% died in front collisions, 13.7% in near-side impacts, 13.5% in rollovers and 5.5% in other/combined collisions. Overall, 80.5% died within one hour after the crash. The presence of fatal injuries to the head, neck, thorax and abdomen were observed in 63.6%, 10.7%, 61.6% and 27.4% respectively. All occupants with severe injuries to the head or neck had signs of direct impact with contact point injuries to the skin or skull. Injuries to the heart and spleen were less common in front-seat passengers compared to drivers. Seat belt abrasions were more common and lower extremity fractures less common in both front-seat and rear-seat passengers compared to drivers. Blood alcohol and/or drug concentrations suggestive of impairment were present in 30% of all occupants, with alcohol more often detected among front-seat passengers compared to drivers.Few driver-specific and passenger-specific patterns of injury could be identified. When attempting to assess an occupant’s seating position within a vehicle, autopsy findings should be interpreted with caution and only in conjunction with documentation from the crash scene.

TEMPO-Oxidized Cellulose Beads as Potential pH-Responsive Carriers for Site-Specific Drug Delivery in the Gastrointestinal Tract.

The development of controlled drug delivery systems based on bio-renewable materials is an emerging strategy. In this work, a controlled drug delivery system based on mesoporous oxidized cellulose beads (OCBs) was successfully developed by a facile and green method. The introduction of the carboxyl groups mediated by the TEMPO(2,2,6,6-tetramethylpiperidine-1-oxyradical)/NaClO/NaClO2 system presents the pH-responsive ability to cellulose beads, which can retain the drug in beads at pH = 1.2 and release at pH = 7.0. The release rate can be controlled by simply adjusting the degree of oxidation to achieve drug release at different locations and periods. A higher degree of oxidation corresponds to a faster release rate, which is attributed to a higher degree of re-swelling and higher hydrophilicity of OCBs. The zero-order release kinetics of the model drugs from the OCBs suggested a constant drug release rate, which is conducive to maintaining blood drug concentration, reducing side effects and administration frequency. At the same time, the effects of different model drugs and different drug-loading solvents on the release behavior and the physical state of the drugs loaded in the beads were studied. In summary, the pH-responsive oxidized cellulose beads with good biocompatibility, low cost, and adjustable release rate have shown great potential in the field of controlled drug release.

Pharmacokinetics of levofloxacin mesylate in healthy adult giant panda after single-dose administration via different routes.

The pharmacokinetics of levofloxacin mesylate in healthy adult giant panda is unknown. In this study, the pharmacokinetics of levofloxacin after intramuscular administration at a dose of 2mg/kg and oral administration at a dose of 3mg/kg in healthy adult giant pandas was determined. Levofloxacin concentrations in plasma were determined using liquid chromatography. In the levofloxacin intramuscular administration group, the absorption and elimination half-lives of the drug were determined to be 0.123 (range: 0.02) hr and 5.402 (range: 0.70) hr, respectively. In the levofloxacin oral administration group, the absorption and elimination half-lives were determined to be 0.325 (range: 0.02) hr and 7.143 (range: 0.63) hr, respectively. Furthermore, the blood-drug concentration of levofloxacin was found to be above 1μg/ml after 8hr of intramuscular administration and above 0.5μg/ml after 12hr of oral administration. In this study, HPLC conditions and pretreatment methods of plasma samples were optimized and a detection method was established. Our results indicated that in healthy adult giant pandas, levofloxacin was rapidly absorbed and slowly eliminated. This study will therefore provide to be a guide in veterinary research and will be helpful in the rational use of levofloxacin in giant panda.

Effect of Porous Silicon Nanoparticle Drug-Loading System on Ulcerative Colitis.

Ulcerative colitis (UC) is a non-specific intestinal inflammatory disease. UC occurred in developed countries in the past, but in the past 20 years, the incidence of UC in developing countries has also shown a clear upward trend. The hospitalization rate and surgical rate of UC have been high, and may lead to the occurrence of intestinal malignant tumors, which has greatly affected the quality of life and life expectancy of patients. Because of this, how to effectively treat UC has become a hotspot in modern gastrointestinal diseases. Due to the limitation of the dosage form of the drug and the special environment of the gastrointestinal tract, traditional oral drugs have the disadvantage of not being able to make the drug effective in specific lesions when treating inflammatory bowel disease. Therefore, it is of great scientific significance and application value to develop drug carriers that can target the inflammatory sites and slow-release drugs to treat inflammation. In this study, TNBS method was used to prepare a rat model of ulcerative colitis, and the effect of modified porous silicon nanoparticles as a drug carrier in the treatment of UC was investigated. We first induced acute enteritis model in C57BL/6 rats through TNBS, and then used in vivo fluorescence imaging and immunofluorescence staining technology to prove that porous silicon nanoparticles can indeed be specifically concentrated in the damaged part of the mouse intestine, and then administered by gastric administration. The drug method allows rats to take different types and concentrations of drug-loaded porous silicon nanoparticles, and finally collect relevant samples for evaluation of drug efficacy after the end of the administration cycle. The disease activity index showed the best gastrointestinal recovery in mice treated with modified drug-loaded porous silicon nanoparticles. The pathological analysis of rat colons using HE staining proved that the improved drug-loaded porous silicon nanoparticles had a more significant therapeutic effect. TUNEL staining results showed that the level of apoptosis in the colon injury site of rats treated with modified drug-loaded porous silicon nanoparticles was reduced. The test results of drug concentration in rat colon tissue blood also proved that porous silicon nanoparticle drug-loading system can reduce the release of inflammatory factors in vivo. Based on the TNBS-induced UC rat model, this paper evaluates the therapeutic effect of modified drug-loaded porous silicon nanoparticles. The results show that in the treatment of ulcerative colitis, the nanoparticle drug-loaded system is a more effective treatment way.

Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor, and surgical resection is the first choice for the treatment of the disease, but since the advent of tyrosine kinase inhibitors (TKIs) such as imatinib (IM), the prognosis of the disease has undergone revolutionary changes. According to the current version of the guidelines, most GIST patients receive a fixed dose without taking into account their own individual differences, resulting in a wide difference in blood concentration, adverse reactions and prognosis. With more studies on the relationship between blood drug concentrations and prognosis, the concept of individualized therapy has been paid more attention by researchers. Therapeutic drug monitoring (TDM) has also been made available for the research field of GIST targeted therapy. How to reduce the incidence of drug resistance and adverse reactions in patients with GISTs has become the focus of the current research. This article reviews the common monitoring methods and timing of TKIs blood concentration, the reasonable range of blood drug concentration, the toxic or adverse effects caused by high blood drug concentration, some possible factors affecting blood drug concentration and recent research progress, in order to discuss and summarize the treatment strategy of individual blood drug concentration, improve the prognosis of patients and reduce the adverse effects as much as possible.

Transdermal iontophoresis delivery system for terazosin hydrochloride: an in vitro and in vivo study

This study aimed to construct a transdermal iontophoresis delivery system for terazosin hydrochloride (IDDS-TEH), which included a positive and negative electrode hydrogel prescription. Intact guinea pig skin was used as a model for the skin barrier function, and the current intensity, terazosin hydrochloride (TEH) concentration, pH, competitive salt, and transdermal enhancer properties were studied. The blood drug concentration was determined in Sprague–Dawley (SD) rats using HPLC, and the antihypertensive effects of IDDS-TEH were evaluated in spontaneously hypertensive rats (SHRs). The results showed that the steady-state penetration rate of TEH increased (from 80.36 µg·cm−2·h−1 to 304.93 µg·cm−2·h−1), followed by an increase in the current intensity (from 0.10 mA·cm−2 to 0.49 mA·cm−2). The pH values also had a significant influence on percutaneous penetration. The blood concentration of IDDS-TEH was significantly higher (p < .05) than with passive diffusion, which could not be detected. The main pharmacokinetic parameters of the high current group (0.17 mA·cm−2) and the low current group (0.09 mA·cm−2) were AUC0– t : 5873.0 ng·mL−1·h and 2493.7 ng·mL−1·h, respectively. Meanwhile, the pharmacodynamic results showed that IDDS-TEH significantly decreased the blood pressure of SHRs compared with the TEH hydrogel without loading current. Therefore, TEH could be successfully delivered by the transdermal iontophoresis system in vitro and in vivo, and further clinical studies should be explored to develop a therapeutically useful protocol.

Ten Challenges Associated with Management of Paracetamol Overdose: An Update on Current Practice and Relevant Evidence from Epidemiological and Clinical Studies

Paracetamol is a commonly used medication all over the world. Although it is relatively safe, it results in serious toxicities requiring emergency department visits and hospitalisations, and may cause death. Toxicity can be predicted from drug blood concentration using Rumack-Matthew nomogram or from the ingested amount per body weight. Patients with expected toxicities are treated with activated charcoal if presented within two hours and N-acetylcysteine besides symptomatic and supportive measures. The present review represents a compilation of ten common challenging situations associated with management of paracetamol overdose. They include high risk patients, hypersensitivity reactions to the antidote, massive ingestions, late presentations, multiple ingestions of immediate release formulations, modified release ingestions, repeated supratherapeutic ingestions for therapeutic purposes, paediatric exposures, toxicity during pregnancy, and co-administered medications. Medical practitioners, who treat the patients presenting with paracetamol overdose and pharmacists working with drug or poison information centers, would benefit from having all ten challenging scenarios presented together in one place.

Preparation and in vivo/in vitro characterization of Ticagrelor PLGA sustained-release microspheres for injection

ABSTRACT The objective of this paper was to develop a PLGA carrier Ticagrelor sustained-release microspheres preparation, which was expected to continue to release Ticagrelor for 14 days with a high encapsulation rate. Ticagrelor microspheres were prepared successfully with average diameter of 7.31 µm, drug loading of 12.49 ± 0.32% and EE up to 79.09 ± 1.69%. In the release medium of PH7.4 PBS, the microspheres showed good drug release behavior in vitro. In vivo release results also showed that the sustained-release microspheres could effectively control drug release in vivo and maintain a relatively stable blood drug concentration for about 2 weeks. The results indicate that Ticagrelor sustained-release microspheres can be used for long-term treatment of acute coronary syndrome.

Anti-tumor effect of local injectable hydrogel-loaded endostatin alone and in combination with radiotherapy for lung cancer

Endostatin (ES) can effectively inhibit neovascularization in most solid tumors and has the potential to make oxygen delivery more efficient and increase the efficacy of radiotherapy (RT). With a short half-life, ES is mainly administered systemically, which leads to low intake in tumor tissue and often toxic systemic side effects. In this study, we used hyaluronic acid-tyramine as a carrier to synthesize an ES-loaded hydrogel drug (ES/HA-Tyr) that can be injected locally. ES/HA-Tyr has a longer half-life and fewer systemic toxic side effects, and it exerts a better anti-angiogenic effect and anti-tumor effect with RT. In vitro, ES/HA-Tyr showed sustained release in the release assay and a stronger ability to inhibit the proliferation of human umbilical vascular endothelial cells (HUVECs) in the MTT assay; it exhibited a more potent effect against HUVEC invasion and a stronger anti-angiogenic effect on HUVECs in tube formation. In vivo, ES/HA-Tyr increased local drug concentration, decreased blood drug concentration, and caused less systemic toxicity. Further, ES/HA-Tyr effectively reduced tumor microvessel density, increased tumor pericyte coverage, decreased tumor hypoxia, and increased RT response. ES/HA-Tyr + RT also had increased anti-tumor and anti-angiogenic effects in Lewis lung cancer (LLC) xenograft models. In conclusion, ES/HA-Tyr showed sustained release, lower systemic toxicity, and better anti-tumor effects than ES. In addition, ES/HA-Tyr + RT enhanced anti-angiogenic effects, reduced tumor hypoxia, and increased the efficacy of RT in LLC-bearing mice.

The Role of Nanomaterials in Stroke Treatment: Targeting Oxidative Stress.

Stroke has a high rate of morbidity and disability, which seriously endangers human health. In stroke, oxidative stress leads to further damage to the brain tissue. Therefore, treatment for oxidative stress is urgently needed. However, antioxidative drugs have demonstrated obvious protective effects in preclinical studies, but the clinical studies have not seen breakthroughs. Nanomaterials, with their characteristically small size, can be used to deliver drugs and have demonstrated excellent performance in treating various diseases. Additionally, some nanomaterials have shown potential in scavenging reactive oxygen species (ROS) in stroke according to the nature of nanomaterials. The drugs' delivery ability of nanomaterials has great significance for the clinical translation and application of antioxidants. It increases drug blood concentration and half-life and targets the ischemic brain to protect cells from oxidative stress-induced death. This review summarizes the characteristics and progress of nanomaterials in the application of antioxidant therapy in stroke, including ischemic stroke, hemorrhagic stroke, and neural regeneration. We also discuss the prospect of nanomaterials for the treatment of oxidative stress in stroke and the challenges in their application, such as the toxicity and the off-target effects of nanomaterials.

How much sleep do you need? A comprehensive review of fatigue related impairment and the capacity to work or drive safely

In developed countries, deaths attributable to driving or working while intoxicated have steadily declined over recent decades. In part, this has been due to (a) public education programs about the risks and (b) the deterrence value associated with penalties and prosecutions based on an individual being ‘deemed impaired’ if they exceed a proscribed level of blood alcohol or drug concentration while driving/working. In contrast, the relative proportion of fatigue-related accidents have remained stubbornly high despite significant public and workplace education. As such, it may be useful to introduce the legal principle of ‘deemed impaired’ with respect to fatigue and/or sleep loss. A comprehensive review of the impairment and accident literature was performed, including 44 relevant publications. Findings from this review suggests that a driver or worker might reasonably be ‘deemed impaired’ once the amount of sleep falls below five hours in the prior 24. Building on the legal principles first outlined in recent New Jersey legislation (Maggie’s Law), this review argues that an individual can reasonably be ‘deemed impaired’ based on prior sleep wake behaviour. In Maggie’s Law, a driver can be indirectly ‘deemed impaired’ if they have not slept in the prior 24 h. Based on the extant literature, we argue that, relative to drug and alcohol intoxication, this may be overly conservative. While roadside measurement of fatigue and prior sleep-wake behavior is not yet possible, we suggest that public education programs should provide specific guidance on the amount of sleep required and that post-accident forensic examination of prior sleep wake behaviours may help the community to determine unsafe behaviours and liability more objectively than is currently the case.

Whole blood or plasma: what is the ideal matrix for pharmacokinetic-driven drug candidate selection?

In the present era of drug development, quantification of drug concentrations following pharmacokinetic studies has preferentially been performed using plasma as a matrix rather than whole blood. However, it is critical to realize the difference between measuring drug concentrations in blood versusplasmaand the consequences thereof. Pharmacokinetics using plasma data may be misleading if concentrations differ between plasma and red blood cells (RBCs) because of differential binding in blood. In this review, factors modulating the partitioning of drugs into RBCs are discussed andthe importance of determining RBC uptake of drugs for drug candidate selection is explored. In summary, the choice of matrix (plasma vs whole blood) is an important consideration to be factored induring drug discovery.