Deutetrabenazine Provides Long-Term Benefit for Tardive Dyskinesia Regardless of Underlying Condition and Dopamine Receptor Antagonist Use: A Post Hoc Analysis of the 3-Year, Open-Label Extension Study.

BACKGROUND: Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited. METHODS: Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RIM-TD, deutetrabenazine was titrated based on dyskinesia control and tolerability. In this post hoc analysis of RIM-TD, total motor Abnormal Involuntary Movement Scale (AIMS) score and adverse events (AEs) were analyzed by underlying condition and DRA use at parent study baseline. RESULTS: Of 343 patients enrolled in RIM-TD, 336 were included in the analysis by underlying condition, and 337 were included in the analysis by DRA use. One hundred eighty-nine of 205 (92%) patients with psychotic disorders (schizophrenia/schizoaffective disorder) and 65 of 131 (50%) with mood and other disorders (depression/bipolar disorder/other) were receiving a DRA. Mean (SE) deutetrabenazine doses at week 145 were 40.4 (1.13), 38.5 (1.21), 39.9 (1.00), and 38.5 (1.48) mg/d for patients with psychotic disorders, those with mood and other disorders, and those receiving DRAs or not, respectively. Mean (SD) changes in total motor AIMS score from this study baseline to week 145 were -6.3 (4.53), -7.1 (4.92), -6.1 (4.42), and -7.5 (5.19). Exposure-adjusted incidence rates (number of AEs/patient-years) of AEs were similar across groups: any (1.02, 1.71, 1.08, 1.97), serious (0.10, 0.12, 0.10, 0.12), and leading to discontinuation (0.07, 0.05, 0.06, 0.05). CONCLUSIONS: Long-term deutetrabenazine provided clinically meaningful improvements in TD-related movements, with a favorable benefit-risk profile, regardless of underlying condition or DRA use.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of dopamine-receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting.

INTRODUCTION: Dopamine (D)2,3-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). AREAS COVERED: Eight D2,3-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects. EXPERT OPINION: Since the introduction of D2,3-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)3-RAs and neurokinin (NK)1-RAs have been developed. The classical D2,3-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D2,3-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT3-RA, dexamethasone and a NK1-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.Side effects differ among various D2,3-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D2,3-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.

Sex similarities and dopaminergic differences in interval timing.

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Commonly used antiemetics for prophylaxis of postoperative nausea and vomiting after Caesarean delivery with neuraxial morphine: a network meta-analysis.

BACKGROUND: Dopamine antagonists, 5-HT3 antagonists, and dexamethasone are frequently used in obstetrics to prevent postoperative nausea and vomiting (PONV). However, the superiority of any drug class is yet to be established. This network meta-analysis aimed to compare the efficacy of these antiemetics for PONV prophylaxis in women receiving neuraxial morphine for Caesarean delivery. METHODS: We searched PubMed, Embase, CENTRAL, Web of Science, and Wanfang Data for eligible randomised controlled trials. Primary outcomes were the incidences of postoperative nausea (PON) and postoperative vomiting (POV) within 24 h after surgery. We used a Bayesian random-effects model and calculated odds ratios with 95% credible intervals for dichotomous data. We performed sensitivity and subgroup analyses for primary outcomes. RESULTS: A total of 33 studies with 4238 women were included. In the primary analyses of all women, 5-HT3 antagonists, dopamine antagonists, dexamethasone, and 5-HT3 antagonists plus dexamethasone significantly reduced PON and POV compared with placebo, and 5-HT3 antagonists plus dexamethasone were more effective than monotherapy. In the subgroup analyses, similar results were seen in women receiving epidural morphine or intrathecal morphine alone but not in women receiving intrathecal morphine with fentanyl or sufentanil. However, most included studies had some concerns or a high risk of bias, and the overall certainty of the evidence was low or very low. CONCLUSIONS: Combined 5-HT3 antagonists plus dexamethasone are more effective than monotherapy in preventing PONV associated with neuraxial morphine after Caesarean delivery. Future studies are needed to determine the role of prophylactic antiemetics in women receiving intrathecal morphine and lipophilic opioids. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42023454602.

Brain connectivity changes to fast versus slow dopamine increases.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder.

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence.

Reassessment of amphetamine- and phencyclidine-induced locomotor hyperactivity as a model of psychosis-like behavior in rats.

Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.

Characterisation of methylphenidate-induced excitation in midbrain dopamine neurons, an electrophysiological study in the rat brain.

Methylphenidate (MPH) is a drug routinely used for patients with attention deficit and hyperactivity disorder (ADHD). Concerns arise about psychostimulant use, with dramatic increases in prescriptions. Besides, antipsychotic drugs are often administered in combination with MPH. In this study, we examine the consequences of MPH exposure in combination with dopamine D2 receptor antagonism (eticlopride) on midbrain dopaminergic neurons in anaesthetised rodents, using in vivo extracellular single-cell electrophysiology. As expected, we show that methylphenidate (2 mg/kg, i.v.) decreases the firing and bursting activities of ventral tegmental area (VTA) dopamine neurons, an effect that is reversed with eticlopride (0.2 mg/kg, i.v.). However, using such a paradigm, we observed higher firing and bursting activities than under baseline conditions. Furthermore, we demonstrate that such an effect is dependent on dual alpha-1 and dopamine D1 receptors, as well as glutamatergic transmission, through glutamate N-Methyl-D-aspartate (NMDA) receptor activation. Chronic MPH treatment during adolescence greatly dampens MPH-induced excitatory effects measured at adulthood. To conclude, we demonstrated here that a combination of methylphenidate and a dopamine D2 receptor antagonist produced long-lasting consequences on midbrain dopamine neurons, via glutamatergic-dependent mechanisms.

Cannabidiol impairs the rewarding effects of methamphetamine: Involvement of dopaminergic receptors in the nucleus accumbens.

Cannabidiol, as component of cannabis, can potentially hinder the rewarding impact of drug abuse; however, its mechanism is ambiguous. Moreover, the nucleus accumbens (NAc), as a key area in the reward circuit, extensively receives dopaminergic projections from the ventral tegmentum area. To elucidate the role of accumbal D1 and D2 dopamine receptor families in Cannabidiol's inhibitory impact on the acquisition and expression phases of methamphetamine (MET), the conditioned place preference (CPP) procedure as a common method to assay reward characteristics of drugs was carried out. Six groups of rats were treated by various doses of SCH23390 or Sulpiride (0.25, 1, and 4 µg/0.5 µL) in the NAc as D1 or D2 dopamine receptor family antagonists, respectively, prior to infusion of Cannabidiol (10 µg/5 µL) in the lateral ventricle (LV) over conditioning phase in the acquisition experiments. In the second step of the study, animals received SCH23390 or Sulpiride in the NAc before Cannabidiol (50 µg/5 µL) infusion into the LV in the expression phase of MET to illuminate the influence of SCH23390 or Sulpiride on the inhibitory impact of Cannabidiol on the expression of MET-induced CPP. Intra-NAc administration of either SCH23390 or Sulpiride impaired Cannabidiol's suppressive impact on the expression phase, while just Sulpiride could suppress the Cannabidiol's impact on the acquisition phase of the MET-induced CPP. Also, the inhibitory impact of Sulpiride was stranger in both phases of MET reward. It seems that Cannabidiol prevents the expression and acquisition phases of MET-induced CPP partly through the dopaminergic system in the NAc.

Intra-dorsal striatal acetylcholine M1 but not dopaminergic D1 or glutamatergic NMDA receptor antagonists inhibit consolidation of duration memory in interval timing.

The striatal beat frequency model assumes that striatal medium spiny neurons encode duration via synaptic plasticity. Muscarinic 1 (M1) cholinergic receptors as well as dopamine and glutamate receptors are important for neural plasticity in the dorsal striatum. Therefore, we investigated the effect of inhibiting these receptors on the formation of duration memory. After sufficient training in a peak interval (PI)-20-s procedure, rats were administered a single or mixed infusion of a selective antagonist for the dopamine D1 receptor (SCH23390, 0.5 µg per side), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor (D-AP5, 3 µg), or M1 receptor (pirenzepine, 10 µg) bilaterally in the dorsal striatum, immediately before initiating a PI-40 s session (shift session). The next day, the rats were tested for new duration memory (40 s) in a session in which no lever presses were reinforced (test session). In the shift session, the performance was comparable irrespective of the drug injected. However, in the test session, the mean peak time (an index of duration memory) of the M1 + NMDA co-blockade group, but not of the D1 + NMDA co-blockade group, was lower than that of the control group (Experiments 1 and 2). In Experiment 3, the effect of the co-blockade of M1 and NMDA receptors was replicated. Moreover, sole blockade of M1 receptors induced the same effect as M1 and NMDA blockade. These results suggest that in the dorsal striatum, the M1 receptor, but not the D1 or NMDA receptors, is involved in the consolidation of duration memory.

Characteristics of Inpatients Prescribed Dopamine Receptor Blocking Agents.

Dopamine receptor blocking agents (DRBAs, also known as antipsychotics) are frequently used in hospitalized patients. These medications carry a significant side effect burden and should be used judiciously. This purpose of this study is to examine patient, disease, and medication characteristics associated with the use of DRBAs in the inpatient setting to better understand current prescribing patterns and opportunities for optimization. A retrospective analysis was performed of 17,224 patients with at least one inpatient DRBA order placed between 1/1/2018-12/31/2019. The study population at this community hospital network in the United States contained those with (71.0%) and without (29.0%) psychiatric diagnoses, and the mean number of DRBA medications for each patient was 2.4 +/- 1.1. The characteristics of single, male, government-sponsored health insurance, movement disorder, DRBA adverse effects, and medication non-adherence were associated with significantly greater mean total DRBA medications prescribed. Medication non-adherence and prescription of a long-acting injectable (LAI) DRBA were greater in single and male patients, while suicidality was more likely in those with a movement disorder or DRBA adverse effect. Specific agents were also significantly associated with cardiovascular disease and metabolic disorder diagnoses. Based on the findings of this study, several patient, disease, and medication factors are related to the use of DRBAs in the hospital setting. It is important to further explore these associations in order to determine the appropriateness of DRBA prescribing and identify areas for improvement.

Cariprazine as a Treatment Option for Depressive Episodes Associated with Bipolar 1 Disorder in Adults: An Evidence-Based Review of Recent Data.

Depressive episodes, the most frequent episodes in bipolar disorder, contribute in large part to poor functional outcomes. Very few treatments, however, have been approved by the Food and Drug Administration for the treatment of bipolar depression. Cariprazine, a broad-spectrum dopamine antagonist/partial agonist with dopamine D3/D2 (preferring D3) and serotonin 5-HT1A receptor partial agonist properties, was recently approved. A review of the literature suggests that it is an effective and well-tolerated treatment for bipolar depression.

A first-in-human oral dose study of mesdopetam (IRL790) to assess its safety, tolerability, and pharmacokinetics in healthy male volunteers.

The management of Parkinson's disease (PD) is frequently compromised by complications induced by dopaminergic treatment such as involuntary movements (dyskinesias) and psychosis. Mesdopetam (IRL790) is a novel dopamine D3 receptor antagonist developed for the management of complications of therapy in PD. This study evaluated the safety, tolerability, and pharmacokinetics of escalating single and multiple doses of mesdopetam. We conducted a prospective, single-center, randomized, double-blind, placebo-controlled phase I, and first-in-human (FIH) study with mesdopetam administered to healthy male subjects. Overall, mesdopetam was well-tolerated up to a 120 mg single dose and up to 80 mg upon multiple dosing. Adverse events (AEs) were mainly related to the nervous system and were dose-dependent. No serious adverse events occurred and no AEs led to withdrawal. The results of the single-ascending-dose and multiple-ascending-dose parts indicated dose- and time-independent pharmacokinetics with rapid absorption and maximum plasma levels that were generally reached within 2 h after dosing. No accumulation was observed upon multiple dosing. It is concluded that mesdopetam was safe and well-tolerated in healthy male volunteers. Pharmacokinetic analysis indicated rapid absorption and dose-linear pharmacokinetics of mesdopetam, with a plasma half-life of around 7 h, upon single and repeated dosing. The pharmacokinetics of mesdopetam supports twice-daily use in patients.

A prospective, randomized, double-blind trial of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department.

OBJECTIVE: To compare the efficacy of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department (ED). BACKGROUND: Migraine is a common, incapacitating neurological condition. Although chlorpromazine and prochlorperazine are known to be safe, efficacious treatments for migraine, they have never been directly compared. DESIGN: We performed a prospective, randomized, double-blind clinical trial at a tertiary hospital in Melbourne, Australia. Adults aged 18-65 years, who presented with migraine, were eligible for recruitment. Sixty-six patients were randomized to either chlorpromazine 12.5 mg or prochlorperazine 12.5 mg, both infused in 500 ml of sodium chloride 0.9% over 30 min. Headache severity score, nausea severity score, and the presence of photophobia and phonophobia were assessed at 0, 30, 60, and 120 min. Adverse effects and the need for rescue therapy were recorded. The primary outcome was a reduction in headache severity score from baseline at 60 min post-commencement of the study medicine infusion. RESULTS: Sixty-five patients were included in the analysis. There was a median reduction in headache severity score at 60 min of 3.0 (interquartile range 1.0-4.0) in the chlorpromazine arm versus 2.0 (1.0-4.0) in the prochlorperazine arm (median difference -0.5 (95% confidence interval, -1.9 to 0.9)). We saw no evidence of a difference in secondary outcomes at 30, 60, or 120 min. Side effects were reported in 16/32 (50%) patients in the chlorpromazine group versus 7/33 (21%) in the prochlorperazine group (p = 0.020). Rescue therapy was required in 7/32 (22%) patients in the chlorpromazine group versus 12/33 (36%) in the prochlorperazine group (p = 0.277). CONCLUSIONS: Both chlorpromazine and prochlorperazine are efficacious treatments for acute migraine in adult patients presenting to the ED. This trial found no evidence of superiority of either agent over the other. Caution should be used when prescribing these medicines in the borderline hypotensive patient; in that circumstance, prochlorperazine should be preferentially used.

Dopamine Prevents Ultraviolet B-induced Development and Progression of Premalignant Cutaneous Lesions through its D2 Receptors.

Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited VEGFA-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions. PREVENTION RELEVANCE: This investigation demonstrates the role of dopamine and its D2 receptors in UVB induced premalignant squamous cell skin lesions and how DA through its D2 receptors inhibits the development and progression of these lesions and subsequently prevents squamous cell carcinoma of the skin.

Amisulpride: A Review in Post-Operative Nausea and Vomiting.

Amisulpride intravenous (IV) injection (Barhemsys®; hereafter referred to as IV amisulpride), a selective dopamine receptor antagonist, is approved in the USA as a single IV infusion for the prevention and treatment of post-operative nausea and vomiting (PONV) in adults. Results from placebo-controlled phase III trials showed that IV amisulpride is efficacious both in the prevention of PONV (used either alone or in combination with an antiemetic of a different class) and in the treatment of PONV (irrespective of prior antiemetic prophylaxis status). When administered as a single IV infusion, amisulpride had a tolerability profile that was generally similar to that of placebo, with no significant safety concerns identified. Thus, IV amisulpride is a useful additional option in the prevention and treatment of PONV in adults, particularly for patients who have failed previous antiemetic prophylaxis and for whom effective treatment options may be limited.

A novel nasal co-loaded loratadine and sulpiride nanoemulsion with improved downregulation of TNF-α, TGF-ß and IL-1 in rabbit models of ovalbumin-induced allergic rhinitis.

PURPOSE: The work aimed to develop a co-loaded loratadine and sulpiride nasal nanoemulsion for allergic rhinitis management. METHODS: Compatibility studies were conducted adopting differential scanning calorimetry and Fourier transform infrared spectroscopy. Nanoemulsion formulations were prepared using soybean lecithin, olive oil and tween 80. Sodium cholate and glycerol were employed as co-surfactants. Nanoemulsions were assessed for viscosity, pH, droplet size, polydispersity index, zeta potential, electrical conductivity, entrapment, In vitro drug release and corresponding kinetics. Stability of the selected formulation was investigated. The biological effectiveness was evaluated in rabbit models of ovalbumin-induced allergic rhinitis by measuring TNF-α, TGF-ß and IL-1. RESULTS: Compatibility studies revealed absence of drug/drug interactions. Nanoemulsions exhibited > 90% entrapment efficiency. The selected nanoemulsion demonstrated small droplet size (85.2 ± 0.2 nm), low PDI (0.35 ± 0.0) and appropriate Zeta Potential (-23.3 ± 0.2) and stability. It also displayed enhanced in vitro drug release following the Higuashi Diffusion and Baker-Lonsdale models. The mean relative mRNA expression of TNF-α, IL-1 and TGF-ß significantly decreased from 9.59 ± 1.06, 4.15 ± 0.02 and 4.15 ± 0.02 to 1.28 ± 0.02, 1.93 ± 0.06 and 1.56 ± 0.02 respectively after treatment with the selected nanoemulsion formulation. CONCLUSION: The results reflected a promising potent effect of the combined loratadine and sulpiride nasal nanoemulsion in managing the symptoms of allergic rhinitis.

Effectiveness of Standard Combination Therapy in Pediatric Migraine.

BACKGROUND: A combination of parenteral medications (often referred to as standard combination therapy) is frequently used in the treatment of acute migraine in the pediatric emergency department (PED). The primary aim of this study was to evaluate the two-hour, 24-hour, and seven-day impact of one such regimen on pain in children who present to the PED. Standard combination therapy for purposes of our study is defined as a bolus of intravenous saline, and a combination of intravenous ketorolac, prochlorperazine, and diphenhydramine. METHODS: This prospective observational study included 120 children between the ages seven and 18 years who presented to the PED with migraine, whose parents could read and understand the consent form in English, and who were treated with standard combination therapy. The primary outcome measure for this study was the change in severity of pain as noted by the child using the Faces Pain Scale-Revised. We analyzed normally distributed continuous variables by mean and standard deviation, whereas non-normally distributed continuous variables are reported by median and interquartile range. RESULTS: Nonparametric Friedman testing on the entire cohort (n = 120) noted that there was a statistically significant change in the Faces pain scale from before administration of standard combination therapy to the two-hour, 24-hour, and one-week time point with a reduction in pain score of 87.5%, 100%, and 50%, respectively, at the three time points. CONCLUSIONS: This study noted moderate relief of pain after administration of standard combination therapy, which persisted at one-week after administration.

Striatal dopamine D1 receptors control motivation to respond, but not interval timing, during the timing task.

Dopamine plays a critical role in behavioral tasks requiring interval timing (time perception in a seconds-to-minutes range). Although some studies demonstrate the role of dopamine receptors as a controller of the speed of the internal clock, other studies demonstrate their role as a controller of motivation. Both D1 dopamine receptors (D1DRs) and D2 dopamine receptors (D2DRs) within the dorsal striatum may play a role in interval timing because the dorsal striatum contains rich D1DRs and D2DRs. However, relative to D2DRs, the precise role of D1DRs within the dorsal striatum in interval timing is unclear. To address this issue, rats were trained on the peak-interval 20-sec procedure, and D1DR antagonist SCH23390 was infused into the bilateral dorsocentral striatum before behavioral sessions. Our results showed that the D1DR blockade drastically reduced the maximum response rate and increased the time to start responses with no effects on the time to terminate responses. These findings suggest that the D1DRs within the dorsal striatum are required for motivation to respond, but not for modulation of the internal clock speed.

Intravenous Amisulpride Does Not Meaningfully Prolong the QTc Interval at Doses Effective for the Management of Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) are significant issues in surgical patients, and additional treatment options are needed. Dopaminergic antiemetics have been popular for their efficacy, but their use has been limited by safety concerns, especially the potential for torsade de pointes arising from QT interval prolongation. Intravenous (IV) amisulpride, a dopamine D2 and D3 antagonist shown to be effective at preventing and treating PONV at doses of 5 and 10 mg, respectively, has a dose-dependent effect on QT but at 5 mg is not associated with clinically meaningful prolongation of the heart rate-corrected QT (QTc) interval. This study was designed to evaluate the QT effect of a 10-mg dose of amisulpride, alone and when simultaneously coadministered with ondansetron, an antiemetic of a different class, also known to prolong the QT interval. METHODS: In this randomized, double-blind, placebo-controlled, 3-period, crossover study, healthy male and female volunteers 18-65 years of age received IV, in a random sequence: (1) amisulpride 10 mg given twice, 2 hours apart; (2) amisulpride 10 mg and ondansetron 4 mg, given simultaneously; and (3) placebo. RESULTS: Thirty subjects were enrolled, and 29 completed all 3 treatment periods. The largest mean placebo-corrected change-from-baseline QT interval corrected for heart rate using Fridericia's formula (QTcF) (ΔΔQTcF) after the first and second amisulpride dose was 5.2 milliseconds (90% confidence interval [CI], 3.53-6.96 milliseconds) and 8.0 milliseconds (90% CI, 5.49-10.58 milliseconds), respectively. After coadministration of amisulpride and ondansetron, the largest mean ΔΔQTcF was 7.3 milliseconds (90% CI, 5.48-9.16 milliseconds). The slope of the amisulpride concentration-change-from-baseline QTcF (ΔQTcF) relationship was 0.006 ms/ng/mL (90% CI, 0.0020-0.0098). No QTc outliers (absolute QTcF value >480 milliseconds or increase from baseline >30 milliseconds) were seen in any period. CONCLUSIONS: A 10-mg dose of IV amisulpride, given alone or in combination with ondansetron, does not have a clinically significant effect on the QT interval.