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Neurobiology of Disease Aug 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Topics: Animals; Dyskinesia, Drug-Induced; Levodopa; Oxidopamine; Mice; Male; Mice, Inbred C57BL; Serotonin 5-HT4 Receptor Agonists; Antiparkinson Agents; Corpus Striatum; Receptors, Serotonin, 5-HT4; Parkinsonian Disorders; Pyridines; Neurons; Piperidines; Pyrimidines
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559 -
Cellular Physiology and Biochemistry :... May 2024Adrenaline quickly inhibits the release of histamine from mast cells. Besides β2-adrenergic receptors, several in vitro studies also indicate the involvement of...
BACKGROUND/AIMS
Adrenaline quickly inhibits the release of histamine from mast cells. Besides β2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties.
METHODS
Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists.
RESULTS
Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a β2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells.
CONCLUSION
This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell-stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by β2-adrenergic receptors.
Topics: Animals; Mast Cells; Epinephrine; Rats; Prazosin; Cell Degranulation; Male; Exocytosis; Patch-Clamp Techniques; Adrenergic alpha-1 Receptor Antagonists; Rats, Wistar
PubMed: 38852193
DOI: 10.33594/000000703 -
Medical Science Monitor : International... Jun 2024BACKGROUND Emergence agitation, or delirium, occurs during early recovery from general anesthesia and involves disorientation, excitation, and uncontrolled physical...
BACKGROUND Emergence agitation, or delirium, occurs during early recovery from general anesthesia and involves disorientation, excitation, and uncontrolled physical movements. Dexmedetomidine is an alpha agonist that has sedative, anxiolytic, analgesic, and sympatholytic activities and is used as a continuous infusion to prevent emergence agitation. This study aimed to evaluate patients aged 65 years and older undergoing general anesthesia to determine the 90% effective dose (ED90) of dexmedetomidine continuous intraoperative infusion to prevent emergence agitation. MATERIAL AND METHODS We enrolled 44 patients aged 65 years and older undergoing spinal surgery under general anesthesia. Dexmedetomidine administration commenced 30 minutes before surgery completion, with a predetermined infusion dose (μg/kg/h), without a loading dose. The initial dose was 0.2 μg/kg/h, and subsequent step size was ±0.05 μg/kg/h. We tried to find ED90 of dexmedetomidine using the biased-coin design. Vital signs, extubation quality scores, extubation-related complications, and postoperative outcomes were monitored. RESULTS Dexmedetomidine ED₉₀ for smooth emergence in older patients was 0.34 μg/kg/h. Peri-extubation vital signs remained within 20% of baseline values, without requiring pharmacological intervention. No hypoxia, hypoventilation, or post-extubation agitation occurred. In the recovery room, 1 patient briefly exhibited excitement but quickly calmed. Nine patients initially unresponsive in the recovery room fully awoke and were promptly discharged. CONCLUSIONS For older patients who are vulnerable to adverse effects of anesthetics and opioids, dexmedetomidine enables gentle awakening without adverse vital sign changes, respiratory depression, excessive sedation, or emergence agitation (ED₉₀=0.34 μg/kg/h). Further studies should involve a larger patient cohort, considering diverse medical conditions in older individuals.
Topics: Humans; Dexmedetomidine; Aged; Male; Female; Hypnotics and Sedatives; Anesthesia Recovery Period; Anesthesia, General; Spine; Aged, 80 and over; Dose-Response Relationship, Drug; Emergence Delirium
PubMed: 38851875
DOI: 10.12659/MSM.944427 -
BMC Veterinary Research Jun 2024When inhalant anesthetic equipment is not available or during upper airway surgery, intravenous infusion of one or more drugs are commonly used to induce and/or maintain... (Comparative Study)
Comparative Study
BACKGROUND
When inhalant anesthetic equipment is not available or during upper airway surgery, intravenous infusion of one or more drugs are commonly used to induce and/or maintain general anesthesia. Total intravenous anesthesia (TIVA) does not require endotracheal intubation, which may be more difficult to achieve in rabbits. A range of different injectable drug combinations have been used as continuous infusion rate in animals. Recently, a combination of ketamine and propofol (ketofol) has been used for TIVA in both human patients and animals. The purpose of this prospective, blinded, randomized, crossover study was to evaluate anesthetic and cardiopulmonary effects of ketofol total intravenous anesthesia (TIVA) in combination with constant rate infusion (CRI) of midazolam, fentanyl or dexmedetomidine in eight New Zealand White rabbits. Following IV induction with ketofol and endotracheal intubation, anesthesia was maintained with ketofol infusion in combination with CRIs of midazolam (loading dose [LD]: 0.3 mg/kg; CRI: 0.3 mg/kg/hr; KPM), fentanyl (LD: 6 µg/kg; CRI: 6 µg/kg/hr; KPF) or dexmedetomidine (LD: 3 µg/kg; CRI: 3 µg/kg/hr; KPD). Rabbits in the control treatment (KPS) were administered the same volume of saline for LD and CRI. Ketofol infusion rate (initially 0.6 mg kg minute [0.3 mg kg minute of each drug]) was adjusted to suppress the pedal withdrawal reflex. Ketofol dose and physiologic variables were recorded every 5 min.
RESULTS
Ketofol induction doses were 14.9 ± 1.8 (KPM), 15.0 ± 1.9 (KPF), 15.5 ± 2.4 (KPD) and 14.7 ± 3.4 (KPS) mg kg and did not differ among treatments (p > 0.05). Ketofol infusion rate decreased significantly in rabbits in treatments KPM and KPD as compared with saline. Ketofol maintenance dose in rabbits in treatments KPM (1.0 ± 0.1 mg/kg/min) and KPD (1.0 ± 0.1 mg/kg/min) was significantly lower as compared to KPS (1.3 ± 0.1 mg/kg/min) treatment (p < 0.05). Ketofol maintenance dose did not differ significantly between treatments KPF (1.1 ± 0.3 mg/kg/min) and KPS (1.3 ± 0.1 mg/kg/min). Cardiovascular variables remained at clinically acceptable values but ketofol infusion in combination with fentanyl CRI was associated with severe respiratory depression.
CONCLUSIONS
At the studied doses, CRIs of midazolam and dexmedetomidine, but not fentanyl, produced ketofol-sparing effect in rabbits. Mechanical ventilation should be considered during ketofol anesthesia, particularly when fentanyl CRI is used.
Topics: Animals; Rabbits; Fentanyl; Dexmedetomidine; Midazolam; Ketamine; Anesthesia, Intravenous; Propofol; Anesthetics, Intravenous; Cross-Over Studies; Male; Female; Heart Rate; Prospective Studies; Blood Pressure; Anesthetics, Combined; Infusions, Intravenous; Hypnotics and Sedatives
PubMed: 38851722
DOI: 10.1186/s12917-024-04112-w -
Respiratory Medicine 2024Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs)... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
BACKGROUND
Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event.
OBJECTIVE
We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed.
METHODS
This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV) were randomized to receive Salbutamol Easyhaler (2 × 200 μg), Ventoline Evohaler with spacer (4 × 100 μg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 μg) as a reliever. The treatment was repeated if FEV did not recover to at least -10 % of baseline.
RESULTS
180 participants (69 % females, mean age 46 yrs [range 18-80], FEV%pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose.
CONCLUSION
The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks.
Topics: Humans; Methacholine Chloride; Female; Bronchoconstriction; Male; Adult; Asthma; Middle Aged; Albuterol; Dry Powder Inhalers; Forced Expiratory Volume; Bronchodilator Agents; Young Adult; Administration, Inhalation; Metered Dose Inhalers; Adolescent; Bronchial Provocation Tests; Treatment Outcome; Aged; Inhalation Spacers; Budesonide, Formoterol Fumarate Drug Combination
PubMed: 38851404
DOI: 10.1016/j.rmed.2024.107693 -
BMC Neurology Jun 2024Dexmedetomidine (Dex), midazolam, and propofol are three distinct sedatives characterized by varying pharmacological properties. Previous literature has indicated the... (Comparative Study)
Comparative Study
BACKGROUND
Dexmedetomidine (Dex), midazolam, and propofol are three distinct sedatives characterized by varying pharmacological properties. Previous literature has indicated the positive impact of each of these sedatives on ICU patients. However, there is a scarcity of clinical evidence comparing the efficacy of Dex, midazolam, and propofol in reducing mortality among people with epilepsy (PWE). This study aimed to assess the impact of Dex, midazolam, and propofol on the survival of PWE.
METHODS
The data were retrospectively retrieved from the Medical Information Mart for Intensive Care (MIMIC)-IV database (version 2.0). PWE were categorized into Dex, midazolam, and propofol groups based on the intravenously administered sedatives. PWE without standard drug therapy were included in the control group. Comparative analyses were performed on the data among the groups.
RESULTS
The Dex group exhibited a significantly lower proportion of in-hospital deaths and a markedly higher in-hospital survival time compared to the midazolam and propofol groups (p < 0.01) after propensity score matching. Kaplan-Meier curves demonstrated a significant improvement in survival rates for the Dex group compared to the control group (p = 0.025). Analysis of Variance (ANOVA) revealed no significant differences in survival rates among the Dex, midazolam, and propofol groups (F = 1.949, p = 0.143). The nomogram indicated that compared to midazolam and propofol groups, Dex was more effective in improving the survival rate of PWE.
CONCLUSION
Dex might improve the survival rate of PWE in the ICU compared to no standard drug intervention. However, Dex did not exhibit superiority in improving survival rates compared to midazolam and propofol.
Topics: Humans; Dexmedetomidine; Midazolam; Propofol; Male; Female; Middle Aged; Hypnotics and Sedatives; Retrospective Studies; Intensive Care Units; Epilepsy; Adult; Aged; Databases, Factual; Hospital Mortality
PubMed: 38849716
DOI: 10.1186/s12883-024-03693-1 -
Medicine Jun 2024The goal of this study was to evaluate the dose-response relationship between dexmedetomidine and propofol in sedating patients and to determine the optimal dosage of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The goal of this study was to evaluate the dose-response relationship between dexmedetomidine and propofol in sedating patients and to determine the optimal dosage of dexmedetomidine during gastrointestinal endoscopy.
METHODS
One hundred fifty patients were divided into 5 groups, each receiving a loading dose of dexmedetomidine (0.4, 0.6, 0.8, 1.0 µg/kg) or saline, with propofol for sedation. The median effective concentration (EC50) of propofol was calculated using the modified Dixon up-and-down approach. Adverse effects, vital signs, procedure, and recovery times were recorded.
RESULTS
The EC50 of propofol in groups NS, D0.4, D0.6, D0.8, and D1.0 were 3.02, 2.44, 1.97, 1.85, and 1.83 µg/mL, respectively. Heart rate in the dexmedetomidine groups decreased more than the NS group (P < .001). The mean arterial pressure (MAP) in the NS group experienced a decline compared to groups D0.8 and D1.0 when the plasma concentration and effect-site concentration reached equilibrium. Additionally, the respiratory rate was found to be lower in groups NS, D0.4, D0.6, and D0.8 (P < .05). Recovery time in groups D0.8 and D1.0 was longer than the NS group (P < .05). Bruggemann comfort scales score was higher in group D1.0 (P < .05). No significant difference was found in the incidences of hypotension and bradycardia, and the dose of ephedrine and atropine. Respiratory depression was significantly reduced in groups D0.8 and D1.0 compared to the NS group.
CONCLUSION
A single dose of 0.6 to 0.8 µg/kg of dexmedetomidine should be recommended in combination with propofol for gastrointestinal endoscopy. And the EC50 of propofol is 1.97 to 1.85 µg/mL.
Topics: Humans; Dexmedetomidine; Propofol; Male; Female; Double-Blind Method; Endoscopy, Gastrointestinal; Hypnotics and Sedatives; Adult; Middle Aged; Dose-Response Relationship, Drug; Heart Rate
PubMed: 38847682
DOI: 10.1097/MD.0000000000038421 -
Journal of Controlled Release :... Jul 2024The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and...
The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
Topics: Dogs; Animals; Solubility; Molecular Dynamics Simulation; Felodipine; Probucol; Carvedilol; Lipids; Body Fluids; Bile Acids and Salts; Male; Intestinal Secretions
PubMed: 38844179
DOI: 10.1016/j.jconrel.2024.06.008 -
International Journal of Cardiology Sep 2024Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse....
BACKGROUND
Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied.
METHODS
In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders).
RESULTS
Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most.
CONCLUSIONS
In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided.
Topics: Humans; Female; Pregnancy; Adrenergic beta-Antagonists; Registries; Adult; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Infant, Newborn; Heart Diseases; Infant, Small for Gestational Age; Perinatal Mortality
PubMed: 38844094
DOI: 10.1016/j.ijcard.2024.132234 -
Scientific Reports Jun 2024This study in older hospitalized patients with heart failure with reduced ejection fraction (HFrEF) aimed to examine the prevalence of beta-blocker prescription and its... (Observational Study)
Observational Study
This study in older hospitalized patients with heart failure with reduced ejection fraction (HFrEF) aimed to examine the prevalence of beta-blocker prescription and its associated factors. A total of 190 participants were recruited from July 2019 to July 2020. The inclusion criteria included: (1) aged ≥ 60 years, (2) having a diagnosis of chronic HFrEF in the medical records, (3) hospitalized for at least 48 h. The participants had a mean age of 75.5 ± 9.1, and 46.8% were female. Of these, 55.3% were prescribed beta-blockers during admission. To explore the factors associated with beta-blocker prescription, multivariable logistic regression analysis was applied and the results were presented as odds ratios (OR) and 95% confidence intervals (CI). On multivariate logistic regression models, higher NYHA classes (OR 0.49, 95%CI 0.26-0.94), chronic obstructive pulmonary disease (OR 0.17, 95% CI 0.04-0.85), chronic kidney disease (OR 0.40, 95% CI 0.19-0.83), and heart rate under 65 (OR 0.34, 95% CI 0.12-0.98) were associated with a reduced likelihood of prescription. In this study, we found a low rate of beta-blocker prescriptions, with only around half of the participants being prescribed beta-blockers. Further studies are needed to examine the reasons for the under-prescription of beta-blockers, and to evaluate the long-term benefits of beta-blockers in elderly patients with HFrEF in this population.
Topics: Humans; Heart Failure; Female; Adrenergic beta-Antagonists; Male; Aged; Stroke Volume; Aged, 80 and over; Vietnam; Middle Aged; Drug Prescriptions; Hospitalization; Pulmonary Disease, Chronic Obstructive
PubMed: 38839862
DOI: 10.1038/s41598-024-63479-w