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AAPS PharmSciTech Jul 2021An emulsion is a biphasic dosage form comprising of dispersed phase containing droplets that are uniformly distributed into a surrounding liquid which forms the... (Review)
Review
An emulsion is a biphasic dosage form comprising of dispersed phase containing droplets that are uniformly distributed into a surrounding liquid which forms the continuous phase. An emulsifier is added at the interface of two immiscible liquids to stabilize the thermodynamically unstable emulsion. Various types of emulsions such as water-in-oil (w-o), oil-in-water (o-w), microemulsions, and multiple emulsions are used for delivering certain drugs in the body. Water (aqueous) phase is commonly used for encapsulating proteins and several other drugs in water-in-oil-in-water (w-o-w) emulsion technique. But this method has posed certain problems such as decreased stability, burst release, and low entrapment efficiency. Thus, a novel "solid-in-oil-in-water" (s-o-w) emulsion system was developed for formulating certain drugs, probiotics, proteins, antibodies, and tannins to overcome these issues. In this method, the active ingredient is encapsulated as a solid and added to an oil phase, which formed a solid-oil dispersion. This dispersion was then mixed with water to form a continuous phase for enhancing the drug absorption. This article focuses on the various studies done to investigate the effectiveness of formulations prepared as solid-oil-water emulsions in comparison to conventional water-oil-water emulsions. A summary of the results obtained in each study is presented in this article. The s-o-w emulsion technique may become beneficial in near future as it has shown to improve the stability and efficacy of the entrapped active ingredient.
Topics: Diclofenac; Drug Carriers; Drug Stability; Emulsions; Microspheres; Nanostructures; Oils; Polylactic Acid-Polyglycolic Acid Copolymer; Proteins; Water
PubMed: 34212274
DOI: 10.1208/s12249-021-02074-y -
Clinical Pharmacokinetics Dec 2021Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders,...
BACKGROUND
Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the L-ornithine salt of phenylacetate, is under development for hepatic encephalopathy.
OBJECTIVE
This analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program.
METHODS
Phenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child-Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis.
RESULTS
Phenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child-Pugh C than in Child-Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy.
CONCLUSIONS
Dose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population.
Topics: Ammonia; Glutamine; Humans; Phenylacetates
PubMed: 34125423
DOI: 10.1007/s40262-021-01047-5 -
Basic & Clinical Pharmacology &... Sep 20213-Quinuclidinyl benzilate (BZ) ranks among incapacitating military warfare agents. It acts as a competitive inhibitor on muscarinic receptors leading to non-lethal...
3-Quinuclidinyl benzilate (BZ) ranks among incapacitating military warfare agents. It acts as a competitive inhibitor on muscarinic receptors leading to non-lethal mental impairment. The present study aimed to investigate toxicokinetics of BZ in rats. Moreover, BZ can be exploited to produce a pharmacological model of Alzheimer's disease; thus, this paper focuses mainly on the BZ distribution to the brain. Wistar rats were administered i.p. with BZ (2 and 10 mg/kg). The BZ concentration was determined using LC-MS/MS in plasma, urine, bile, brain, kidney and liver. The sample preparation was based on a solid phase extraction (liquids) or protein precipitation (organ homogenates). The plasma concentration peaked at 3 min (204.5 ± 55.4 and 2185.5 ± 465.4 ng/ml). The maximal concentration in the brain was reached several minutes later. Plasma elimination half-life was 67.9 ± 3.4 in the 2 mg/kg group and 96.6 ± 27.9 in the 10 mg/kg group. BZ concentrations remained steady in the brain, with slow elimination (t 506.9 ± 359.5 min). Agent BZ is excreted mainly via the urine. Steady BZ concentration in the brain could explain the previously published duration of the significant impairment in passive avoidance tasks in rats after an injection of BZ.
Topics: Animals; Bile; Brain; Male; Metabolome; Muscarinic Antagonists; Quinuclidinyl Benzilate; Rats; Rats, Wistar; Toxicokinetics; Urine
PubMed: 34145973
DOI: 10.1111/bcpt.13627 -
American Journal of Health-system... Feb 2022To advance the implementation of consciousness-promoting therapies in patients with acute disorders of consciousness, the availability of potential therapeutic agents in...
PURPOSE
To advance the implementation of consciousness-promoting therapies in patients with acute disorders of consciousness, the availability of potential therapeutic agents in formulations suitable for administration in hospitalized patients in the presence of complex comorbid conditions is paramount. The purpose of this study is to evaluate the long-term stability of extemporaneously prepared preservative-free methylphenidate hydrochloride (HCl) 5 mg/mL intravenous solution for experimental use.
METHODS
A methylphenidate 5 mg/mL solution was prepared under proper aseptic techniques with Methylphenidate Hydrochloride, USP, powder mixed in sterile water for solution. Methylphenidate HCl 5 mg/mL solution was sterilized by filtration technique under USP <797>-compliant conditions. Samples were stored refrigerated (2-8°C) and analyzed at approximately days 1, 30, 60, 90, 180, and 365. At each time point, chemical and physical stability were evaluated by visual inspection, pH measurement, membrane filtration procedure, turbidometric or photometric technique, and high-performance liquid chromatography analysis.
RESULTS
Over the 1-year study period, the samples retained 96.76% to 102.04% of the initial methylphenidate concentration. There was no significant change in the visual appearance, pH level, or particulate matter during the study period. The sterility of samples was maintained and endotoxin levels were undetectable throughout the 1-year stability period.
CONCLUSION
Extemporaneously prepared preservative-free methylphenidate 5 mg/mL intravenous solution was physically and chemically stable at 32, 61, 95, 186, and 365 days when stored in amber glass vials at refrigerated temperatures (2-8°C).
Topics: Chromatography, High Pressure Liquid; Drug Compounding; Drug Stability; Drug Storage; Humans; Methylphenidate
PubMed: 34788364
DOI: 10.1093/ajhp/zxab420 -
Journal of Psychiatric Research Aug 2022Iron and zinc have been associated with attention-deficit/hyperactivity disorder (ADHD), executive functioning, and response to methylphenidate, given their link with... (Randomized Controlled Trial)
Randomized Controlled Trial
Iron and zinc have been associated with attention-deficit/hyperactivity disorder (ADHD), executive functioning, and response to methylphenidate, given their link with the dopaminergic system. This study aimed to investigate the effect of withdrawing methylphenidate after long-term treatment on serum levels of ferritin and zinc; and if baseline (pre-discontinuation) serum levels of these nutritional markers moderated the effects of withdrawing methylphenidate on ADHD and oppositional defiant disorder (ODD) symptoms, and working memory. Blood samples were collected from 63 children and adolescents who participated in a randomized, placebo-controlled methylphenidate discontinuation study. They were assigned to either seven weeks of continued treatment with methylphenidate or to gradual withdrawal to placebo. With mixed models for repeated measures we (i) compared changes in ferritin and zinc serum levels between both groups, and (ii) investigated moderating effects of ferritin and zinc on the effects of discontinuation on ADHD and ODD symptoms, and working memory. We additionally explored correlations of baseline and change serum levels with respective symptom scores. Withdrawing methylphenidate led to a decrease in ferritin levels. Higher baseline ferritin was associated with a larger increase (i.e., worsening) of teacher-rated hyperactivity-impulsivity and ODD symptoms after withdrawal; and higher baseline zinc with a larger increase in number of errors on the working memory task after withdrawal. Serum levels did not correlate with ADHD and ODD symptoms. Our preliminary results suggest that ferritin and zinc may be potential biomarkers for the effectiveness of long-term treatment with methylphenidate.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Ferritins; Humans; Methylphenidate; Zinc
PubMed: 35714551
DOI: 10.1016/j.jpsychires.2022.06.014 -
PloS One 2023Almost 10% of the population develop depression or anxiety disorder during their lifetime. Considering that people who are exposed to high stress are more likely to...
BACKGROUND
Almost 10% of the population develop depression or anxiety disorder during their lifetime. Considering that people who are exposed to high stress are more likely to develop mental disorders, it is important to detect and remove mental stress before depression or anxiety disorder develops. We aimed to develop an objective screening test that quantifies mental stress in workers so that they can recognize and remove it before the disorder develops.
METHODS
We obtained urine specimens from 100 healthy volunteers (49 men and 51 women; age = 48.2 ± 10.8 years) after they received medical checks and answered the Brief Job Stress Questionnaire (BJSQ). Participants were divided into high- and low- stress groups according to their total BJSQ scores. We further analyzed six urinary neurotransmitters (dopamine, serotonin, 5-hydoroxyindoleacetic acid, gamma-aminobutyric acid, homovanillic acid, and vanillylmandelic acid) using liquid chromatography-mass spectrometry to compare their levels between the two groups.
RESULTS
We obtained the concentrations of the six analytes from 100 examinees and revealed that the levels of urinary dopamine (p = 0.0042) and homovanillic acid (p = 0.020) were significantly lower in the high-stress group than those in the low-stress group. No biases were observed between the two groups in 36 laboratory items. The stress index generated from the six neurotransmitter concentrations recognized high-stress group significantly. Moreover, we discovered that the level of each urinary neurotransmitter changed depending on various stress factors, such as dissatisfaction, physical fatigue, stomach and intestine problems, poor appetite, poor working environments, sleep disturbance, isolation, worry, or insecurity.
CONCLUSION
We revealed that urinary neurotransmitters could be a promising indicator to determine underlying mental stress. This study provides clues for scientists to develop a screening test not only for workers but also for patients with depression.
Topics: Male; Humans; Female; Adult; Middle Aged; Dopamine; Homovanillic Acid; Stress, Psychological; Occupational Stress; Anxiety Disorders
PubMed: 37682855
DOI: 10.1371/journal.pone.0287613 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023To investigate the effect of sleep deprivation on the metabolism of the hippocampal region in mice.
OBJECTIVE
To investigate the effect of sleep deprivation on the metabolism of the hippocampal region in mice.
METHODS
The mice were randomly assigned to three groups, a control group, a 24-h sleep deprivation (SD) group, and a 48-h SD group. Each group had 10 mice. The sleep deprivation model was induced by the modified multiple platform method. The mice's anxiety-like behaviors were assessed with the open field test (OFT) and their depression-like behaviors were assessed with the sucrose preference test (SPT), the forced swimming test (FST), and tail suspension test (TST). High performance liquid chromatography (HPLC) was performed to determine the levels of 6 monoamine neurotransmitters, including 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), gamma-aminobutyric acid (GABA), 5-dihydroxyphenylacetic acid (5-DOPAC), and homovanillic acid (HVA), and 4 amino acids, including glutamic acid (Glu), aspartic acid (Asp), serine (Ser), and taurine (Tau), in the hippocampal region. Immunofluorescence staining was performed to examine the expression of glial cells in the hippocampal region of the mice. The main indicators measured were the levels of monoamine neurotransmitters and amino acids.
RESULTS
According to the results of the behavioral analysis, in comparison with the findings for the control group, the 24-h SD mice exhibited increased consumption of sucrose in SFT, significantly decreased total immobility time in FST and TST, and increased total distance covered in OFT, while the 48-h SD mice showed decreased consumption of sucrose in SFT, prolonged total immobility time in FST and TST, and decreased total distance covered in OFT. The results of the HPLC analysis of the monoamine neurotransmitter showed that 24-h SD mice had in their hippocampal region increased levels of DA (<0.001) and NE (<0.01) and decreased levels of GABA (<0.05) in comparison with those of the control mice, while their 5-HT, 5-DOPAC, and HVA levels were not significantly different from those of the control mice. In comparison with those of the control mice, the 48-h SD mice had, in their hippocampal region, decreased levels of 5-HT and NE (all <0.05), decreased DA (<0.01), and increased level of GABA (<0.01), while the levels of 5-DOPAC and HAV were not significantly different. The 48-h SD group showed a significant decrease in the levels of Tau and Glu in comparison with those of the 24-h SD group (all <0.05). According to the results of immunofluorescence assay, there was no significant difference between the control group and the 24-h SD group in the cell count of glial fibrillary acidic protein (GFAP)-positive cells, while a decline in GFAP-positive cells in comparison with that of the control group was observed in the 48-h SD group.
CONCLUSION
SD of 24 hours may induce anxiety-like behavioral changes in mice by activating their hippocampal glial cells, upregulating the levels of 5-HT, DA, and NE, and increasing the levels of Glu and Tau in the hippocampal region. SD of 48 hours may induce depression-like behavioral changes in mice by inhibiting the activation of glial cells in the hippocampal region and regulating in the opposite direction the levels of the above-mentioned monoamine neurotransmitters and amino acids in the hippocampal region.
Topics: Mice; Animals; Sleep Deprivation; Serotonin; Amino Acids; 3,4-Dihydroxyphenylacetic Acid; Hippocampus; Dopamine; Norepinephrine; Homovanillic Acid; Neurotransmitter Agents; gamma-Aminobutyric Acid; Sucrose
PubMed: 38162057
DOI: 10.12182/20231160203 -
Journal of Child and Adolescent... May 2023Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A...
Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A 12-month, open-label safety study with SDX/d-MPH in children with ADHD showed that SDX/d-MPH was well tolerated and comparable with other methylphenidate products. In this analysis of the 12-month study, the objective was to characterize the effect of SDX/d-MPH on growth in children with ADHD over 12 months. This was a analysis of a dose-optimized, open-label, phase 3 safety study of SDX/d-MPH in children aged 6-12 years with ADHD (NCT03460652). Weight and height -score analyses were conducted. -score change from baseline was calculated based on the baseline values for the subjects remaining in the study at the observation time point. Subjects ( = 238) from the treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. During treatment, the mean weight and height -scores decreased over time from their respective baselines. At the 12-month time point, mean (standard deviation [SD]) -score changes from baseline for weight and height for the subjects remaining in the study were -0.20 (0.50) and -0.21 (0.39), respectively; however, these mean changes in Z-scores were not clinically significant (change <0.5 SD). Long-term treatment with SDX/d-MPH was associated with modest reductions in expected weight and lower-than-expected increases in height: effects that plateaued or diminished later in treatment. The overall effects of SDX/d-MPH on growth velocity (the change in weight and height from one time point to the next) were minimal, and the range of changes was not considered clinically significant. ClinicalTrials.gov identifier: NCT03460652.
Topics: Child; Humans; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Double-Blind Method; Methylphenidate; Treatment Outcome
PubMed: 37204277
DOI: 10.1089/cap.2023.0012 -
Environmental Science and Pollution... Jul 2023Bioremediation of pharmaceuticals has gained large research efforts, but there is still a need to improve the performance of bioremediation systems by selecting...
Bioremediation of pharmaceuticals has gained large research efforts, but there is still a need to improve the performance of bioremediation systems by selecting effective organisms. In this study, we characterized the capability to remove clarithromycin (CLA) and diclofenac (DCF) by the bacterium Streptomyces rochei, and the fungi Phanerochaete chrysosporium and Trametes versicolor. The macrolide antibiotic CLA and the non-steroid anti-inflammatory DCF were selected because these are two of the most frequently detected drugs in water bodies. Growth and content of the PhCs and a DCF metabolite (MET) by the energy crop Arundo donax L. were also evaluated under hydroponic conditions. The removal rate (RR) by S. rochei increased from 24 to 40% at 10 and 100 µg CLA L, respectively, averaged over incubation times. At 144 h, the RR by P. chrysosporium was 84%, while by T. versicolor was 70 and 45% at 10 and 100 CLA µg L. The RR by S. rochei did not exceed 30% at 1 mg DCF L and reached 60% at 10 mg DCF L, whereas approached 95% and 63% by P. chrysosporium and T. versicolor, respectively, at both doses. Root biomass and length of A. donax were strongly affected at 100 µg CLA L. CLA concentration in roots and shoots increased with the increase of the dose and translocation factor (TF) was about 1. DCF severely affected both shoot fresh weight and root length at the highest dose and concentration in roots and shoots increased with the increase of the dose. DCF concentrations were 16-19 times higher in roots than in shoots, and TF was about 0.1. MET was detected only in roots and its proportion over the parent compound decreased with the increase of the DCF dose. This study highlights the potential contribution of A. donax and the tested microbial inoculants for improving the effectiveness of bioremediation systems for CLA and DCF removal.
Topics: Diclofenac; Wastewater; Clarithromycin; Biodegradation, Environmental; Trametes; Poaceae
PubMed: 37249765
DOI: 10.1007/s11356-023-27660-4 -
Environmental Science & Technology Apr 2020Biotransformation plays a crucial role in regulating the bioaccumulation potential and toxicity of organic compounds in organisms but is, in general, poorly understood...
Biotransformation plays a crucial role in regulating the bioaccumulation potential and toxicity of organic compounds in organisms but is, in general, poorly understood for emerging contaminants. Here, we have used diclofenac as a model compound to study the impact of biotransformation on the bioaccumulation potential and toxicity in two keystone aquatic invertebrates: and . In both species, diclofenac was transformed into several oxidation products and conjugates, including two novel products, that is, diclofenac taurine conjugate (DCF-M403) and unexpected diclofenac methyl ester (DCF-M310.03). The ratios of biotransformation products to parent compound were 12-17 for DCF-M403 and 0.01-0.7 for DCF-M310.03 after 24 h exposure. Bioconcentration factors (BCFs) of diclofenac were 0.5 and 3.2 L kg in and , respectively, whereas BCFs of DCF-M310.03 was 164.5 and 104.7 L kg, respectively, representing a 25- to 110-fold increase. Acute toxicity of DCF-M310.03 was also higher than the parent compound in both species, which correlated well with the increased bioconcentration potential. The LC of diclofenac in was 216 mg L, while that of metabolite DCF-M310.03 was reduced to only 0.53 mg L, representing a 430-fold increase in acute toxicity compared to diclofenac. DCF-M403 is less toxic than its parent compound toward , which may be linked to its slightly lower hydrophobicity. Furthermore, the transformation of diclofenac to its methyl ester derivative was explored in crude invertebrate extracts spiked with an -adenosylmethionine cofactor, revealing possible catalysis by an -adenosylmethionine-dependent carboxylic acid methyltransferase. Methylation of diclofenac was further detected in fish hepatocytes and human urine, indicating a broader relevance. Therefore, potentially methylated metabolites of polar contaminants should be considered for a comprehensive risk assessment in the future.
Topics: Animals; Aquatic Organisms; Bioaccumulation; Biotransformation; Diclofenac; Humans; Water Pollutants, Chemical
PubMed: 32036646
DOI: 10.1021/acs.est.9b07127