Chemosensory function and food perception is affected in COPD, but unrelated to sarcopenia risk.

BACKGROUND & AIMS: Patients with advanced COPD often have difficulty maintaining sufficient dietary intake. Chemosensory function influences food choice and intake but is often overlooked in dietary assessment and intervention strategies. This study aimed to assess differences in chemosensory function and hedonic evaluation of food between patients with COPD and age- and gender-matched healthy controls. Additionally, a possible association between increased risk of sarcopenia or frailty and chemosensory impairments was explored. METHODS: We recruited 53 COPD patients (34 males, mean age 66.6 ± 7.6 years) and 53 controls (25 males, mean age 68.4 ± 5.7 years). Chemosensory function was assessed using a smell threshold, smell identification (Sniffin' Sticks, Burghart) and taste recognition test (Taste Strips, Burghart) and through self-report. Sensory properties (appearance, smell, taste, mouthfeel) of four standardized food products were evaluated on 9-point hedonic rating scales. Sarcopenia risk was assessed with the SARC-F. RESULTS: The COPD group scored lower on both the smell (p = 0.026 for threshold, p = 0.001 for identification) and taste recognition tests (p < 0.001) and also reported more smell and taste impairments (p < 0.001) compared to controls. Hedonic evaluation of food items' appearance (p = 0.009) and smell (p = 0.033) was lower in COPD patients. Within the COPD group, risk of sarcopenia was not associated with chemosensory function. CONCLUSION: This study demonstrates that COPD patients have poorer chemosensory function and experience more impairments compared to controls. COPD patients also tend to evaluate foods less positive than do their controls but within COPD patients, sarcopenia risk is not associated with chemosensory function.

3D printed, personalized sustained release cortisol for patients with adrenal insufficiency.

The standard of care for patients with Adrenal Insufficiency (AI) is suboptimal. Administration of hydrocortisone three times a day produces plasma cortisol fluctuations associated with negative health outcomes. Furthermore, there is a high inter-individual variability in cortisol need, necessitating a personalized approach. It is hypothesized that a personalized, sustained release formulation would enhance the pharmacotherapy by mimicking the physiological cortisol plasma concentration at a higher level. Therefore, a novel 24 h sustained release 3D printed (3DP) hydrocortisone formulation has been developed (M3DICORT) by coupling hot-melt extrusion with fused deposition modeling. A uniform drug distribution in the 3DP tablets is demonstrated by a content of 101.66 ± 1.60 % with an acceptance value of 4.01. Furthermore, tablets had a stable 24 h dissolution profile where the intra-batch standard deviation was ± 2.8 % and the inter-batch standard deviation was ± 6.8 %. Tablet height and hydrocortisone content were correlated (R2 = 0.996), providing a tool for easy dose personalization. Tablets maintained critical quality attributes, such as dissolution profile (f2 > 60) and content uniformity after process transfer from a single-screw extruder to a twin-screw extruder. Impurities were observed in the final product which should be mitigated before clinical assessment. To our knowledge, M3DICORT is the first 3DP hydrocortisone formulation specifically developed for AI.

Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients.

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

Population pharmacokinetics of ceftriaxone administered as continuous or intermittent infusion in critically ill patients.

OBJECTIVES: To describe the population pharmacokinetics and protein-binding characteristics of unbound ceftriaxone administered as continuous or intermittent infusion. Additionally, to determine the optimal dosing regimen in critically ill patients. METHODS: A pharmacokinetic study was performed in the ICU of a tertiary teaching hospital. Patients were treated with ceftriaxone as continuous or intermittent infusion. A population pharmacokinetic model was developed with non-linear mixed-effects analysis. Subsequently, the PTA of a 100% T>MIC was assessed for influential patient characteristics using Monte Carlo simulation. RESULTS: Fifty-five patients were included. The pharmacokinetics of ceftriaxone was best described by a one-compartment model with non-linear saturable protein binding including the following covariates: body weight, estimated CLCR, serum albumin concentration and mode of administration. For pathogens with an MIC of 1 mg/L, the simulation demonstrated that intermittent infusion of 2 g/24 h only resulted in a ≥90% PTA in patients with a reduced CLCR (0-60 mL/min). Intermittent infusion of 2 g/12 h led to sufficient exposure if CLCR was 0-90 mL/min and continuous infusion of 2 g/24 h led to a ≥90% PTA in all simulations (CLCR 0-180 mL/min). CONCLUSIONS: In the critically ill, the clearance of unbound ceftriaxone is closely related to CLCR. Furthermore, ceftriaxone protein binding is saturable, variable and dependent on serum albumin concentration. Intermittent dosing of 2 g/24 h ceftriaxone leads to subtherapeutic exposure in patients with a normal or increased CLCR. Treating these patients with continuous infusion of 2 g/24 h is more effective than an intermittent dosing regimen of 2 g/12 h.

[Fatal intoxication with nicotine for e-cigarette]. / Fatale intoxicatie met nicotine voor e-sigaret.

BACKGROUND: Since the introduction of the electronic e-cigarette a few years ago, its use has greatly increased. The liquid formulations used in these e-cigarettes contain nicotine in high concentrations; ingestion of these liquids can be fatal. CASE DESCRIPTION: A 42-year-old male was admitted to the Intensive Care ward due to cardiac arrest. The patient had ingested highly concentrated liquid nicotine, originating from a vial with liquid for e-cigarettes. When the ambulance personnel found the patient he did not have a pulse; following CPR and administration of adrenaline his pulse returned. Upon admission, the plasma nicotine level was high at 3.0 mg/l (reference values for a smoker are 0.01-0.05 mg/l) and the patient's neurological function was poor. The patient was treated symptomatically, but eventually died of a postanoxic encephalopathy. CONCLUSION: Nicotine e-liquids are highly concentrated. Intentional ingestion can lead to toxic levels of nicotine which are associated with cardiac arrhythmias or arrest. Because even a few millilitres can be lethal, nicotine intoxication due to e-liquid ingestion should be considered potentially life-threatening.

A fast and sensitive LC-MS/MS method for the quantification of fosfomycin in human urine and plasma using one sample preparation method and HILIC chromatography.

Fosfomycin is an old antibiotic that is increasingly prescribed because of emergence of the antibiotic resistance and the growing incidence of multi-drug resistant infections. Surprisingly, little is known about its pharmacokinetics (PK) and the pharmacodynamics (PD). Quantification of fosfomycin in both urine and plasma provides insight into the PK/PD characteristics of fosfomycin, which is crucial for the optimization of the therapy and the prevention of the emergence of resistance. An analytical method is therefore needed for the quantification of fosfomycin in both urine and plasma. A fast and sensitive tandem mass spectrometry method in combination with HILIC chromatography for the quantification of fosfomycin with a universal sample preparation method for urine and plasma was developed and validated according to FDA guidelines. The universal sample preparation method only requires 100µL of a sample, the addition of the internal standard fosfomycin-13C3 benzylamine and an ultrafiltration step. The method is applicable for the concentration range of 0.75-375mg/L (R2 of 0.9998 in both matrices) encompassing the clinically relevant concentration range based on the susceptibility of possible (uro)pathogens in the clinical setting. The validation results for urine and plasma for all QC levels, were <2.1% and <3.2% for accuracy, <1.5% and <1.7% for within day precision and <5.0% and <3.8% for between day precision, respectively. No matrix effects were encountered and the total recovery in urine and plasma was high (102.5% and 99.4%). Prepared samples were stable at 4°C and 15°C for at least 72h and stored samples at -80°C were stable for at least 6 months. Selectivity and sensitivity were confirmed and no carry-over was observed. The method was successfully applied in two pharmacokinetic studies in healthy volunteers and patients respectively.

[Fosfomycin, an old antibiotic with new possibilities]. / Fosfomycine, een oud antibioticum met nieuwe mogelijkheden.

- Fosfomycin is a broad-spectrum antibiotic agent used orally for uncomplicated cystitis. The intravenous form of administration has recently been authorised in the Netherlands.- Thanks to its broad spectrum and extensive tissue penetration, fosfomycin offers possibilities for the treatment of infections in different organs.- Infections with multidrug-resistant bacteria pose a significant threat to public health. Many of these multidrug-resistant bacteria are sensitive to fosfomycin, which means fosfomycin may be an option for the treatment of infections with multidrug-resistant bacteria. - There is a lack of knowledge about the pharmacological properties of fosfomycin to establish a good dosing schedule. Knowledge is also lacking about the safety of fosfomycin and the extent of its tolerability in the treatment of different infections. - More research is needed before fosfomycin can be used in the battle against multidrug-resistant bacteria.

Effects of Supplementation of the Synbiotic Ecologic® 825/FOS P6 on Intestinal Barrier Function in Healthy Humans: A Randomized Controlled Trial.

BACKGROUND AND AIMS: Probiotics, prebiotics and synbiotics have been suggested as dietary strategies to improve intestinal barrier function. This study aimed to assess the effect of two weeks synbiotic supplementation on intestinal permeability under basal and stressed conditions. Secondary aims were the assessment of two weeks synbiotic supplementation on systemic immune function and gastrointestinal symptoms including defecation pattern. DESIGN: Twenty healthy adults completed a double-blind, controlled, randomized, parallel design study. INTERVENTION: Groups either received synbiotic (1.5 × 1010 CFU Ecologic® 825 + 10 g fructo-oligosaccharides (FOS P6) per day) or control supplements for two weeks. OUTCOMES: Intestinal segment specific permeability was assessed non-invasively by oral administration of multiple sugar probes and, subsequently, assessing the excretion of these probes in urine. This test was conducted at baseline and at the end of intervention, in the absence and in the presence of an indomethacin challenge. Indomethacin was applied to induce a compromised gut state. Plasma zonulin, cytokines and chemokines were measured at baseline and at the end of intervention. Gastrointestinal symptoms and stool frequency were recorded at baseline and daily during intervention. RESULTS: Significantly more male subjects were in the synbiotic group compared to the control group (P = 0.025). Indomethacin significantly increased urinary lactulose/rhamnose ratio versus without indomethacin, both in the control group (P = 0.005) and in the synbiotic group (P = 0.017). Urinary sugar recoveries and ratios, plasma levels of zonulin, cytokines and chemokines, and gastrointestinal symptom scores were not significantly different after control or synbiotic intervention. Stool frequency within the synbiotic group was significantly increased during synbiotic intervention compared to baseline (P = 0.039) and higher compared to control intervention (P = 0.045). CONCLUSION: Two weeks Ecologic® 825/FOS P6 supplementation increased stool frequency, but did not affect intestinal permeability neither under basal nor under indomethacin-induced stressed conditions, immune function or gastrointestinal symptoms in healthy adults.

Cardiac monitoring of high-dose verapamil in cluster headache: An international Delphi study.

BACKGROUND: In many patients, high-dose verapamil (HDV) is the only effective prophylactic treatment for cluster headache. Although cardiac adverse events and EKG abnormalities are relatively common, evidence-based guidelines for screening and monitoring patients on HDV are lacking. GOAL AND METHODS: Using the Delphi approach, we interviewed 22 international clinical experts in cardiac rhythm disorders to formulate EKG guidelines for the pretreatment screening and monitoring of cluster headache patients using HDV. RESULTS: The panel agreed only on performing pretreatment EKG to screen for pre-existing cardiac arrhythmia. Pretreatment EKG was deemed not necessary by most panel members for patients who did not have cardiac adverse events during a previous period of cluster headache attacks treated with HDV. Half the panel advised Holter EKG for patients on verapamil ≥ 480 mg/day. The highest recommended daily doses varied between 240 and 960 mg. Contraindications for use of verapamil largely followed FDA guidelines. DISCUSSION: Experts in cardiac rhythm disorders agreed on pretreatment EKG monitoring, but no consensus was reached on EKG monitoring during HDV treatment and around dose adjustments.

Conformation of Novel Azo-Dyes Bearing End-Capped Oligo(ethylene glycol) Studied by UV-vis and NMR Spectroscopy.

Two novel azo-dyes bearing an end-capped oligo(ethylene glycol) chain were synthesized and then studied by UV-visible and NMR spectroscopy. For both azobenzenes, the end-capped oligo(ethylene glycol) segment is on the para position of the first phenyl ring. On the second phenyl ring, a methoxy group is added on the para position for one azo-dye and no substitution group on the other, which made them electronically a push-push and a push system, respectively. The presence of the methoxy group changes significantly the absorption and the photoisomerization behaviors and results in a much less intense absorbance for the trans isomer and a shift from 350 to 360 nm. In the kinetic studies the azobenzene bearing a methoxy group shows a zero-order and a first-order kinetics as a function of the time scale of the study as well as an aggregation phenomenon. This azo-dye in different solvents has been studied by (1)H NMR and pulsed gradient NMR experiments to understand the effects of the photoisomerization and the aggregation on the self-diffusion of these molecules in solutions.

Nutrition education in European medical schools: results of an international survey.

Consumers and patients are unsure of whom to trust for nutritional advice. Although medical doctors are seen as experts in nutrition and their advice is regularly followed, data are lacking on the amount of nutrition education in European medical school curricula. In line with US research, we distributed a survey on required and/or optional nutrition contact hours to medical education directors of all accredited medical schools (N=217) in Western European Union countries (N=14). In total, respondents from 32 medical schools (14.7%) from 10 countries indicated that nutrition education, in some form, was required in 68.8% of schools where, on average, 23.68 h of required nutrition education was provided. The results from this small-scale survey are comparable to a 2010 US study; conversely, European educators were satisfied with the amount of nutrition education. We substantiate the increasing concern over the inadequate amounts of nutrition education provided to medical students in Europe.

Role of protein contaminants in the immunogenicity of alginates.

Alginate is widely used for cell microencapsulation and transplantation. There is a lack of standardization of alginate purity and composition. In a previous study, we compared different alginate purification methods and concluded that polyphenol and endotoxin contaminants were eliminated efficiently but residual protein contaminants persisted with all of the methods under evaluation. The objective of this study was to test the hypothesis that residual proteins play a role in the immunogenicity of certain alginate preparations. Using preparative size exclusion chromatography (SEC) and a large scale purification protocol that was derived from the findings obtained with SEC, we substantially decreased the protein content of alginate preparations. When implanted into mouse peritoneum, barium alginate beads made of alginates that were purified using SEC or the derived large scale protocol induced significantly less pericapsular cell adhesion than those made with control alginates. In conclusions, these results suggest that removing residual protein contamination may decrease the immunogenicity of certain alginate preparations. The measurement of proteins could be used as a screening method for evaluating alginate preparations.

Pharmacokinetics and sputum penetration of azithromycin during once weekly dosing in cystic fibrosis patients.

In this study we examined pharmacokinetics, systemic exposure and sputum penetration of azithromycin (AZM) in CF patients on chronic daily AZM therapy after changing to a once weekly dosing scheme. Eight adult CF patients using AZM 500 mg/day were changed to a once weekly dose of 1000 mg during 3 months. Once per month sputum and blood samples were collected. AZM was quantified in blood plasma and polymorphonuclear neutrophils. The cumulative weekly dose was reduced with a factor of 3.5 (7x500 mg vs. 1x1000 mg weekly). This led to a reduction in area under the curve (AUC+/-S.D.) with a factor of 2.5+/-0.8 in plasma, 2.8+/-0.9 in blood, 2.2+/-1.1 in PMNNs and to a reduction in average sputum concentration with a factor of 3.0 (+/-1.5). At 1000 mg once weekly reduced but still substantial concentrations were achieved in PMNNs and in sputum. Although not significant, a tendency towards less than linear reduction was found. In order to calculate and propose an optimal dosing scheme we need to establish a relation between exposure levels and clinical efficacy.

Study of hydration of cross-linked high amylose starch by solid state 13C NMR spectroscopy.

Starch is subjected to chemical treatments such as cross-linking or hydroxypropylation to meet the material requirements for food uses or controlled release in the pharmaceutical industries. In this work, two types of cross-linking formulations have been employed for the preparation of high amylose starch for use as an excipient for sustained drug release. The structural differences and chain dynamics of the modified starches in the dry and hydrated states have been compared by the use of variable contact time cross polarization-magic angle spinning solid state (13)C NMR spectroscopy.

[Partial resistance to acenocoumarol and phenprocoumon caused by enzyme polymorphism]. / Partiële acenocoumarol- en fenprocoumonresistentie door enzympolymorfisme.

A 78-year-old man was treated with coumarin derivatives following myocardial infarction. The international normalised ratio was not increased by using standard loading doses and dose adjustments for acenocoumarol and phenprocoumon. The desired level of anticoagulation was achieved with a high dosage of phenprocoumon (18-21 mg daily). This dose was associated with a phenprocoumon serum concentration that was ten times higher than the normal therapeutic concentration. The serum concentration of vitamin K1 was low. After exclusion of alternative causes, we concluded that the exceptionally high dose of phenprocoumon needed was due to partial resistance to coumarin derivatives. Partial resistance is related to a polymorphism of the gene coding for the enzyme vitamin K epoxide reductase. The patient was successfully treated with chronic high-dose phenprocoumon. Resistance to coumarin derivatives caused by a congenital polymorphism in the vitamin K reductase gene is a rare phenomenon. Resistance is seldom absolute. The desired anticoagulation effect can be achieved with doses that are 10-20 times higher than standard doses. Phenprocoumon is advantageous in this situation because it requires fewer tablets than acenocoumarol. Determination of serum concentrations of acenocoumarol and phenprocoumon can be used to exclude other causes of treatment resistance.

Pharmacokinetics of azithromycin in plasma, blood, polymorphonuclear neutrophils and sputum during long-term therapy in patients with cystic fibrosis.

Chronic therapy with the macrolide antibiotic azithromycin (AZM) is widely practiced in the treatment of patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa. Azithromycin dosage is variable, based on published studies, and not supported by pharmacokinetic data. This study describes the pharmacokinetics of the long-term administration of AZM (500 mg per day) in CF patients. AZM concentrations were quantified in the plasma, blood, isolated polymorphonuclear neutrophils (PMNNs), and sputum of 8 adult CF patients. The AZM distribution t1/2 was 0.1 hours in plasma. The (mean +/- standard deviation) elimination t(1/2) was 102 +/- 20 hours in plasma, 180 +/- 68 hours in blood, and 289 +/- 166 hours in PMNNs. The C(max) of AZM was 0.67 +/- 0.31 mg/L in plasma and 2.01 +/- 0.74 mg/L in blood, of which 1.44 +/- 0.69 mg/L was found in PMNNs. In sputum the concentration of AZM ranged from 12 to 53 mg/L and was still detectable at concentrations in the range 4 to 27 mg/L 10 days after the last dose. On average, the concentration in PMNNs was 2100 times the C(plasma) 24 hours after dosing AZM. These results confirm the accumulation of AZM in PMNNs. The authors conclude that sputum levels are elevated far above plasma and blood concentrations. The long t(1/2) in blood and PMNNs and the slow decrease in sputum levels indicate a less frequent dosing schedule (for instance once weekly) should be studied in future clinical trials of AZM in patients with cystic fibrosis.