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Pulmonary Pharmacology & Therapeutics Jun 2024Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant.
INTRODUCTION
Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a.
METHODS
The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (C) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC) for the analytes were between 80 and 125 %.
RESULTS
In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB C in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for C and 127.34 % for AUC). In Study 1, GB AUC lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for C and 129.12 % for AUC. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC, although not for C. Both formulations were similarly well tolerated in all three studies.
CONCLUSIONS
Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.
Topics: Beclomethasone; Humans; Formoterol Fumarate; Metered Dose Inhalers; Cross-Over Studies; Male; Glycopyrrolate; Drug Combinations; Administration, Inhalation; Adult; Double-Blind Method; Female; Aerosol Propellants; Middle Aged; Young Adult; Area Under Curve; Therapeutic Equivalency; Bronchodilator Agents; Anti-Asthmatic Agents; Fluorocarbons
PubMed: 38663512
DOI: 10.1016/j.pupt.2024.102299 -
International Immunopharmacology May 2024There is an increasing tendency for sepsis patients to suffer from diaphragm atrophy as well as mortality. Therefore, reducing diaphragm atrophy could benefit sepsis...
There is an increasing tendency for sepsis patients to suffer from diaphragm atrophy as well as mortality. Therefore, reducing diaphragm atrophy could benefit sepsis patients' prognoses. Studies have shown that Anisodamine (Anis) can exert antioxidant effects when blows occur. However, the role of Anisodamine in diaphragm atrophy in sepsis patients has not been reported. Therefore, this study investigated the antioxidant effect of Anisodamine in sepsis-induced diaphragm atrophy and its mechanism. We used cecal ligation aspiration (CLP) to establish a mouse septic mode and stimulated the C2C12 myotube model with lipopolysaccharide (LPS). After treatment with Anisodamine, we measured the mice's bodyweight, diaphragm weight, fiber cross-sectional area and the diameter of C2C12 myotubes. The malondialdehyde (MDA) levels in the diaphragm were detected using the oxidative stress kit. The expression of MuRF1, Atrogin1 and JAK2/STAT3 signaling pathway components in the diaphragm and C2C12 myotubes was measured by RT-qPCR and Western blot. The mean fluorescence intensity of ROS in C2C12 myotubes was measured by flow cytometry. Meanwhile, we also measured the levels of Drp1 and Cytochrome C (Cyt-C) in vivo and in vitro by Western blot. Our study revealed that Anisodamine alleviated the reduction in diaphragmatic mass and the loss of diaphragmatic fiber cross-sectional area and attenuated the atrophy of the C2C12 myotubes by inhibiting the expression of E3 ubiquitin ligases. In addition, we observed that Anisodamine inhibited the JAK2/STAT3 signaling pathway and protects mitochondrial function. In conclusion, Anisodamine alleviates sepsis-induced diaphragm atrophy, and the mechanism may be related to inhibiting the JAK2/STAT3 signaling pathway.
Topics: Animals; Male; Mice; Antioxidants; Cell Line; Diaphragm; Disease Models, Animal; Janus Kinase 2; Lipopolysaccharides; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy; Sepsis; Signal Transduction; SKP Cullin F-Box Protein Ligases; Solanaceous Alkaloids; STAT3 Transcription Factor; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 38652962
DOI: 10.1016/j.intimp.2024.112133 -
Journal of Cellular and Molecular... Apr 2024X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized...
X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. The disease, which still lacks a cure, could benefit from the pharmacologic stimulation of other GPCRs, activating the cAMP-intracellular pathway in the kidney cells expressing the AVPR2. On the basis of our previous studies, we here hypothesized that the β3-adrenergic receptor could be such an ideal candidate. We evaluated the effect of continuous 24 h stimulation of the β3-AR with the agonist BRL37344 and assessed the effects on urine output, urine osmolarity, water intake and the abundance and activation of the key renal water and electrolyte transporters, in the mouse model of X-NDI. Here we demonstrate that the β3-AR agonism exhibits a potent antidiuretic effect. The strong improvement in symptoms of X-NDI produced by a single i.p. injection of BRL37344 (1 mg/kg) was limited to 3 h but repeated administrations in the 24 h, mimicking the effect of a slow-release preparation, promoted a sustained antidiuretic effect, reducing the 24 h urine output by 27%, increasing urine osmolarity by 25% and reducing the water intake by 20%. At the molecular level, we show that BRL37344 acted by increasing the phosphorylation of NKCC2, NCC and AQP2 in the renal cell membrane, thereby increasing electrolytes and water reabsorption in the kidney tubule of X-NDI mice. Taken together, these data suggest that human β3-AR agonists might represent an effective possible treatment strategy for X-NDI.
Topics: Male; Animals; Mice, Inbred C57BL; Disease Models, Animal; Adrenergic beta-3 Receptor Agonists; Antidiuretic Agents; Kidney Concentrating Ability; Polydipsia
PubMed: 38652212
DOI: 10.1111/jcmm.18301 -
International Journal of Chronic... 2024To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany.
PURPOSE
To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany.
PATIENTS AND METHODS
Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting β-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period.
RESULTS
In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period.
CONCLUSION
In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.
Topics: Humans; Male; Pulmonary Disease, Chronic Obstructive; Female; Retrospective Studies; Germany; Aged; Administration, Inhalation; Middle Aged; Muscarinic Antagonists; Bronchodilator Agents; Adrenergic beta-2 Receptor Agonists; Nebulizers and Vaporizers; Glycopyrrolate; Drug Combinations; Chlorobenzenes; Quinuclidines; Treatment Outcome; Benzyl Alcohols; Beclomethasone; Formoterol Fumarate; Drug Therapy, Combination; Time Factors; Aged, 80 and over
PubMed: 38646606
DOI: 10.2147/COPD.S431291 -
Dose-response : a Publication of... 2024Isoproterenol (ISO), a chemically synthesized catecholamine, belongs to β-adrenoceptor agonist used to treat bradycardia. The β-adrenergic agonist is an essential...
Isoproterenol (ISO), a chemically synthesized catecholamine, belongs to β-adrenoceptor agonist used to treat bradycardia. The β-adrenergic agonist is an essential regulator of myocardial metabolism and contractility; however, excessive exposure to ISO can initiate oxidative stress and inflammation. This study aims to investigate the molecular mechanisms underlying ISO-induced cardiac remodeling, the protective efficacy of resveratrol (RSVR), and its liposomal formulation (L-RSVR) against such cardiac change. Wistar albino rats were evenly divided into 4 groups. Control group, ISO group received ISO (50 mg/kg, s.c.) twice a week for 2 weeks, and RSVR- and L-RSVR-treated groups in which rats received either RSVR or L-RSVR (20 mg/kg/day, p.o.) along with ISO for 2 weeks. ISO caused a significant elevation of the expression levels of BAX and MEF2 mRNA, S100A1 and cytochrome C proteins, as well as DNA fragmentation in cardiac tissue compared to the control group. Treatment with either RSVR or L-RSVR for 14 days significantly ameliorated the damage induced by ISO, as evidenced by the improvement of all measured parameters. The present study shows that L-RSVR provides better cardio-protection against ISO-induced cardiac injury in rats, most likely through modulation of cardiac S100A1 protein expression and inhibition of inflammation and apoptosis.
PubMed: 38645382
DOI: 10.1177/15593258241247980 -
Scientific Reports Apr 2024Brown adipose tissue (BAT) which is a critical regulator of energy homeostasis, and its activity is inhibited by obesity and low-grade chronic inflammation. Ginsenoside...
Brown adipose tissue (BAT) which is a critical regulator of energy homeostasis, and its activity is inhibited by obesity and low-grade chronic inflammation. Ginsenoside Rg3, the primary constituent of Korean red ginseng (steamed Panax ginseng CA Meyer), has shown therapeutic potential in combating inflammatory and metabolic diseases. However, it remains unclear whether Rg3 can protect against the suppression of browning or activation of BAT induced by inflammation. In this study, we conducted a screening of ginsenoside composition in red ginseng extract (RGE) and explored the anti-adipogenic effects of both RGE and Rg3. We observed that RGE (exist 0.25 mg/mL of Rg3) exhibited significant lipid-lowering effects in adipocytes during adipogenesis. Moreover, treatment with Rg3 (60 μM) led to the inhibition of triglyceride accumulation, subsequently promoting enhanced fatty acid oxidation, as evidenced by the conversion of radiolabeled H-fatty acids into H-HO with mitochondrial activation. Rg3 alleviated the attenuation of browning in lipopolysaccharide (LPS)-treated beige adipocytes and primary brown adipocytes by recovered by uncoupling protein 1 (UCP1) and the oxygen consumption rate compared to the LPS-treated group. These protective effects of Rg3 on inflammation-induced inhibition of beige and BAT-derived thermogenesis were confirmed in vivo by treating with CL316,243 (a beta-adrenergic receptor agonist) and LPS to induce browning and inflammation, respectively. Consistent with the in vitro data, treatment with Rg3 (2.5 mg/kg, 8 weeks) effectively reversed the LPS-induced inhibition of brown adipocyte features in C57BL/6 mice. Our findings confirm that Rg3-rich foods are potential browning agents that counteract chronic inflammation and metabolic complications.
Topics: Ginsenosides; Animals; Thermogenesis; Panax; Lipopolysaccharides; Mitochondria; Mice; Plant Extracts; Adipose Tissue, Brown; Adipose Tissue, Beige; Mice, Inbred C57BL; Male; Adipogenesis
PubMed: 38644456
DOI: 10.1038/s41598-024-59758-1 -
Respiratory Medicine Jun 2024Patient adherence to maintenance medication is critical for improving clinical outcomes in asthma and is a recommended guiding factor for treatment strategy. Previously,...
INTRODUCTION
Patient adherence to maintenance medication is critical for improving clinical outcomes in asthma and is a recommended guiding factor for treatment strategy. Previously, the APPaRENT studies assessed patient and physician perspectives on asthma care; here, a post-hoc analysis aimed to identify patient factors associated with good adherence and treatment prescription patterns.
METHODS
APPaRENT 1 and 2 were cross-sectional online surveys of 2866 adults with asthma and 1883 physicians across Argentina, Australia, Brazil, Canada, China, France, Italy, Mexico, and the Philippines in 2020-2021. Combined data assessed adherence to maintenance medication, treatment goals, use of asthma action plans, and physician treatment patterns and preferences. Multivariable logistic regression models assessed associations between patient characteristics and both treatment prescription (by physicians) and patient treatment adherence.
RESULTS
Patient and physician assessments of treatment goals and adherence differed, as did reporting of short-acting β-agonist (SABA) prescriptions alongside maintenance and reliever therapy (MART). Older age and greater patient-reported severity and reliever use were associated with better adherence. Patient-reported prescription of SABA with MART was associated with household smoking, severe or poorly controlled asthma, and living in China or the Philippines.
CONCLUSIONS
Results revealed an important disconnect between patient and physician treatment goals and treatment adherence, suggesting that strategies for improving patient adherence to maintenance medication are needed, focusing on younger patients with milder disease. High reliever use despite good adherence may indicate poor disease control. Personalised care considering patient characteristics alongside physician training in motivational communication and shared decision-making could improve patient management and outcomes.
Topics: Humans; Asthma; Cross-Sectional Studies; Male; Female; Adult; Middle Aged; Medication Adherence; Philippines; Physicians; Cost of Illness; China; Australia; Canada; Mexico; Adrenergic beta-2 Receptor Agonists; Brazil; Argentina; Age Factors; Anti-Asthmatic Agents; Practice Patterns, Physicians'; France; Surveys and Questionnaires; Treatment Adherence and Compliance; Italy
PubMed: 38636683
DOI: 10.1016/j.rmed.2024.107637 -
Open Veterinary Journal Jan 2024There is an obvious lack of information about the effects of ractopamine, a ß-adrenergic agonist, on the growth performance and immune responses of rabbits,...
BACKGROUND
There is an obvious lack of information about the effects of ractopamine, a ß-adrenergic agonist, on the growth performance and immune responses of rabbits, particularly in those receiving the viral rabbit hemorrhagic disease (RHD) vaccine.
AIM
The current study was undertaken to study the effects of ractopamine on growth performances and immunological parameters in rabbits inoculated with the viral RHD vaccine.
METHODS
Experimental rabbits were grouped into four groups, the first acted as a control and received distilled water, the second received ractopamine, the third received inactivated RHD vaccine, and the fourth received both ractopamine, and inactivated RHD vaccine. Then, blood analysis, histopathological, histomorphometric, and immunohistochemistry (IHC) examinations were followed.
RESULTS
The obtained results demonstrated that ractopamine induced significant increases in body weight gain, neutrophils, monocytes, nitric oxide, lysosome, and improved feed conversion rate. A significant decrease in lymphocytes with insignificant decreases in eosinophils, phagocytic % and index, serum total protein, , , and globulin were observed. Vaccinated rabbits only showed a marked rise in WBCs, neutrophils, monocytes, eosinophils, basophils, phagocytic index and activity, nitric oxide, lysosome activity, total protein, albumin, globulin, and a decrease in lymphocytes. Rabbits that received ractopamine and then vaccinated had insignificant increases in body weight, weight gain, WBCs, neutrophils, monocyte, eosinophils, basophils, phagocytic activity, and index, globulins besides a significant decrease in lymphocytes. Pathologically, rabbits that received ractopamine alone, with a vaccine or vaccinated only showed an increase in villus length, villus width, and absorption surface area. IHC of rabbits' liver and kidneys of the control and vaccinated group showed negative expression for caspase-3, but rabbits received ractopamine only or rabbits vaccinated and received ractopamine showed diffuse positive moderate expression for caspase-3.
CONCLUSION
Ractopamine induced several adverse effects on the immune responses of the rabbits inoculated with the viral HRD vaccine.
Topics: Animals; Caspase 3; Vaccines, Inactivated; Nitric Oxide; Antibodies, Viral; Body Weight; Weight Gain; gamma-Globulins; Viral Vaccines; Phenethylamines
PubMed: 38633153
DOI: 10.5455/OVJ.2024.v14.i1.12 -
Drug Design, Development and Therapy 2024Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine...
PURPOSE
Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine enhances lidocaine IVRA is unclear but may involve modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
MATERIALS AND METHODS
Lidocaine IVRA with varying dexmedetomidine concentrations was performed in the tails of Sprague-Dawley rats. Tail-flick and tail-clamping tests assessed IVRA analgesia and anesthesia efficacy and duration. Contributions of α adrenergic receptors and HCN channels were evaluated by incorporating an α adrenergic receptor antagonist, the HCN channel inhibitor ZD7288, and the HCN channel agonist forskolin. Furthermore, whole-cell patch clamp electrophysiology quantified the effects of dexmedetomidine on HCN channels mediating hyperpolarization-activated cation current (I) in isolated dorsal root ganglion neurons.
RESULTS
Dexmedetomidine dose-dependently extended lidocaine IVRA duration and analgesia, unaffected by α receptor blockade. The HCN channel inhibitor ZD7288 also prolonged lidocaine IVRA effects, while the HCN channel activator forskolin shortened effects. In dorsal root ganglion neurons, dexmedetomidine concentration-dependently inhibited I amplitude and shifted the voltage-dependence of HCN channel activation.
CONCLUSION
Dexmedetomidine prolongs lidocaine IVRA duration by directly inhibiting HCN channel activity, independent of α adrenergic receptor activation. This HCN channel inhibition represents a novel mechanism underlying the anesthetic and analgesic adjuvant effects of dexmedetomidine in IVRA.
Topics: Rats; Animals; Lidocaine; Dexmedetomidine; Rats, Sprague-Dawley; Colforsin; Anesthesia, Conduction; Cations
PubMed: 38618283
DOI: 10.2147/DDDT.S450971 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Mar 2024To investigate the effects of 7 nicotinic acetylcholine receptor (nAChR) agonist on β3-adrenoceptor agonist-induced impairment of white fat homeostasis and beige...
OBJECTIVE
To investigate the effects of 7 nicotinic acetylcholine receptor (nAChR) agonist on β3-adrenoceptor agonist-induced impairment of white fat homeostasis and beige adipose formation and heat production in obese mice.
METHODS
Forty obese C57BL/6J mice were randomized into high-fat feeding group, β3-adrenoceptor agonist-treated model group, 7 nAChR agonist group, and 7 nAChR inhibitor group (=10), with another 10 mice with normal feeding as the blank control group. White adipose tissue from the epididymis of the mice were sampled for HE staining of the adipocytes. The expression levels of TNF-, IL-1β, IL-10 and TGF-β in the white adipose tissue were determined by ELISA, and the mRNA levels of iNOS, Arg1, UCP-1, PRDM-16 and PGC-1 were detected using RT-qPCR. Western blotting was performed to detect the expression levels of NF-κB P65, p-JAK2, p-STAT3 in the white adipose tissue.
RESULTS
Compared with those in the blank control group, the mice with high-fat feeding showed significantly increased body weight, more fat vacuoles in the white adipose tissue, increased volume of lipid droplets in the adipocytes, upregulated iNOS mRNA expression and protein expression of TNF- and IL-1β, and lowered expression of Arg-1 mRNA and IL-10 and TGF-β proteins ( < 0.01). Treatment with 7 nAChR significantly reduced mRNA levels of PRDM-16, PGC-1 and UCP-1, lowered TNF- and IL-1β expressions, increased IL-10 and TGF-β expressions, and reduced M1/M2 macrophage ratio in the white adipose tissues ( < 0.05 or 0.01).
CONCLUSION
Activation of 7 nAchR improves white adipose tissue homeostasis impairment induced by β3 agonist, promotes transformation of M1 to M2 macrophages, reduces inflammatory response in white adipose tissue, and promote beige adipogenesis and thermogenesis in obese mice.
Topics: Animals; Male; Mice; Adipogenesis; Adipose Tissue, White; alpha7 Nicotinic Acetylcholine Receptor; Homeostasis; Interleukin-10; Mice, Inbred C57BL; Mice, Obese; Receptors, Adrenergic; RNA, Messenger; Thermogenesis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha
PubMed: 38597441
DOI: 10.12122/j.issn.1673-4254.2024.03.11