scholarly journals Physicochemical Stability and Compatibility Testing of Voriconazole in All-in-One Parenteral Nutrition Admixtures

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1447
Author(s):  
Emilie Reber ◽  
Peter Neyer ◽  
Katja A. Schönenberger ◽  
Christoph Saxer ◽  
Luca Bernasconi ◽  
...  
Keyword(s):  
Parenteral Nutrition ◽  
Lipid Droplets ◽  
Drug Stability ◽  
Glass Electrode ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Monitoring Method ◽  
Safe Patient Care ◽  
Quality Issue ◽  
Digital Assessment

(1) Drug compatibility with all-in-one (AiO) parenteral nutrition (PN) admixtures is a very important pharmaceutical quality issue to be answered based on appropriate laboratory testing. We assessed voriconazole (V), a poorly water-soluble (logP ≈ 1) single-daily dosed antifungal drug monitored in patients and thus candidate for AiO PN admixing for convenient and safe patient care. We evaluated V compatibility and stability in AiO PN admixtures through adapted therapeutic drug monitoring method (drug stability) and visual microscopic emulsion stability by lipid droplets analysis improved by an automated microscopic digital assessment. (2) V was added in concentrations of 0.05/0.25/0.5 mg/mL (143.1/715.7/1431.5 µM), correlating to daily therapeutic dosing, to three commercially available industrial AiO PN admixtures. Three aliquots were stored in the refrigerator (4 °C), at room temperature (24 °C) and under stress conditions in a water bath (37 °C). Samples taken at 0/24/48/72/168 h after admixing were subjected to a stability-indicating one-week analysis. Assessment included visual examination, lipid droplet measurement according to an established and validated method (bright-field microscopy using oil immersion), pH measurement (glass electrode) and V identification/quantification (LC–MS/MS). (3) After one week, all samples at 37 °C showed slight yellow discoloration. The pH values remained stable. All samples met specifications for lipid droplets according to size (upper size ≤8µm, mean size <4.5 ± 2 µm) and number (n ≤ 9 lipid droplets >5 µm). V concentrations were within an acceptable range, calculated for every timepoint as percent of the theoretical concentration spiked into the AiO PN. The median recovery was 98.2% (min–max, 90–112%). (4) At therapeutic doses, commercial V formulations were compatible and stable within specifications over one week in commonly used volumes of commercial AiO PN admixtures at 4–37 °C.

Personalized antibiotic therapy – a rapid high performance liquid chromatography–tandem mass spectrometry method for the quantitation of eight antibiotics and voriconazole for patients in the intensive care unit

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Tony Böhle ◽  
Ulrike Georgi ◽  
Dewi Fôn Hughes ◽  
Oliver Hauser ◽  
Gudrun Stamminger ◽  
...  
Keyword(s):  
Intensive Care ◽  
Antibiotic Therapy ◽  
High Performance ◽  
High Specificity ◽  
Serum Levels ◽  
Turnaround Time ◽  
Target Range ◽  
Therapeutic Drug ◽  
Monitoring Method ◽  
Adjustment Procedure

AbstractObjectivesFor a long time, the therapeutic drug monitoring of anti-infectives (ATDM) was recommended only to avoid the toxic side effects of overdosing. During the last decade, however, this attitude has undergone a significant change. Insufficient antibiotic therapy may promote the occurrence of drug resistance; therefore, the “one-dose-fits-all” principle can no longer be classified as up to date. Patients in intensive care units (ICU), in particular, can benefit from individualized antibiotic therapies.MethodsPresented here is a rapid and sufficient LC-MS/MS based assay for the analysis of eight antibiotics (ampicillin, cefepime, cefotaxime, ceftazidime, cefuroxime, linezolid, meropenem, and piperacillin) applicated by continuous infusion and voriconazole. In addition a dose adjustment procedure for individualized antibiotic therapy has been established.ResultsThe suggested dose adjustments following the initial dosing of 121 patient samples from ICUs, were evaluated over a period of three months. Only a minor percentage of the serum levels were found to be within the target range while overdosing was often observed for β-lactam antibiotics, and linezolid tended to be often underused. The results demonstrate an appreciable potential for β-lactam savings while enabling optimal therapy.ConclusionsThe presented monitoring method provides high specificity and is very robust against various interferences. A fast and straightforward method, the developed routine ensures rapid turnaround time. Its application has been well received by participating ICUs and has led to an expanding number of hospital wards participating in ATDM.

scholarly journals Cyclodextrin Multicomponent Complexes: Pharmaceutical Applications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1099
Author(s):  
Virginia Aiassa ◽  
Claudia Garnero ◽  
Marcela R. Longhi ◽  
Ariana Zoppi
Keyword(s):  
Amino Acids ◽  
Pharmaceutical Industry ◽  
Drug Effects ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Water Soluble Polymers ◽  
Soluble Polymers ◽  
Pharmaceutical Applications ◽  
Auxiliary Substance ◽  
Acids And Bases

Cyclodextrins (CDs) are naturally available water-soluble cyclic oligosaccharides widely used as carriers in the pharmaceutical industry for their ability to modulate several properties of drugs through the formation of drug–CD complexes. The addition of an auxiliary substance when forming multicomponent complexes is an adequate strategy to enhance complexation efficiency and to facilitate the therapeutic applicability of different drugs. This review discusses multicomponent complexation using amino acids; organic acids and bases; and water-soluble polymers as auxiliary excipients. Special attention is given to improved properties by including information on the solubility, dissolution, permeation, stability and bioavailability of several relevant drugs. In addition, the use of multicomponent CD complexes to enhance therapeutic drug effects is summarized.

scholarly journals P052 Should measurement of ascorbic acid become routine in the management of patients on home parenteral nutrition?

2019 ◽  
Vol 104 (7) ◽  
pp. e2.58-e2
Author(s):  
Amy-Jo Hooley ◽  
Brandy Cox ◽  
David Devadason ◽  
James Hunter
Keyword(s):  
Ascorbic Acid ◽  
Vitamin C ◽  
Parenteral Nutrition ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Micronutrient Deficiency ◽  
Water Soluble ◽  
List Type ◽  
Vitamin C Deficiency

AimTo assess if routine monitoring of vitamin C in long term parenteral nutrition (PN) patients should be routinely carried out, following a case report of a child with clinical vitamin C deficiency.MethodsVitamin C is an essential water soluble nutrient that cannot be synthesised or stored by humans.1 It is a potent antioxidant with anti-inflammatory and immune- supportive roles,1 Vitamin C levels are depleted in critically ill patients, those with restricted diets, smokers, and those with severe digestive disorders. The stability of micronutrients in PN bags is assumed but rarely confirmed, although a decrease in vitamin C content has been observed when there is a long delay between preparation and packaging.2 The patient, a five year old child stable on long term established full PN presented with a one month gradual reduction in mobility, refusal to weight bear, intermittent temperatures, raised CRP and asymptomatic hypercalcaemia on routine bloods. Investigations included bone profile, vitamin D, and parathyroid hormone levels, and routine sepsis screening. Following the extensive work up for systemic disorders and multiple conversations with orthopaedic and radiology specialists, it was discovered that the patient had bilateral metaphyseal irregularities, which were felt to be in keeping with recognised radiological appearances seen in severe vitamin C deficiency. As a result of this her PN bags were made manufactured and analysed in house quality control laboratory using a method involving UV –vis spectrophotometer to analyse the rate of oxidative decomposition of vitamin C within the bags.ResultsIn the United Kingdom children on long term PN programmes are routinely monitored for selected micronutrient deficiency, but not routinely vitamin C. The vitamin C was increased in the PN to three times the baseline dose for this patient, and a dramatic improvement in the patients symptoms were observed within 5 days, and radiological improvement was noted within 6 weeks after commencing treatment. Unfortunately baseline vitamin C levels were not obtained prior to starting treatment, but levels one month later still showed a significant clinical deficiency. The test bags that were analysed within the laboratory showed that on manufacture the bags contained 48.34 mg/L of ascorbic acid, but by 48 hours this had decreased to 8.5 mg/L.ConclusionVitamin C in PN is at significant risk of degradation by oxidation. Awareness of signs and symptoms of micronutrient deficiency and vigilance of micronutrient deficiencies not routinely measured in children on parenteral nutrition is important. Also more research is required into the oxidation rate of vitamin C in PN to establish how much is required within the PN bag to ensure the recommended daily intake in a PN dependent patient.ReferencesCarr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300. Published 2017 December 11. doi:10.1186/s13054-017-1891-yConroy S, Alsenani A, Sammons H. Factors influencing reported rate of paediatric medication errors. Archives of Disease in Childhood 2014;99:e3. https://adc.bmj.com/content/99/8/e3.19

scholarly journals Metabolism of palmitate in perfused rat liver. Isolation of subcellular fractions containing triacylglycerol

1979 ◽  
Vol 184 (1) ◽  
pp. 63-71 ◽  
Author(s):  
J Kondrup
Keyword(s):  
Rat Liver ◽  
Lipid Droplets ◽  
Microsomal Fraction ◽  
Fold Increase ◽  
Water Soluble ◽  
Particulate Fraction ◽  
Isotopic Equilibrium ◽  
Precursor Pool ◽  
Pass Perfusion ◽  
Fat Fraction

1. The metabolism of [1-14C]palmitate in rat liver was studied in a single-pass perfusion system at concentrations of 0.2 or 1 mM. 2. After the perfusion the liver was homogenized and the floating fat was isolated. The incorporation of [1-14C]palmitate into triacylglycerol in this pool increased 9-fold when the palmitate concentration in the medium was increased from 0.2 to 1 mM. In time studies with 1 mM-[1-14C]palmitate 75% of the total accumulation of triacylglycerol occurred in this pool. Our results support the concept that the floating-fat fraction contains the storage pool of triacylglycerol, i.e. the cytoplasmic lipid droplets. 3. In a particulate preparation consisting mainly of mitochondria and microsomal fraction the incorporation of [1-14C]palmitate into triacylglycerol was proportional to the fatty acid concentration. Triacylglycerol in the perfusate medium and in the particulate fraction was in isotopic equilibrium, which indicates that the particulate fraction contained the precursor pool for secreted triacylglycerol, i.e. the pool in endoplasmic reticulum and Golgi apparatus. 4. The oxidation to labelled water-soluble products and to CO2 was increased 14-fold by the 5-fold increase in palmitate concentration.

scholarly journals Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Amit V. Desai ◽  
Laura L. Kovanda ◽  
William W. Hope ◽  
David Andes ◽  
Johan W. Mouton ◽  
...  
Keyword(s):  
Steady State ◽  
Invasive Aspergillosis ◽  
Filamentous Fungi ◽  
Aspartate Aminotransferase ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Exposure Response

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

scholarly journals Differential Impacts of Soybean and Fish Oils on Hepatocyte Lipid Droplet Accumulation and Endoplasmic Reticulum Stress in Primary Rabbit Hepatocytes

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Xueping Zhu ◽  
Zhihui Xiao ◽  
Yumin Xu ◽  
Xingli Zhao ◽  
Ping Cheng ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Parenteral Nutrition ◽  
Er Stress ◽  
Lipid Droplets ◽  
Hepatic Function ◽  
Mitochondrial Damage ◽  
Lipid Emulsions ◽  
Hepatocyte Injury ◽  
High Doses ◽  
Primary Rabbit

Parenteral nutrition-associated liver disease (PNALD) is a severe ailment associated with long-term parenteral nutrition. Soybean oil-based lipid emulsions (SOLE) are thought to promote PNALD development, whereas fish oil-based lipid emulsions (FOLE) are thought to protect against PNALD. This study aimed to investigate the effects of SOLE and FOLE on primary rabbit hepatocytes. The results reveal that SOLE caused significant endoplasmic reticulum (ER) and mitochondrial damage, ultimately resulting in lipid droplets accumulation and ER stress. While these deleterious events induce hepatocyte injury, FOLE at high doses cause only minor ER and mitochondrial damage, which has no effect on hepatic function. SOLE also significantly upregulated glucose-regulated protein 94 mRNA and protein expression. These data indicate that SOLE, but not FOLE, damage the ER and mitochondria, resulting in lipid droplets accumulation and ER stress and, finally, hepatocyte injury. This likely contributes to the differential impacts of SOLE and FOLE on PNALD development and progression.

scholarly journals Preparation and Characterization of Two Immunogens and Production of Polyclonal Antibody with High Affinity and Specificity for Darunavir

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4075
Author(s):  
Ibrahim A. Darwish ◽  
Abdulrahman A. Almehizia ◽  
Awwad A. Radwan ◽  
Rashed N. Herqash
Keyword(s):  
Polyclonal Antibody ◽  
Accurate Determination ◽  
Antiviral Drug ◽  
Water Soluble ◽  
Enzyme Linked Immunosorbent Assay ◽  
Therapeutic Drug ◽  
Uv Spectrophotometry ◽  
Spectroscopic Techniques ◽  
Amino Group ◽  
High Affinity

Darunavir (DRV) is a potent antiviral drug used for treatment of infections with human immunodeficiency virus (HIV). Effective and safe treatment with DRV requires its therapeutic drug monitoring (TDM) in patient’s plasma during therapy. To support TDM of DRV, a specific antibody with high affinity is required in order to develop a sensitive immunoassay for the accurate determination of DRV in plasma. In this study, two new and different immunogens were prepared and characterized. These immunogens were the DRV conjugates with keyhole limpet hemocyanin (KLH) protein. The first immunogen (DRV-KLH) was prepared by zero-length direct linking of DRV via its aromatic amino group with the tyrosine amino acid residues of KLH by diazotization/coupling reaction. The second immunogen (G-DRV-KLH) was prepared by conjugation of the N-glutaryl derivative of DRV (G-DRV) with KLH. The 5-carbon atoms-spacing G-DRV hapten was synthesized by reaction of DRV via its aromatic amino group with glutaric anhydride. The reaction was monitored by HPLC and the chemical structure of G-DRV was confirmed by mass, 1H-NMR, and 13C-NMR spectroscopic techniques. The hapten (G-DRV) was linked to the KLH protein by water-soluble 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) coupling procedure. The pertinence of the coupling reactions of haptens to protein was confirmed, and the immunogens were characterized by ultraviolet (UV) spectrophotometry. Both DRV-KLH and G-DRV-KLH were used for the immunization of animals and the animal’s antiserum that showed the highest affinity was selected. The collected antiserum (polyclonal antibody) had very high affinity to DRV (IC50 value = 0.2 ng mL−1; defining IC50 as the DRV concentration that can inhibit antibody binding by 50% of its maximum binding) and high specificity to DRV among other drugs used in the combination therapy with DRV. Cumulative results from direct and competitive enzyme-linked immunosorbent assay (ELISA) using this polyclonal antibody proved that the immunogens were highly antigenic and elicited a specific polyclonal antibody. The produced polyclonal antibody is valuable for the development of highly sensitive and selective immunoassays for TDM of DRV.

Evaluation of a Pediatric Multiple Vitamin Preparation for Total Parenteral Nutrition in Infants and Children I. Blood Levels of Water-Soluble Vitamins

PEDIATRICS ◽  
1986 ◽  
Vol 77 (4) ◽  
pp. 530-538
Author(s):  
M. C. Moore ◽  
H. L. Greene ◽  
B. Phillips ◽  
L. Franck ◽  
R. J. Shulman ◽  
...  
Keyword(s):  
Parenteral Nutrition ◽  
Vitamin B12 ◽  
Total Parenteral Nutrition ◽  
Preterm Infants ◽  
Reference Range ◽  
Water Soluble ◽  
Infants And Children ◽  
Blood Levels ◽  
Vitamin Preparation ◽  
Group 1

This study represents the first attempt to evaluate the response to the only intravenous vitamin preparation (MVI Pediatric) for infants and children receiving total parenteral nutrition. Eighteen preterm infants (group 1), 26 term infants and children receiving total parenteral nutrition for 2 to 4 weeks (group 2A), and eight infants and children receiving total parenteral nutrition for 3 to 6 months (group 2B) were studied. Term gestation infants and children up to 11 years of age received daily vitamin doses that approximated the 1974 Recommended Dietary Allowances and coincided with the 1975 American Medical Association Nutrition Advisory Group total parenteral nutrition dosage guidelines for children weighing more than 10 kg. Preterm infants received 65% of these dosages. RBC transketolase (vitamin B1), glutathione reductase (B2), and glutamic oxaloacetic transaminase (B6) activities were maintained at normal levels, and niacin levels were maintained within the reference range (7.1 ± 0.32 µg/mL) in all study patients. Pantothenate, biotin, and ascorbate were maintained at reference levels in groups 2A and 2B. In group 1, ascorbic acid was increased significantly during treatment from 1.53 ± 0.16 to 3.60 by seven days and to 2.54 ± 0.62 by day 28 of treatment (reference normals = 0.99 ± 0.1 mg/dL). RBC folate was maintained within the reference range of 411 ± 76 pg/mL; however, pantothenate and biotin levels increased significantly to more than 2 SD above reference values during treatment, and vitamin B12, levels, which were above the reference range initially, were maintained at more than 2 SD above the reference range throughout treatment. The elevation in vitamin B12 was seen in both group 1 and 2 patients. Overall, the recommended dosages appeared adequate to prevent deficiency; however, the elevated levels of several vitamins in premature infants indicated that further studies should be done to determine more appropriate dosage levels for this group of high-risk patients.

scholarly journals Storing carbon in leaf lipid sinks enhances perennial ryegrass carbon capture especially under high N and elevated CO2

2019 ◽  
Vol 71 (7) ◽  
pp. 2351-2361 ◽  
Author(s):  
Zac Beechey-Gradwell ◽  
Luke Cooney ◽  
Somrutai Winichayakul ◽  
Mitchell Andrews ◽  
Shen Y Hea ◽  
...  
Keyword(s):  
Leaf Area ◽  
Perennial Ryegrass ◽  
Lipid Droplets ◽  
Feedback Inhibition ◽  
Leaf Growth ◽  
Water Soluble ◽  
Atmospheric Co2 ◽  
Soluble Carbohydrates ◽  
Elevated Atmospheric Co2 ◽  
N Supply

Abstract By modifying two genes involved in lipid biosynthesis and storage [cysteine oleosin (cys-OLE)/diacylglycerol O-acyltransferase (DGAT)], the accumulation of stable lipid droplets in perennial ryegrass (Lolium perenne) leaves was achieved. Growth, biomass allocation, leaf structure, gas exchange parameters, fatty acids, and water-soluble carbohydrates were quantified for a high-expressing cys-OLE/DGAT ryegrass transformant (HL) and a wild-type (WT) control grown under controlled conditions with 1–10 mM nitrogen (N) supply at ambient and elevated atmospheric CO2. A dramatic shift in leaf carbon (C) storage occurred in HL leaves, away from readily mobilizable carbohydrates and towards stable lipid droplets. HL exhibited an increased growth rate, mainly in non-photosynthetic organs, leading to a decreased leaf mass fraction. HL leaves, however, displayed an increased specific leaf area and photosynthetic rate per unit leaf area, delivering greater overall C capture and leaf growth at high N supply. HL also exhibited a greater photosynthesis response to elevated atmospheric CO2. We speculate that by behaving as uniquely stable microsinks for C, cys-OLE-encapsulated lipid droplets can reduce feedback inhibition of photosynthesis and drive greater C capture. Manipulation of many genes and gene combinations has been used to increase non-seed lipid content. However, the cys-OLE/DGAT technology remains the only reported case that increases plant biomass. We contrast cys-OLE/DGAT with other lipid accumulation strategies and discuss the implications of introducing lipid sinks into non-seed organs for plant energy homeostasis and growth.

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