1A Agonist Research Articles

Pharmacological Interventions for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Tourette Disorder: A Systematic Review and Network Meta-Analysis.

Objective: To evaluate the comparative efficacy of pharmacological interventions for children and adolescents with a dual diagnosis of persistent tic disorders or Tourette disorder and attention-deficit/hyperactivity disorder (TD + ADHD). Methods: We searched CENTRAL, Embase, PubMed, PsycInfo, Web of Sciences, ClinicalTrials.gov, and WHO ICTRP up to September 2023 to identify double-blinded randomized controlled trials (RCTs) assessing pharmacological interventions for children and adolescents with TD + ADHD. Outcomes were change in ADHD symptoms (primary) and tics (secondary) severity. Standardized mean difference (SMD) was calculated and pooled in random-effects network meta-analysis. The Confidence in Network Meta-Analysis framework was adopted to determine certainty of evidence. Results: We included 8 RCTs involving 575 participants. Network meta-analyses demonstrated that α2 agonists (SMD, 95% confidence interval [CI] ADHD: -0.72 [-1.13 to -0.31]; TD: -0.70 [-0.96 to -0.45]) and stimulants + α2 agonists (ADHD: -0.84 [-1.54 to -0.13]; TD: -0.60 [-1.04 to -0.17]) were more efficacious than placebo for ADHD symptoms and tics severity. Stimulants alone were more efficacious than placebo for ADHD symptoms severity only, but they did not worsen tics (ADHD: -0.54 [-1.05 to -0.03]; TD: -0.22 [-0.49 to 0.05]). There were no significant differences between any pairs of medications that were found efficacious against placebo for ADHD symptoms or tics severity. Certainty in the evidence varied from low to very low. Conclusions: Stimulants are efficacious for ADHD symptoms severity and do not increase tics severity in TD + ADHD. α2 agonists are efficacious for both ADHD symptoms and tics severity in TD + ADHD. These findings should inform guidelines and help guide shared decision-making to choose a medication for children with TD + ADHD.

Targeting α1- and α2-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression

This study assessed the ability of α1 and α2-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α1 agonist phenylephrine, (5) α1 antagonist prazosin, (6) α1D antagonist BMY-7378, (7) α2 agonist clonidine, (8) α2 antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α1 drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3–1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.

Comparison of the Effect of Scalp Block With Ropivacaine vs. Ropivacaine and Clonidine on Postoperative Pain in Patients Undergoing Craniotomy Surgery Under General Anesthesia.

Introduction Clonidine, an α2 agonist known for its hypotensive and analgesic effects, has proven beneficial in various routes of administration such as oral, intravenous, and local infiltration. Scalp blocks enhance hemodynamic stability during surgery and reduce intraoperative opioid requirements compared to controls in numerous studies. Additionally, they are effective in managing postoperative pain, resulting in reduced opioid consumption. Research has shown that clonidine can enhance and prolong the effects of intrathecal, epidural, and peripheral nerve blocks (e.g., brachial plexus, peribulbar). Here, we investigated the impact of adding clonidine at a dose of 1 μg/kg to scalp blocks performed with 0.5% ropivacaine for supra-tentorial craniotomy Material and methods This study was conducted on 60 patients under theAmerican Society of Anesthesiologists (ASA) grade I and II who were scheduled for elective supratentorial craniotomy. Patients were divided into two equal groups of 30 and received a scalp block following general anesthesia. Patients in Group A (n=30) received a scalp block of 0.5% ropivacaine plus 1 ml of normal saline (total 21 cc). Patients in Group B (n=30) received a scalp block of 0.5% ropivacaine and clonidine (1 μg/kg) combined with 0.5 ml of normal saline (total 21 cc). Blood pressure, heart rate, peripheral oxygen saturation (SpO2), visual analog score, Ramsay sedation score, duration of analgesia, and analgesia requirement in the first 24 hours were recorded from baseline and postoperatively. Results The duration of first rescue analgesia for Group A was 4.30 ± 1.5 hours and that of Group B was 9.10 ± 1.4 hours. Duration of analgesia was significantly prolonged in patients receiving ropivacaine with clonidine for scalp nerve block. The amount of tramadol given in the first 24 hours in Group A, 62.50 ± 25.00 mg, was highcompared to Group B, 57.14 ± 18.89 mg. The mean arterial blood pressure differed significantly in both groups at 30 minutes, 1 hour, 3 hours, and 12 hours after scalp block postoperatively and lower in Group B. Although changes in pulse rate, and SpO2 were not statistically significant in both groups, patients were hemodynamically stable and did not require any ionotropic support. Ramsay sedation score and visual analog score postoperatively were not significant. There were no significant adverse effects noted in any groups. Conclusion Our study concluded that administering clonidine at a dosage of 1 μg/kg, in combination with 0.5% ropivacaine for scalp nerve block procedures, significantly extends the duration of analgesia and enhances its quality, all while maintaining stable hemodynamic parameters.

The growth hormone secretagogue receptor 1a agonists, anamorelin and ipamorelin, inhibit cisplatin-induced weight loss in ferrets: Anamorelin also exhibits anti-emetic effects via a central mechanism

This study investigated whether ghrelin mimetics, namely anamorelin and ipamorelin, can alleviate weight loss and inhibition of feeding observed during acute and delayed phases of cisplatin-induced emesis in ferrets. The potential of anamorelin to inhibit electrical field stimulation (EFS)-induced contractions of isolated ferret ileum was compared with ipamorelin. In other experiments, ferrets were administered anamorelin (1–3 mg/kg), ipamorelin (1–3 mg/kg), or vehicle intraperitoneally (i.p.) 30 s before cisplatin (5 mg/kg, i.p.) and then every 24 h, and their behaviour was recorded for up to 72 h. Food and water consumption was measured every 24 h. The effect of anamorelin (10 µg) was also assessed following intracerebroventricular administration. Anamorelin and ipamorelin inhibited EFS-induced contractions of isolated ileum by 94.4 % (half-maximal inhibitory concentration [IC50]=14.0 µM) and 54.4 % (IC50=11.7 µM), respectively. Neither of compounds administered i.p. had any effect on cisplatin-induced acute or delayed emesis, but both inhibited associated cisplatin-induced weight loss on the last day of delayed phase (48–72 h) by approximately 24 %. Anamorelin (10 µg) administered intracerebroventricularly reduced cisplatin-induced acute emesis by 60 % but did not affect delayed emesis. It also improved food and water consumption by approximately 20 %–40 % during acute phase, but not delayed phase, and reduced associated cisplatin-induced weight loss during delayed phase by ∼23 %. In conclusion, anamorelin and ipamorelin administered i.p. had beneficial effects in alleviating cisplatin-induced weight loss during delayed phase, and these effects were seen when centrally administered anamorelin. Anamorelin inhibited cisplatin-induced acute emesis following intracerebroventricular but not intraperitoneal administration, suggesting that brain penetration is important for its anti-emetic mechanism of action.

A comparative evaluation of intraperitoneal bupivacaine alone and bupivacaine with dexmedetomidine for post-operative analgesia following laparoscopic cholecystectomy.

Intraperitoneal instillation of local anaesthetic agents alone or in combination with opioids, α2 agonists such as Dexmedetomidine have been found to reduce postoperative pain following laparoscopic cholecystectomy. The study was designed to compare the better drug among Bupivacaine alone and Bupivacaine with Dexmedetomidine with respect to their analgesic efficacy and safety profile. in patients undergoing laparoscopic cholecystectomy. The study was carried out on sixty patients of the American Society of Anaesthesiologists (ASA) physical status I-II of either sex with ages ranging from 18 to 60 years posted for elective laparoscopic cholecystectomy under General Anaesthesia, equally divided into two groups, randomly allocated to one of the Groups using the table of randomization. Group B received Intraperitoneal Bupivacaine 40 ml 0.25% +5 ml normal saline and Group BD received Intraperitoneal Bupivacaine 40 ml 0.25% + Dexmedetomidine1 μg/kg diluted in 5 ml Normal saline. The mean heart rate and blood pressure (systolic, diastolic and mean) readings were significantly lower in Group BD than in Group B. The mean duration of analgesia in our study was longer in Group BD (7.5 ± 0.73 hours) when compared to Group B (5.9 ± 0.55 hours) with p-value & 0.0001 and CI 1.27 to 1.9, which was statistically significant. However, the post-operative analgesic requirement (rescue/demand) in Group B was clinically earlier and statistically significant as compared to Group BD. Postoperative VAS score ≥3 was considered the benchmark for providing rescue analgesia in the form of injection of Diclofenac 75 mg IV. In our study, we observed the pain scores via VAS/NRS at 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h and 24 h postoperatively. A comparison of pain scores from 30 min to 10hrs postoperatively showed a significant difference in both Groups with Group B having significantly higher VAS scores and lower VAS scores with Group BD. Our study suggests that there is a shorter duration of action of 0.25% Bupivacaine alone as compared to 0.25% Bupivacaine + Dexmedetomidine. Since the laparoscope is still inside the abdominal cavity the drugs are easy to administer with no adverse effects and with a good safety profile because of the visualization of drug deposition in the right place. Intraperitoneal instillation of Bupivacaine with Dexmedetomidine for postoperative analgesia was very promising as a part of multimodal analgesia in laparoscopic cholecystectomy.

Alpha2 Agonist Use in Critically Ill Adults: A Focus on Sedation and Withdrawal Prevention.

The management of sedation in critically ill adults poses a unique challenge to clinicians. Dexmedetomidine, an α2 agonist, has a unique mechanism and favorable pharmacokinetics, making it an attractive intravenous option for sedation and delirium in the intensive care unit. However, patients may be at risk for withdrawal with prolonged use, adding to the complexity of sedation and agitation management in this patient population. Enteral α2 agents have the benefit of cost savings and ease of administration, thus playing a role in the ability to decrease intravenous sedative use and prevent dexmedetomidine withdrawal. Clonidine and guanfacine are the two most common enteral α2 agents utilized for this purpose, however, there is a paucity of evidence regarding the comparative benefit between the two agents. The decision to use one vs the other agent should be determined based on their differing pharmacology, pharmacokinetics, and side effect profile. The most effective dosing strategy for these agents is also unknown. Ultimately, more robust literature is required to determine enteral α2 agonists place in therapy. This narrative review evaluates the currently available literature on the use of α2 agonists in critically ill adults with an emphasis on sedation, delirium, and withdrawal.

Identification of hypothermia-inducing neurons in the preoptic area and activation of them by isoflurane anesthesia and central injection of adenosine

Hibernation and torpor are not passive responses caused by external temperature drops and fasting but are active brain functions that lower body temperature. A population of neurons in the preoptic area was recently identified as such active torpor-regulating neurons. We hypothesized that the other hypothermia-inducing maneuvers would also activate these neurons. To test our hypothesis, we first refined the previous observations, examined the brain regions explicitly activated during the falling phase of body temperature using c-Fos expression, and confirmed the preoptic area. Next, we observed long-lasting hypothermia by reactivating torpor-tagged Gq-expressing neurons using the activity tagging and DREADD systems. Finally, we found that about 40–60% of torpor-tagged neurons were activated by succeeding isoflurane anesthesia and by icv administration of an adenosine A1 agonist. Isoflurane-induced and central adenosine-induced hypothermia is, at least in part, an active process mediated by the torpor-regulating neurons in the preoptic area.Graphical abstract

Effect of dexmedetomidine infusion on characteristics of spinal anesthesia with hyperbaric bupivacaine: A randomized controlled trial

Dexmedetomidine is a highly selective and potent α2 agonist having both sedative and analgesic properties. This study was aimed to assess the effects of intravenous dexmedetomidine on sensory, motor, haemodynamic parameters and sedation during subarachnoid block (SAB) with 0.5% hyperbaric bupivacaine. Sixty patients undergoing infraumbilical and lower limb surgeries were allocated into 2 groups, group D (n=30) received dexmedetomidine infusion at the rate of 0.5 µg/kg/h over an hour prior to SAB and continued till the end of surgery whereas patients in group C (n=30) received similar volume of normal saline infusion for the same duration. Onset of sensory block was 63.77 ± 7.42 s in group D compared with 126.2 ± 12.83s in group C. Two segment regression time was 177.03 ± 11.64 min in group D and 85.67 ± 10.32 min in group C and analgesia duration was 287.67 ± 14.84 min in group D and 149 ± 13.16 min in group C. Onset of motor block was 3.95 ± 0.65 min in group D and 4.5 ± 0.62 min in group C. Motor blockade duration was prolonged in group D compared with group C. There was significant difference between the groups in respect to block characteristics. Administration of intravenous dexmedetomidine during SAB hastens the onset and prolongs the duration of sensory and motor block. It also provides conscious sedation and additional analgesia.

A pathway to precision medicine: coronary and cerebral arterial transcriptomic analysis reveals distinct pathophysiological adaptations in two clinically relevant porcine models of heart failure

Traditional treatments for heart failure (HF) with reduced ejection fraction (HFrEF) are ineffective at treating HF with preserved ejection fraction (HFpEF), establishing a need for more targeted therapeutic approaches. To date, the comparative vascular adaptions induced by these two distinct forms of HF have been largely unexplored. Therefore, the objective of this study was to compare HFrEF and HFpEF pathophysiological adaptions in both coronary and cerebral microvasculature in two clinically relevant swine models of HF. We hypothesized that HFrEF and HFpEF will induce differing pathophysiological adaptations within the microvasculature of the heart as well as peripheral tissues, such as the brain. Intact female Ossabaw swine (2 months old) were fed a Western Diet for 4 months to develop metabolic syndrome (HOMA-IR: HFrEF 2.94 ± 0.34; HFpEF 2.95 ± 0.59). At 6 months of age, animals were either subjected to 90 minutes ischemia followed by reperfusion (I/R) to induce a myocardial infarction (MI) recapitulating cardiometabolic HFrEF (38.0 ± 3.9% EF) or were aortic banded to induce pressure-overload with relevance to cardiometabolic HFpEF (61.5 ± 1.7% EF). Following humane euthanasia, coronary arterioles (139.5 ± 4.9 μm inner diameter) and middle cerebral artery second order pial arterioles (281.1 ± 16.7 μm) from each model were dissected and either cannulated and pressurized for myography experiments or flash frozen for RNA isolation, sequencing, and predictive pathway analysis. Smooth muscle dependent U46619 (thromboxane A2 agonist)-induced constriction of cerebral arterioles was not different between groups (HFrEF 46.9 ± 10.3%; HFpEF 50.7 ± 4.8%), however, smooth muscle dependent dilation to sodium nitroprusside (SNP, nitric oxide mimetic) was significantly reduced in HFrEF (37.1 ± 14.0%) compared to HFpEF (83.6 ± 4.6%), suggesting the dilatory capacity of peripheral vessels is impaired when EF% is reduced. Furthermore, RNA-sequencing comparison between HFrEF and HFpEF uncovered 35 differentially expressed genes in the coronary (n=3) and 23 differentially expressed genes in cerebral (n=3) arterioles (q ≤ 0.1). Ingenuity pathway analysis predicted upstream regulators that code for angiotensinogen, STAT3, and interferon-Ƴ were inhibited (z-score > -2.0) in the HFrEF model, which was associated with decreased proliferation of smooth muscle cells and vasculogenesis with increased organismal death and inflammation in the coronary arterioles. Furthermore, analysis of the cerebral arterioles predicted inhibition of angiotensinogen (z-score > -2.0) in the HFrEF model which was associated with increased fibroblast cell death, dedifferentiation of smooth muscle cells, and recruitment of macrophages. Together, these data reveal distinct pathophysiological functional and transcriptomic adaptions between HFrEF and HFpEF in the coronary and cerebral arterioles. Additionally, these data provide three candidate genes that regulate these pathophysiological processes and could be targeted for potential therapeutic intervention. Funding: REGENCOR and Department of Defense (DOD) W81XWH-18-1-0179. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comparative evaluation of nebulized versus intravenous dexmedetomidine on intubating conditions during awake fiberoptic nasotracheal intubation

BackgroundThere is a search for an ideal agent to facilitate awake fiberoptic intubation (AFOI). Dexmedetomidine is a selective α2 agonist which can be administered through intravenous, intramuscular, buccal, intranasal & inhalational routes. It provides good intubation conditions without oxygen desaturation but may cause hypotension and bradycardia when administered intravenously. Hence, alternative routes of administering dexmedetomidine which may improve its safety profile are worth exploring. MethodsIn this randomised, controlled, double-blind trial, 46 ASA I/II adult participants scheduled for elective ENT surgery were randomly allocated to Group ND (Nebulised Dexmedetomidine) (n = 23) to receive nebulisation with dexmedetomidine 1μg.kg−1 and Group ID (Intravenous Dexmedetomidine) (n = 23) to receive intravenous dexmedetomidine 1μg.kg−1 before AFOI. All the patients received injection midazolam 1 mg i.v. as premedication before anaesthesia was initiated. The primary outcome was the cough score. The secondary outcomes were the RSS, SAYGO boluses, post-intubation score, hemodynamic parameters, recall of the procedure, patient satisfaction score and any side effects. ResultsThe cough score was significantly lower in nebulized group (2.43 ± 0.992 vs 3.52 ± 1.082) with p = 0.001. RSS(3.30 ± 0.926 vs 4.22 ± 1.126; p = 0.004), number of SAYGO boluses required (2.74 ± 0.864 vs 3.57 ± 1.161; p = 0.009) & the post intubation score (1.48 ± 0.593 vs 2.17 ± 0.778; p = 0.001) were also significantly lower in nebulized group. ConclusionsNebulisation with dexmedetomidine results in desirable degree of sedation and better tolerance of the procedure with adequate attenuation of the haemodynamic responses to intubation.

Dexmedetomidine as an Adjunct to Propofol in Patients Undergoing Elective Endoscopic Retrograde Cholangio-Pancreaticography - A Double-blind Randomized Controlled Study.

Propofol is the drug of choice for procedural sedation. The addition of α2 agonist dexmedetomidine may improve the safety profile of the procedure by providing stable hemodynamics, better sedation quality, and decreasing the side effects of each drug during elective endoscopic retrograde cholangio-pancreaticography (ERCP). Eighty patients aged between 18 and 60 years were distributed randomly into two groups. The dexmedetomidine + propofol group (group DP) received an injection of dexmedetomidine at the dose of 1 mcg/kg in 100 mLsaline, and the propofol group (group P) received plain 100 mL normal saline over 10 min. Subsequently, both groups received a bolus dose of injection propofol 1 mg/kg as sedation, and a modified observer's assessment of alertness/sedation score (MOASS) score was assessed, followed by infusion at the rate of 50 mcg/kg/min during the procedure. A rescue bolus dose (20 mg) of propofol was administered when the patient showed signs of inadequate sedation or analgesia in both groups. Cardiovascular and respiratory parameters were recorded every 10 min throughout the procedure. Post-procedure modified Aldrete score was evaluated for 30 min, and the endoscopist's score was noted at the end of the procedure. There was a significant difference (P = 0.001) in the additional number of rescue doses of propofol administered in group DP (3.47 ± 0.77) as compared to group P (8.78 ± 1.11). The total dose of propofol was lower in group DP (316.59 ± 43.29 mg) than in group P (443 ± 41.1 mg) with P value = 0.001. Statistically significant differences in the hemodynamic values were observed in group DP during infusion (P value < 0.05) of dexmedetomidine and throughout the procedure (P < 0.05) when compared with group P. Endoscopists graded the satisfaction score as very high (3.477 ± 0.77) in group DP. The addition of dexmedetomidine to propofol during ERCP provided better and safer sedation.

Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.

Awake Craniotomy in Conscious Sedation: The Role of A2 Agonists.

In Awake Craniotomy (AC), α2-agonists and remifentanil (clonidine and dexmedetomidine) are used in the preoperative phase and throughout the procedure to combine monitored anesthesia care and local anesthesia. The study aims were to specify the key role of α2-agonists administered and to evaluate complication presence/absence in anesthesiologic management. 42 patients undergoing AC in 3 different centers in the south of Italy (Foggia, San Giovanni Rotondo, and Bari) were recruited. Our protocol involves analgo-sedation by administering Dexmedetomidine and Remifentanil in continuous intravenous infusion, allowing the patient to be sedated and in comfort but contactable and spontaneously breathing. During pre-surgery, the patient is premedicated with intramuscular clonidine (2 µg/kg). In the operating setting, Dexmedetomidine in infusion and Remifentanil in Target Controlled Infusion for effect are started. At the end of the surgical procedure, the infusion of drugs was suspended. There were no intraoperative side effects. The mean duration of interventions was 240 ± 62 min. The average quantity of Remifentanil and Dexmedetomidine infused during interventions were 4.2 ± 1.3 mg and 1.0 ± 0.3 mg, respectively. No significant side effects were described in the post-operative phase. A total of 86% of patients and 93% of surgeons were totally satisfied. Synergy between opioid drugs and α2 agonists plays a fundamental role in ensuring procedure success.

Tonic noradrenergic input to neurons in the dorsal raphe nucleus mediates food intake in male mice

The dorsal raphe nucleus (DRN) is essential for the control of food intake. Efferent projections from the DRN extend to several forebrain regions that are involved in the control of food intake. However, the neurotransmitters released in the DRN related to the control of food intake are not known. We have previously demonstrated that a tonic α1 action on DRN neurons contributes to satiety in the fed rats. In this study we investigated the participation of norepinephrine (NE) signaling in the DRN in the satiety response. Intra-DRN administration of NE causes an increase in the 2-hour food intake of sated mice, an effect that was blocked by previous administration of yohimbine, an α2 antagonist. Similarly, Intra-DRN administration of clonidine, an α2 agonist, increases food intake in sated mice. This result indicates that in the satiated mice exogenous NE acts on α2 receptors to increase food intake. Furthermore, administration of phenylephrine, an α1 agonist, decreases food intake in fasted mice and prazosin, an α1 antagonist, increases food intake in the sated mice. Taken together these results indicate that, in a satiated condition, a tonic α1 adrenergic action on the DRN neurons inhibits food intake and that exogenous NE administered to the DRN acts on α2 adrenergic receptors to increase food intake. These data reinforce the intricate neuronal functioning of the DRN and its effects on feeding.

Comparison of Dexmedetomidine and Propofol for Sedation in Patients Undergoing Upper Limb Orthopedic Surgery under Regional Anesthesia with Brachial Plexus Block

Abstract Background: The search for the ideal sedative during regional anesthesia continues. Propofol is widely as a sedative intraoperatively. It may cause troublesome hemodynamic changes. Dexmedetomidine is an α2 agonist with sedative, anxiolytic, and analgesic properties. In this study, we compared dexmedetomidine with propofol as sedatives during surgeries under brachial plexus block. Materials and Methods: In our study, 70 American Society of Anesthesiologists I Class and II patients about to undergo upper limb surgeries under brachial plexus block were blinded and randomly allocated to receive either propofol (Group P) or dexmedetomidine (Group D) infusion. Brachial plexus block was performed, and after confirmation of adequate sensory and motor block, an initial loading dose of the drug was administered over 10 min, followed by a maintenance dose till the end of the surgery. Titration of the rate of infusion was done so as to maintain Ramsay Sedation Score (RSS) of 3–4 and Bispectral Index (BIS) of 60–80. Hemodynamic and respiratory parameters were monitored intraoperatively. Adverse effects such as hypotension, bradycardia, respiratory depression, and incidence of oversedation and undersedation were also noted. The collected data were evaluated using appropriate statistical tests in SPSS version 22®. P &lt;0.05 was considered statistically significant. Results: The RSS remained at 4 in Group P from 20 min onward and for Group D, RSS remained at 3 after 30 min. Post-induction, there was a reduction in BIS in both the groups, but patients in Group P showed statistically significant lower values of BIS when compared with Group D. The fall in mean arterial pressure was more in Group P as compared to Group D. Nine (25.71%) incidences of hypotension were seen in Group P and none in Group D. The decrease in heart rate was more profound in Group D as compared with Group P and one incidence of bradycardia observed in Group D. The respiratory rate was relatively stable in Group D as compared to Group P. The oxygen saturation (SpO2) values in the majority of the patients in both groups were above 92%, but three patients in Group P had SpO2 &lt;92%. In Group P, 6 (17.14%) incidences of oversedation and 8 (22.85%) incidences of undersedation were observed. In Group D, 7 (20%) incidences of undersedation with no incidence of oversedation were observed. Conclusion: Dexmedetomidine at recommended doses has a better sedative property with less effect on hemodynamics and respiration as compared to propofol.

Adrenoceptors and Hypertension.

Hypertension is a very prevalent condition associated with high mortality and morbidity, secondary to changes resulting in blood vessels and resultant end-organ damage. Haemodynamic changes, including an initial rise in cardiac output followed by an increase in total peripheral resistance, denote the early changes associated with borderline or stage 1 hypertension, especially in young men. Increased sodium reabsorption leading to kidney damage is another mechanism proposed as one of the initial triggers for essential hypertension. The underlying pathophysiological mechanisms include catecholamine-induced α1- and ß1-adrenoceptor stimulation, and renin-angiotensin-aldosterone system activation leading to endothelial dysfunction which is believed to lead to persistent blood pressure elevation.α1 blockers, α2 agonists, and ß blockers were among the first oral anti-hypertensives. They are no longer first-line therapy after outcome trials did not demonstrate any benefits over and above other agents, despite similar blood pressure reductions. Angiotensin-converting enzyme inhibitors(or angiotensin receptor blockers), calcium channel blockers, and thiazide-like diuretics are now considered the first line of therapy, although adrenoceptor agents still have a role as second- or third-line therapy. The chapter also highlights hypertension in specific medical conditions such as pregnancy, phaeochromocytoma, hyperthyroidism, portal hypertension, pulmonary arterial hypertension, and ocular hypertension, to provide an overview for clinicians and researchers interested in the role of adrenoceptors in the pathophysiology and management of hypertension.

Rewarding effects in 4-AcO-DMT administration and withdrawal in rats: A challenge to the opponent-process theory

According to the opponent-process theory of drug addiction, the intake of an addictive substance initiates two processes: a rapid primary process that results in the drug’s rewarding effects, and a slower opponent process that leads to the aversive motivational state of drug aftereffects. This aversive state is integral in the desire, pursuit, and maintenance of drug use, potentially leading to dependence and addiction. However, current observational and experimental evidence suggests that the administration of a 5-hydroxytryptamine receptors-type 2A (5-HT2A) agonist, while capable of inducing a positive mental state in humans, may not generate the behavioral patterns typically associated with drugs of abuse. In this study, we found that administering the 5-HT2A agonist 4-Acetoxy-N,N-dimethyltryptamine fumarate (4-AcO-DMT) did not result in place preference in male rats compared to control saline administration 24 h later, after the drug has been cleared from the organism. However, in a modified place preference test where only the acute motivational effects of the drug were evaluated (excluding withdrawal), 4-AcO-DMT was found to be rewarding. Furthermore, in another modified place preference test where only the motivational effects of drug withdrawal were evaluated (excluding the acute effects of drug administration), the 24-hour aftereffect of 5-HT2A agonist administration also resulted in a robust place preference. Therefore, while 4-AcO-DMT administration was able to induce place preference, its 24-hour aftereffect also produced a strong reward. In the counterbalanced test, this reward from the aftereffect effectively overshadowed its acute rewarding properties, which could potentially create a false impression that 4-AcO-DMT lacks motivational properties. This suggests that 5-HT2A agonist administration follows a different dynamic than that proposed by the opponent-process theory of motivation and implies that the administration of 5-HT2A agonists may lead to behavioral patterns less typical of drugs associated with addiction.

Vascular reactivity is altered in the placentas of fetuses with congenital diaphragmatic hernia

IntroductionInfants with congenital diaphragmatic hernia (CDH) often develop pulmonary hypertension but frequently fail to respond to vasodilator therapy, for instance because of an altered pulmonary vasoreactivity. Investigating such alterations in vivo is impossible. We hypothesised that these alterations are also present in fetoplacental vessels, since both vasculatures are exposed to the same circulating factors (e.g. endothelin-1) and respond similarly to certain stimuli (e.g. hypoxia). As proof-of-concept, we compared fetoplacental vasoreactivity between healthy and CDH-affected placentas. MethodsFetoplacental vascular function of healthy and antenatally diagnosed left-sided CDH fetuses was assessed by wire myography. Placental expression of enzymes and receptors involved in the altered vasoreactive pathways was measured using quantitative PCR. ResultsCDH arteries (n = 6) constricted more strongly to thromboxane A2 agonist U46619 (p < 0.001) and dilated less to bradykinin (p = 0.01) and nitric oxide (NO)-donor sodium nitroprusside (p = 0.04) than healthy arteries (n = 8). Vasodilation to prostacyclin analogue iloprost and adenylate cyclase stimulator forskolin, and vasoconstriction to endothelin-1 were not different between both groups. Angiotensin II did not induce vasoconstriction. Phosphodiesterase inhibitors sildenafil and milrinone did not affect responses to sodium nitroprusside, forskolin, or U46619. The mRNA expression of guanylate cyclase 1 soluble subunit alpha 1 (p = 0.003) and protein kinase cyclic guanine monophosphate (cGMP)-dependent 1 (p = 0.02) were reduced in CDH versus healthy placentas. DiscussionThe identified changes in the thromboxane and NO-cGMP pathways in the fetoplacental vasculature correspond with currently described alterations in the pulmonary vasculature in CDH. Therefore, fetoplacental arteries may provide an opportunity to predict pulmonary therapeutic responses in infants with CDH.

The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke.

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.

OR21-06 Growth Response Of Oral LUM-201 In OraGrowtH210 And OraGrowtH212 Trials In Idiopathic Pediatric Growth Hormone Deficiency (iPGHD): Combined Analysis Interim Analysis Data

Abstract Disclosure: M.J. Tansey: Research Investigator; Self; Lumos Pharma, Inc. S.A. Bowden: Research Investigator; Self; Lumos Pharma, Inc. A.N. Dauber: Research Investigator; Self; Lumos Pharma, Inc. B. Wikiera: Research Investigator; Self; Lumos Pharma, Inc. B. Pyrzak: Research Investigator; Self; Lumos Pharma, Inc. A.T. Bossowski: Research Investigator; Self; Lumos Pharma, Inc. E. Petriczko: Research Investigator; Self; Lumos Pharma, Inc. R. Stawerska: Research Investigator; Self; Lumos Pharma, Inc. E. Moszczynska: Research Investigator; Self; Lumos Pharma, Inc. F. Cassorla: Research Investigator; Self; Lumos Pharma, Inc. Speaker; Self; Lumos Pharma, Inc. M.M. Feldt: Research Investigator; Self; Lumos Pharma, Inc. A.J. Lunsford: Research Investigator; Self; Lumos Pharma, Inc. M.E. Gottschalk: Research Investigator; Self; Lumos Pharma, Inc. M. Marin: Research Investigator; Self; Lumos Pharma, Inc. S.N. Nayak: Research Investigator; Self; Lumos Pharma, Inc. S. Bhuvana: Research Investigator; Self; Lumos Pharma, Inc. D.R. Repaske: Research Investigator; Self; Lumos Pharma, Inc. L.A. Soyka: Research Investigator; Self; Lumos Pharma, Inc. J.S. Fuqua: Research Investigator; Self; Lumos Pharma, Inc. O. Escobar: Research Investigator; Self; Lumos Pharma, Inc. D.A. Bowlby: Research Investigator; Self; Lumos Pharma, Inc. P.Y. Fechner: Research Investigator; Self; Lumos Pharma, Inc. E. Wiltshire: Research Investigator; Self; Lumos Pharma, Inc. M. Harris: Research Investigator; Self; Lumos Pharma, Inc. K.A. Wintergerst: Research Investigator; Self; Lumos Pharma, Inc. A.R. Lafferty: Research Investigator; Self; Lumos Pharma, Inc. B.S. Miller: Research Investigator; Self; Lumos Pharma, Inc. P. Simm: Research Investigator; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. C. Smith: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. D.B. Karpf: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. J.C. McKew: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. Background: LUM-201 (ibutamoren), a growth hormone (GH) secretagogue receptor 1a (GHSR1a) agonist, is a potent, long-acting investigational oral GH secretagogue currently studied in three Idiopathic Pediatric GH Deficiency (iPGHD) studies. The LUM-201 predictive enrichment marker (PEM) is used to identify patients diagnosed with iPGHD (peak stimulated GH &amp;gt;3&amp;lt;10 ng/mL) who are likely to respond to LUM-201. PEM positivity is defined as a baseline insulin-like growth factor-1 (IGF-1) level &amp;gt;30 ng/mL and a peak GH of ≥5 ng/mL in response to a single 0.8 mg/kg dose of LUM-201. Objectives: Report the growth response analyzing the combined interim analysis (IA) data from two Phase 2 trials studying LUM-201 at two different doses (1.6 mg/kg/day or 3.2 mg/kg/day). Methods: IA data from both studies were combined and analyzed for calculated annualized height velocity (AHV). Baseline demographics were analyzed for the two combined cohorts. Results: After 6 months of treatment with LUM-201, the calculated AHV (mean ±SD ) was 8.1±1.9 cm/year in the 1.6 mg/kg/day group and 8.0±1.5 cm/year in the 3.2 mg/kg/day group (N=15 in both groups). After 9 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.3±1.7 cm/year in the 3.2 mg/kg/day group (N=10 in both groups). After 12 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.4 ±1.2 cm/year in the 3.2 mg/kg/day group (N=6 in both groups). LUM-201 was well tolerated; no safety concerns were identified across the dose range in adverse events (AE) data, laboratory values, and ECG values. Conclusions: As the growth velocity was comparable for the two doses of oral LUM-201, this analysis of the combined IA data appears to strongly support 1.6 mg/kg/day as the optimal dose for the Phase 3 trial, as doubling the dose appeared to offer no meaningful improvement in efficacy. Final determination will await final full data set analysis of both studies. Presentation: Saturday, June 17, 2023