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Scientific Reports Apr 2024Fixed dose combinations (FDCs) incorporating two or three medicines in a single inhaler have been created to enhance patient compliance and hence clinical outcomes....
Fixed dose combinations (FDCs) incorporating two or three medicines in a single inhaler have been created to enhance patient compliance and hence clinical outcomes. However, the development of dry powder inhalers (DPIs), particularly for FDCs, faces challenges pertinent to formulation uniformity and reproducibility. Therefore, this project aimed to employ nanotechnology to develop a FDC of DPIs for market-leading medicines-fluticasone propionate (FP) and salmeterol xinafoate (SAL)-for asthma management. Nanoaggregates were prepared using a novel biocompatible and biodegradable poly(ester amide) based on the amino acid tyrosine, utilising a one-step interfacial polymerisation process. The produced tyrosine poly (ester amide) drug-loaded nanoparticles were evaluated for content uniformity, PSA, FTIR, TEM, DSC, XRD and aerodynamic performance (in vitro and in vivo). The optimised formulation demonstrated high entrapment efficiency- > 90%. The aerodynamic performance in terms of the emitted dose, fine particle fraction and respirable dose was superior to the carrier-based marketed product. In-vivo studies showed that FP (above the marketed formulation) and SAL reached the lungs of mice in a reproducible manner. These results highlight the superiority of novel FDC FP/SAL nanoparticles prepared via a one-step process, which can be used as a cost-effective and efficient method to alleviate the burden of asthma.
Topics: Animals; Nanoparticles; Tyrosine; Administration, Inhalation; Lung; Mice; Asthma; Polyesters; Dry Powder Inhalers; Fluticasone; Drug Delivery Systems; Salmeterol Xinafoate; Particle Size; Drug Carriers
PubMed: 38684750
DOI: 10.1038/s41598-024-59588-1 -
NPJ Primary Care Respiratory Medicine Apr 2024Short-acting beta-agonist (SABA) over-use in asthma is harmful for patients and the environment. The Investment and Impact Fund (IIF) 2022/2023 financially rewarded...
Reducing short-acting beta-agonist use in asthma: Impact of national incentives on prescribing practices in England and the findings from SENTINEL Plus early adopter sites.
Short-acting beta-agonist (SABA) over-use in asthma is harmful for patients and the environment. The Investment and Impact Fund (IIF) 2022/2023 financially rewarded English primary care networks that achieved specific targets, including reducing SABA over-use (RESP-02) and lowering the mean carbon footprint per salbutamol inhaler prescribed (ES-02). SENTINEL Plus is a co-designed quality improvement package that aims to improve asthma outcomes and reduce asthma's environmental impact by addressing SABA over-use. We investigated the impact of (i) the IIF incentives and (ii) SENTINEL Plus implementation on asthma prescribing. Using Openprescribing.net data, we demonstrate that IIF 2022-2023 had no significant impact on the total number of SABA prescribed in England (25,927,252 during 12-months pre- and 25,885,213 12-months post-IIF; 0.16% decrease; p=NS), but lower carbon footprint SABA inhaler use increased (Salamol™ prescribing increased from 5.1% to 19% of SABA prescriptions, p < 0.01). In contrast, SENTINEL Plus sites significantly reduced SABA prescribing post-implementation (5.43% decrease, p < 0.05).
Topics: Humans; Adrenergic beta-Agonists; Albuterol; Anti-Asthmatic Agents; Asthma; England; Practice Patterns, Physicians'; Primary Health Care; Quality Improvement
PubMed: 38684652
DOI: 10.1038/s41533-024-00363-0 -
BMJ Open Apr 2024Post-induction anaesthesia often promotes intraoperative hypotension (IOH) that can worsen postoperative outcomes. This study aims to assess the benefit of...
Evaluation of the early use of norepinephrine in major abdominal surgery on medical and surgical postoperative complications: study protocol for a randomised controlled trial (EPON STUDY).
BACKGROUND
Post-induction anaesthesia often promotes intraoperative hypotension (IOH) that can worsen postoperative outcomes. This study aims to assess the benefit of norepinephrine versus ephedrine at the induction of anaesthesia to prevent postoperative complications following major abdominal surgery by preventing IOH.
METHODS AND ANALYSIS
The EPON STUDY is a prospective single-centre randomised controlled trial with the planned inclusion of 500 patients scheduled for major abdominal surgery at the Amiens University Hospital. The inclusion criteria are patients aged over 50 years weighing more than 50 kg with an American Society of Anesthesiologists physical status score of ≥2 undergoing major abdominal surgery under general anaesthesia. Patients are allocated either to the intervention group (n=250) or the standard group (n=250). In the intervention group, the prevention of post-induction IOH is performed with norepinephrine (dilution to 0.016 mg/mL) using an electric syringe pump at a rate of 0.48 mg/h (30 mL/h) from the start of anaesthesia and then titrated to achieve the haemodynamic target. In the control group, the prevention of post-induction IOH is performed with manual titration of ephedrine, with a maximal dose of 30 mg, followed by perfusion with norepinephrine. In both groups, the haemodynamic target to maintain is a mean arterial pressure (MAP) of 65 mm Hg or 70 mm Hg for patients with a medical history of hypertension. An intention-to-treat analysis will be performed. The primary outcome is the Clavien-Dindo score assessed up to 30 days postoperatively. The secondary endpoints are the length of hospital stay and length of stay in an intensive care unit/postoperative care unit; postoperative renal function; postoperative cardiovascular, respiratory, neurological, haematological and infectious complications at 1 month; and volume of intraoperative vascular filling and mortality at 1 month.
ETHICS AND DISSEMINATION
Ethical approval was obtained from the committee of protection of the persons of Ile de France in May 2021 (number 21 05 41). The authors will be involved in disseminating the research findings (through attending conferences and co-authoring papers). The results of the study will be disseminated via peer-reviewed publications and presentations at national and international conferences.
TRIAL REGISTRATION NUMBER
NCT05276596.
Topics: Humans; Norepinephrine; Abdomen; Postoperative Complications; Prospective Studies; Vasoconstrictor Agents; Hypotension; Ephedrine; Randomized Controlled Trials as Topic; Middle Aged; Anesthesia, General; Female; Male; Intraoperative Complications
PubMed: 38684243
DOI: 10.1136/bmjopen-2023-083606 -
Journal of Integrative Neuroscience Apr 2024Much of the existing animal literature on the devaluation task suggests that prior repeated exposure to drugs of abuse during adulthood can impair goal-directed action,...
BACKGROUND
Much of the existing animal literature on the devaluation task suggests that prior repeated exposure to drugs of abuse during adulthood can impair goal-directed action, but the literature on human drug users is mixed. Also, the initiation of drug use often occurs during adolescence, but examinations of the effects of drug exposure during adolescence on behavior in the devaluation task are lacking.
METHODS
We examined whether repeated exposure during adolescence to amphetamine (3 mg/kg injections every-other day from post-natal day 27-45) or ketamine (twice daily 30 mg/kg injections from post-natal day 35-44) would impair behavior in a devaluation test when tested drug-free in adulthood. Rats were trained to press a left lever with a steady cue-light above it for one reinforcer and a right lever with a flashing cue-light above it for a different reinforcer. We tested whether any impairments in goal-directed action could be overcome by compensation between strategies by giving rats information based on lever-location and cue-lights during the test that was either congruent (allowing compensation) or incongruent (preventing compensation between strategies) with the configurations during training.
RESULTS
Our results provided no evidence for impairment of goal-directed action during adulthood after adolescent amphetamine or ketamine exposure.
CONCLUSIONS
We discuss possible reasons for this discrepancy with the prior literature, including (1) the age of exposure and (2) the pattern in the previous literature that most previous demonstrations of drug exposure impairing devaluation in laboratory animals may be attributed to either drug-associated cues present in the testing environment and/or accelerated habit learning in tasks that predispose laboratory animals towards habit formation with extended training (with training procedures that should resist the formation of habits in the current experiment). However, additional research is needed to examine the effects of these factors, as well a potential role for the particular doses and washout periods to determine the cause of our finding of no devaluation impairment after drug exposure.
Topics: Animals; Ketamine; Amphetamine; Male; Rats; Conditioning, Operant; Central Nervous System Stimulants; Rats, Long-Evans; Behavior, Animal; Age Factors; Cues
PubMed: 38682231
DOI: 10.31083/j.jin2304083 -
International Journal of Molecular... Apr 2024Amphetamines (Amph) are psychostimulants broadly used as physical and cognitive enhancers. However, the long-term effects of prenatal exposure to Amph have been poorly...
Amphetamines (Amph) are psychostimulants broadly used as physical and cognitive enhancers. However, the long-term effects of prenatal exposure to Amph have been poorly investigated. Here, we show that continuous exposure to Amph during early development induces long-lasting changes in histone methylation at the tyrosine hydroxylase (TH) homolog and the vesicular monoamine transporter (VMAT) homologue genes. These Amph-induced histone modifications are correlated with enhanced expression and function of CAT-2/TH and higher levels of dopamine, but decreased expression of CAT-1/VMAT in adult animals. Moreover, while adult animals pre-exposed to Amph do not show obvious behavioral defects, when challenged with Amph they exhibit Amph hypersensitivity, which is associated with a rapid increase in /TH mRNA. Because has helped reveal neuronal and epigenetic mechanisms that are shared among animals as diverse as roundworms and humans, and because of the evolutionary conservation of the dopaminergic response to psychostimulants, data collected in this study could help us to identify the mechanisms through which Amph induces long-lasting physiological and behavioral changes in mammals.
Topics: Animals; Caenorhabditis elegans; Vesicular Monoamine Transport Proteins; Tyrosine 3-Monooxygenase; Amphetamine; Caenorhabditis elegans Proteins; Embryonic Development; Gene Expression Regulation, Developmental; Dopamine; Epigenesis, Genetic
PubMed: 38673805
DOI: 10.3390/ijms25084219 -
International Journal of Environmental... Apr 2024Methamphetamine contamination of residential properties remains a serious public health concern for members of the public. External stakeholders including Environmental...
Methamphetamine contamination of residential properties remains a serious public health concern for members of the public. External stakeholders including Environmental Health Officers (EHOs) and testing and remediation technicians are engaged on investigating whether contamination has occurred from manufacturing or smoking processes. More specifically, local council EHOs are responsible for managing clandestine drug laboratories when notified by police and also for responding to public enquiries. However, the full scope of these contaminated properties is not seen by any single stakeholder, making it very challenging to quantify these situations. To evaluate the prevalence of methamphetamine related enquiries from the general public to EHOs, this study surveyed and interviewed officers from around Australia. It was found that public enquiries were infrequent with only 6% of respondents having received enquiries in the last month, which indicates that people are seeking information from other sources. Interestingly, there were case study scenarios that also mentioned issues with awareness and the flow of information. Concerns regarding difficult cases, police notifications, and site visits were also highlighted. The results of this study provide a benchmark of how methamphetamine related cases are managed and highlight the need for trustworthy information that is available to EHOs, governments, industry members, and the public in a unified location.
Topics: Methamphetamine; Humans; Local Government; Australia; Environmental Health; Surveys and Questionnaires; Prevalence; Police
PubMed: 38673366
DOI: 10.3390/ijerph21040455 -
Pharmacology, Biochemistry, and Behavior Jul 2024Research using zebrafish (Danio rerio) has begun to provide novel information in many fields, including the behavioral pharmacology of drug use and misuse. There have...
Research using zebrafish (Danio rerio) has begun to provide novel information in many fields, including the behavioral pharmacology of drug use and misuse. There have been limited studies on the effects of methamphetamine in adult zebrafish and the parameters of exposure (dose, test session length) have not been well-documented. Behavior following drug exposure is generally measured during relatively short sessions (6-10 min is common) in a novel tank environment. Many procedural variables (isolation, netting, novel tank) elicit anxiety-like behavior that is most apparent during the initial portion of a test session. This anxiety-like behavior might mask the initial effects of methamphetamine. During longer test sessions, these anxiety-like responses would be expected to habituate and drug effects should become more apparent. To test this idea, we measured several locomotor activity responses for 50-min following a range of methamphetamine doses (0.1-3.0 mg/L via immersion in methamphetamine solution). Methamphetamine failed to alter swimming velocity, distance travelled, or freezing time. In contrast, methamphetamine produced a dose-dependent decrease in time spent in the bottom of the tank, an increase in the number of visits to the top of the tank, and an increase in the number of transitions along the sides of the tank. The effects of methamphetamine were apparent 10-20 min following exposure and generally persisted throughout the session. These findings indicate that longer test sessions are required to measure methamphetamine-induced changes in behavior in zebrafish, as has been shown in other laboratory animals. The results also suggest that anxiety-like responses associated with various procedural aspects (netting, isolation, novel test apparatus) likely interfere with the ability to observe many behavioral effects of methamphetamine in zebrafish. Based on the current results, habituation to testing procedures to reduce anxiety-like behaviors is recommended in determining the effects of methamphetamine in zebrafish.
Topics: Animals; Zebrafish; Methamphetamine; Dose-Response Relationship, Drug; Behavior, Animal; Anxiety; Male; Central Nervous System Stimulants; Female; Motor Activity; Swimming; Time Factors; Locomotion
PubMed: 38670467
DOI: 10.1016/j.pbb.2024.173777 -
Antibiotics (Basel, Switzerland) Apr 2024The World Health Organization (WHO) promotes research aimed at developing new drugs from natural compounds. Fungi are important producers of bioactive molecules, and...
The World Health Organization (WHO) promotes research aimed at developing new drugs from natural compounds. Fungi are important producers of bioactive molecules, and they are often effective against other fungi and/or bacteria and are thus a potential source of new antibiotics. Basidiomycota crude extracts, which have previously been proven to be active against ATCC27853, were subjected to liquid chromatographic separation by RP-18, leading to six macro-fractions for each fungal extract. The various fractions were tested for their bioactivities against ATCC27853, and ten of them were characterized by HPLC-HRMS and NMR. Further chromatographic separations were performed for a few selected macro-fractions, yielding seven pure compounds. Bioactivity was mainly found in the lipophilic fractions containing fatty acids and their derivatives, such as hydroxy or keto C-18 unsaturated acids, and in various complex lipids, such as glycolipids and related compounds. More hydrophilic molecules, such as GABA, phenethylamine, two chromogenic anthraquinoids and pistillarin, were also isolated, and their antibacterial activities were recorded. The novelties of this research are as follows: (i) the genera and have never been investigated before for the synthesis of antibiotic compounds; (ii) the molecules produced by these genera are known, but their production has never been reported in the investigated fungi; (iii) the determination of bacterial siderophore synthesis inhibition by certain compounds from and .
PubMed: 38667002
DOI: 10.3390/antibiotics13040326 -
Annals of Clinical Microbiology and... Apr 2024Tuberculosis (TB) continues to pose a threat to communities worldwide and remains a significant public health issue in several countries. We assessed the role of...
BACKGROUND
Tuberculosis (TB) continues to pose a threat to communities worldwide and remains a significant public health issue in several countries. We assessed the role of heteroresistance and efflux pumps in bedaquiline (BDQ)-resistant Mycobacterium tuberculosis isolates.
METHODS
Nineteen clinical isolates were included in the study, of which fifteen isolates were classified as MDR or XDR, while four isolates were fully susceptible. To evaluate BDQ heteroresistance, the Microplate Alamar Blue Assay (MABA) method was employed. For screening mixed infections, MIRU-VNTR was performed on clinical isolates. Mutations in the atpE and Rv0678 genes were determined based on next-generation sequencing data. Additionally, real-time PCR was applied to assess the expression of efflux pump genes in the absence and presence of verapamil (VP).
RESULTS
All 15 drug-resistant isolates displayed resistance to BDQ. Among the 19 total isolates, 21.05% (4/19) exhibited a heteroresistance pattern to BDQ. None of the isolates carried a mutation of the atpE and Rv0678 genes associated with BDQ resistance. Regarding the MIRU-VNTR analysis, most isolates (94.73%) showed the Beijing genotype. Fifteen (78.9%) isolates showed a significant reduction in BDQ MIC after VP treatment. The efflux pump genes of Rv0676c, Rv1258c, Rv1410c, Rv1634, Rv1819, Rv2459, Rv2846, and Rv3065 were overexpressed in the presence of BDQ.
CONCLUSIONS
Our results clearly demonstrated the crucial role of heteroresistance and efflux pumps in BDQ resistance. Additionally, we established a direct link between the Rv0676c gene and BDQ resistance. The inclusion of VP significantly reduced the MIC of BDQ in both drug-susceptible and drug-resistant clinical isolates.
Topics: Mycobacterium tuberculosis; Diarylquinolines; Humans; Antitubercular Agents; Microbial Sensitivity Tests; Iran; Tuberculosis, Multidrug-Resistant; Mutation; Membrane Transport Proteins; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Verapamil
PubMed: 38664815
DOI: 10.1186/s12941-024-00694-3 -
BMC Psychiatry Apr 2024Methamphetamine (MA) abuse has resulted in a plethora of social issues. Sleep disturbance is a prominent issue about MA addiction, which serve as a risk factor for...
BACKGROUND
Methamphetamine (MA) abuse has resulted in a plethora of social issues. Sleep disturbance is a prominent issue about MA addiction, which serve as a risk factor for relapse, and the gut microbiota could play an important role in the pathophysiological mechanisms of sleep disturbances. Therefore, improving sleep quality can be beneficial for treating methamphetamine addiction, and interventions addressing the gut microbiota may represent a promising approach.
METHOD
We recruited 70 MA users to investigate the associations between sleep quality and fecal microbiota by the Pittsburgh Sleep Quality Index (PSQI), which was divided into MA-GS (PSQI score < 7, MA users with good sleep quality, n = 49) and MA-BS group (PSQI score ≥ 7, MA users with bad sleep quality, n = 21). In addition, we compared the gut microbiota between the MA-GS and healthy control (HC, n = 38) groups. 16S rRNA sequencing was applied to identify the gut bacteria.
RESULT
The study revealed that the relative abundances of the Thermoanaerobacterales at the order level differed between the MA-GS and MA-BS groups. Additionally, a positive correlation was found between the relative abundance of the genus Sutterella and daytime dysfunction. Furthermore, comparisons between MA users and HCs revealed differences in beta diversity and relative abundances of various bacterial taxa.
CONCLUSION
In conclusion, the study investigated alterations in the gut microbiota among MA users. Furthermore, we demonstrated that the genus Sutterella changes may be associated with daytime dysfunction, suggesting that the genus Sutterella may be a biomarker for bad sleep quality in MA users.
Topics: Humans; Gastrointestinal Microbiome; Methamphetamine; Male; Adult; Feces; Amphetamine-Related Disorders; Female; Sleep Quality; RNA, Ribosomal, 16S; Young Adult; Sleep Wake Disorders
PubMed: 38664669
DOI: 10.1186/s12888-024-05773-5