Mixed Antagonist Research Articles

Metabolism of immune cells in septic shock in children

In septic shock the hyperimmune response and immunosuppression can occur at the same time, being defined as mixed antagonist response syndrome. Under standard conditions, mitochondria supports cellular energy metabolism through the citric cycle and the phosphorylation chain. Both NK and T cells produce an immediate effector response to inflammatory signals using the rapid production of energy in aerobic glycolysis (glucose-lactate]. When the inflammatory signal is eliminated, they return to metabolism in the Krebs cycle. Septic shock in the children was accompanied by immunoparalysis (TNFα <200pg/ml), lower monocyte human antigen (HLA-DR), loss of peripheral non-naive CD4 T cells and low mitochondrial respiration. Children with septic shock had a in hospital mortality rate of 10.8-33.5%, high risk of hospitali­zation in the next 28 days and in the following months with predominantly respiratory infections. The treatment of mitochondrial dysfunction, insufficiently structured, is based on antioxidant medication, but the results await confirmation.

Mechanisms and treatment of opioid-induced pruritus: Peripheral and central pathways.

Pruritus (also known as itch) is defined as an unpleasant and irritating sensation of the skin that provokes an urge to scratch or rub. It is well known that opioid administration can cause pruritus, which is paradoxical as itch and pain share overlapping sensory pathways. Because opioids inhibit pain but can cause itching. Significant progress has been made to improve our understanding of the fundamental neurobiology of itch; however, much remains unknown about the mechanisms of opioid-induced pruritus. The prevention and treatment of opioid-induced pruritus remains a challenge in the field of pain management. The objective of this narrative review is to present and discuss the current body of literature and summarize the current understanding of the mechanisms underlying opioid-induced pruritus, and its relationship to analgesia, and possible treatment options. The incidence of opioid-induced pruritus differs with different opioids and routes of administration, and the various mechanisms can be broadly divided into peripheral and central. Especially central mechanisms are intricate, even at the level of the spinal dorsal horn. There is evidence that opioid receptor antagonists and mixed agonist and antagonists, especially μ-opioid antagonists and κ-opioid agonists, are effective in relieving opioid-induced pruritus. Various treatments have been used for opioid-induced pruritus; however, most of them are controversial and have conflicting results. The use of a multimodal analgesic treatment regimen combined with a mixed antagonist and κ agonists, especially μ-opioid antagonists, and κ-opioid agonists, seems to be the current best treatment modality for the management of opioid-induced pruritus and pain. Opioids remain the gold standard for the treatment of moderate to severe acute pain as well as cancer pain. It is well known that opioid-induced pruritus often does not respond to regular antipruritic treatment, thereby posing a challenge to clinicians in the field of pain management. We believe that our review makes a significant contribution to the literature, as studies on the mechanisms of opioid-induced pruritus and effective management strategies are crucial for the management of these patients.

Utilization and Predictors of Adjuvant Metformin for Children and Adolescents on Mixed Receptor Antagonists (Second-Generation Antipsychotics)

To examine utilization and predictors of adjuvant metformin among pediatric recipients of second-generation antipsychotics (SGAs) (mixed receptor antagonist). This study used 2016-2021 data of a national electronic medical record database. Eligible participants were children aged 6 to 17 with a new SGA prescription for at least 90 days. Predictors of prescribing adjuvant metformin in general and to nonobese pediatric SGA recipients in particular were assessed using conditional logistic regression and logistic regression analyses, respectively. Of 30,009 pediatric SGA recipients identified, 2.3% (n= 785) received adjuvant metformin. Among 597 participants with a body mass index z score documented during the 6-month period before metformin initiation, 83% were obese, and 34% had either hyperglycemia or diabetes. Significant predictors for metformin prescribing were high baseline body mass index z score (odds ratio [OR] 3.5, 95% CI 2.8-4.5, p< .0001), having hyperglycemia or diabetes (OR 5.3, 95% CI 3.4-8.3, p< .0001), and undergoing a switch from a higher metabolic risk SGA to a lower risk one (OR 9.9, 95% CI 3.5-27.5, p= .0025) or a switch in the opposite direction (OR 4.1, 95% CI 2.1-7.9, p= .0051) compared with no switch. Nonobese metformin users were more likely to have a positive body mass index z score velocity before metformin initiation than their obese counterparts. Receiving the index SGA prescribed by a mental health specialist was associated with higher likelihood of receiving adjuvant metformin and receiving metformin before the development of obesity. Utilization of adjuvant metformin among pediatric SGA recipients is uncommon, and early introduction of the medication among nonobese children is rare.

Priming effects of a slot machine game and amphetamine on probabilistic risk-taking in people with gambling disorder and healthy controls

ABSTRACT Introduction The Game of Dice Task (GDT) captures probabilistic risk-taking, which is an important feature of addictions and integral to gambling disorder (GD). No research appears to have assessed effects of gambling-specific priming manipulations or the pharmacological basis of such effects on the GDT. Aims To investigate effects of slot machine gambling (Slots) and d-amphetamine (AMPH; 20 mg) on risk-taking in people with GD and healthy controls (HCs) (n = 30/group). The role of dopamine (DA) was assessed by pre-treating participants with the D2 receptor (D2R)-preferring antagonist, haloperidol (HAL; 3-mg) or mixed D1R-D2R antagonist, fluphenazine (FLU; 3-mg). Hypotheses Slots and AMPH will each increase risk-taking based on fewer (less probable) possible outcomes selected (POS) and poorer net monetary outcomes (NMO; gains minus losses) on the GDT, with stronger effects in Group GD. If DA mediates these effects, outcomes will vary with pre-treatment. Method Participants attended a pre-experimental baseline session and 4 test sessions. Antagonist Group (HAL, FLU) was manipulated between-participants. Pre-treatment (antagonist, placebo) was manipulated within-participants and counterbalanced over sessions for Slots and AMPH test phases. Moderator/mediator effects of trait and neuropsychological factors and GD severity (South Oaks Gambling Screen; SOGS) were explored via covariance. Results AMPH led to an escalation in risky POS over trial blocks in both groups, regardless of pre-treatment. Cognitive inflexibility (high perseveration-proneness) moderated this effect in Group HC. In Group GD, SOGS selectively predicted riskier POS on AMPH sessions. Group GD achieved poorer NMO vs. Group HC on the pre-experimental baseline and Placebo-Slots sessions. Group HC selectively displayed poorer NMO on the Antagonist-Slots session. Conclusions The GDT can detect behavioral and pharmacological priming effects. Cognitive inflexibility and symptom severity moderate AMPH-induced risk-taking in HC and GD participants, respectively. Sensitization-related “wanting” of risk may contribute to the latter effect in people with GD.

P-617 Cost-effectiveness analysis of In Vitro Fertilization (IVF) antagonist protocols utilizing highly purified human menopausal gonadotropin (HP-hMG) and three different recombinant FSH (rFSH) preparations

Abstract Study question Is there a mixed ovarian stimulation antagonist protocol for IVF that obtains more good quality blastocysts with less cost? Summary answer Mixed protocol of HP-hMG and follitropin delta obtains a significantly more good quality blastocysts with significantly lower cost per embryo obtained. What is known already FSH and LH are used for controlled ovarian stimulation (COS) to increase the number of oocytes produced in IVF. Determination of a stimulation protocol and FSH dosage is generally established by the physician based on the patient’s age, body weight and ovarian reserve profile. Mixed protocols (concomitant HP-hMG and rFSH) for ovarian stimulation have been used to obtain better quality oocytes and embryos and thus, higher pregnancy rates compared to the use of rFSH alone. However, to date no data exist comparing cost-effectiveness of mixed protocols using different rFSH preparations. Study design, size, duration This is a cost-effectiveness analysis of the retrospective cohort study encompassing COS for IVF with 3 different mixed protocols performed between January 2018 and September 2019 in 2 fertility clinics. The 267 subjects evaluated were between 18 and 42 years of age and were divided into 3 groups of 89 subjects each according to the rFSH used: group A follitropin alfa; group B follitropin beta and group D follitropin delta. Participants/materials, setting, methods HP-hMG was used in all three groups while different rFSH was prescribed. All three groups used an antagonist protocol. IVF or intra-cytoplasmatic sperm injection (ICSI) was used as clinically indicated. Resulting embryos were cultured until day 5 or 6. The dose of gonadotropins used, the number of mature oocytes (MII), the number of utilizable blastocysts and the FSH/blastocyst ratio were evaluated. For cost-effectiveness analysis we used prices accepted by the provincial healthcare system in Quebec. Main results and the role of chance The mean age of subjects was 34.62 years (± 3.74) and weight 71.65 kg (± 14.61). No significant differences were observed in age or weight among groups. Since follitropin delta is administered in micrograms, the comparison between rFSH preparations was performed using dose equivalence between (10 µg follitropin delta) and (150 IU follitropin alpha and beta). Statistically significant differences were observed among groups in mean total dose of FSH (IU) (A = 4269 IU vs. B = 3947 IU vs. D = 3713 IU, p = 0.01), and number of days of stimulation (A = 11.6 vs. B = 10.6 vs. D = 11.4, p &amp;lt; 0.01). Group D used less gonadotropins despite a longer stimulation. No statistically significant differences were observed in the number of MII oocytes. However, the number of good quality utilizable blastocysts was significantly higher in group D (4.8) than in group A (3.9) or B (3.6). The FSH/blastocyst ratio was significantly lower in group D (370) than in the other groups (A = 541, B = 653). The total price per cycle was similar (A= $4,028 vs. B= $3,649 D= $3,740), however the price per embryo obtained was significantly lower in group D ($779) than in the other groups (A= $1,033, B= $1,014). Limitations, reasons for caution The limitation of this cost-effectiveness analysis is the retrospective nature of the study. Wider implications of the findings Our analysis demonstrates that the price per cycle was similar between the groups, however the price per embryo obtained was significantly lower in group D compared to the other groups. This gives follitropin delta an advantage in terms of cost-effectiveness. Trial registration number NA

Endothelin‐1 dependent expression of GAG genes involves NOX and p38 mediated Smad linker region phosphorylation

Endothelin‐1 (ET‐1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to identify the ET‐1‐mediated signalling pathway involving NADPH oxidase (NOX), p38 MAP kinsae and Smad2 linker region phosphorylation (phospho‐Smad2L) regulate GAG synthesising enzymes mRNA expression (C4ST‐1 and ChSy1) involved in GAG chains hyperelongation in human vascular smooth muscle cells (VSMCs). Signalling intermediates were detected and quantified by Western blotting and the mRNA levels of GAG synthesising enzymes were assessed by quantitative real‐time polymerase chain reaction (qRT‐PCR). ET‐1 treatment of human VSMCs resulted in an increase in phospho‐Smad2L level. The TGF‐β receptor antagonist, SB431542 and the mixed ETA and ETB receptor antagonist bosentan, inhibited ET‐1‐mediated phospho‐Smad2L level. In the presence of apocynin and diphenyleneiodonium chloride (DPI) (NOX inhibitors) and SB239063 (p38 inhibitor) ET‐1‐mediated phospho‐Smad2L levels were inhibited. The gene expression levels of GAG synthesising enzymes post‐ET‐1 treatment were increased compared to untreated controls (p < 0.01). The ET‐mediated the mRNA levels of these enzymes were blocked by the bosentan, SB431542, SB239063, DPI, apocynin and antioxidant N‐acetyl‐L‐cysteine (NAC). ET‐1‐mediated signalling to GAG synthesising enzymes gene expression occurs via transactivation‐dependent pathway involving NOX, p38 MAP kinsae and Smad2 linker region phosphorylation.

A double-blind randomized, multicenter, placebo-controlled study of itopride in functional dyspepsia postprandial distress syndrome.

Itopride, a mixed D2 antagonist and cholinesterase inhibitor, has prokinetic effects on gastric motility. The Leuven Postprandial Distress Scale is a validated patient-reported outcome instrument for functional dyspepsia (FD) postprandial distress syndrome (PDS). We aimed to use the LPDS to assess treatment outcome in PDS and PDS/EPS (epigastric pain syndrome). Patients with PDS, with or without non-predominant EPS symptoms, were enrolled in an 8-week double-blind placebo-controlled multi-center trial with itopride (100mg t.i.d.). Patients completed LPDS diaries and questionnaires to assess treatment response. Mann-Whitney test and mixed models were used. One hundred patients (79% females, 39.1±1.5yo) were included. No significant difference was observed between treatment arms (p=0.6). Compared to baseline, itopride treatment significantly improved the LPDS score (p=0.001) and all individual symptoms (p<0.0001). In the placebo arm, this was only the case for belching and epigastric pain (p<0.05). In an exploratory analysis, outcomes in "pure" PDS (n=45) and overlapping PDS/EPS (n=55) patients were assessed and showed that the latter subgroup has the largest benefit with itopride compared to placebo (p=0.03). Using the LPDS score in a pilot controlled trial in FD, itopride shows no therapeutic benefit over placebo after 8weeks of treatment. In an exploratory post hoc analysis, itopride but not placebo was associated with improvement of symptoms compared to baseline, and this was most prominent in patients with overlapping PDS/EPS. The efficacy of itopride in this subgroup needs to be evaluated in a large study using the same outcome measure. (clinialtrials.org ref.: NCT04647955).

Роль та місце ω-3 жирних кислот у регуляції синдрому системної відповіді на запалення в пацієнтів, які отримують інтенсивну терапію

У статті проаналізовано сучасні наукові дані про роль ω-3 жирних кислот у комплексі нутритивної підтримки у хворих у критичному стані, їх вплив на динаміку синдрому системної відповіді на запалення (SIRS), синдрому протизапальної відповіді (CARS), а також синдрому змішаної антагоністичної дії (MАRS), що розвивається при взаємодії різноспрямованої (запальної/протизапальної) відповіді (SIRS/САRS). Призначення замісної імунокорекції в комплексі інтенсивної терапії критичних станів патогенетично обґрунтоване і показане як компонент цілеспрямованої органопротективної терапії. Наявність у пацієнтів синдромів SIRS або CARS повинно визначати вибір ліпідної емульсії в комплексі парентерального харчування з уключенням емульсій МСТ/ЛСТ з ω-3 жирними кислотами у хворих у клініці інтенсивної терапії. Використання ліпідних емульсій, збагачених риб’ячим жиром, сприяє зменшенню тривалості лікування в стаціонарі пацієнтів із критичними станами.

The rate and Extent of absorption of oral Meptazinol 200 mg on healthy volunteer

Meptazinol is a centrally acting analgesic belonging to the hexahydro-azepine series, which has demonstrated mixed agonist and antagonist activity at opioid receptors.Receptor binding studies have shown that although meptazinol displays only a low affinity for μ and k opioid receptor sites, it has a some what higher affinity for the subpopulation of μ sites. These binding sites also displays a high affinity for the endogenous opioid peptides, and are thought to be responsible for, among other things, analgesia, but not for the mediation of respiratory depression. A component of its analgesic action is also attributable, in mice at least, to an effect on central cholinergic transmission. In this respect it differs from all conventional analgesic drugs which have been examined (1).Based on this information this drug requires no blocking of opioid receptor during the bioequivalence study. But to achieve the highest degree of safety, close monitoring will be performed to detect the occurrence of any side effect, As well as Anarchole 50mg tablets (Naltrexone, the opioid blocker) will be available at the emergency drugs store to treat any opioid side effect

Bifunctional μ opioid and σ1 receptor ligands as novel analgesics with reduced side effects.

Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σ1R), a unique Ca2+-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the μ-opioid receptor (MOR), N-methyl-d-aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB1R). Overwhelming pharmacological and genetic evidence indicates that σ1R antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σ1Rs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σ1R antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σ1R antagonism represents a promising avenue for the development of potent and safer analgesics.

The utilization of agro-industrial waste for soil amendment and liquid biofertilizer mixed bacterial antagonist in eggplant production

This research aimed to improve soil fertility with soil amendment, prepared from agro-industrial waste, and application of antagonistic bacteria for controlling bacterial wilt disease. The experiments were tested on sandy-to-sandy loam soil with low organic matter and nutrients for planting eggplants. Besides the soil improvement with spent mushroom waste and mango peel mixed kernel, the results showed that soil pH, soil organic matter, nitrogen, phosphorus, and potassium increased as available levels. Also, two species of bacterial antagonist named Bacillus subtilis and B. amyloliquifaciens were cultured and mixed in liquid biofertilizer. It was spiked for soil preparation before planting and during crop growth every week, which was affected by eggplant survival from bacterial wilt by 100% and 97% in plot and field-tested, respectively. The results from testing on sandy loam with the use of liquid biofertilizer three times/week showed that Ralstonia solanacearum in soil suppressed to the reduction of 1,000-10,000 times. The yield increased by 25.9%. The optimum harvesting time was 12-15 days of fruit growth with the antioxidant activity. Finally, this study has excellent potential to be extended for farmers who organically grown.

Safety of treatment with ulipristal acetate on the mammary gland: A pilot prospective study

IntroductionHeavy menstrual bleeding is the major complaint in women with symptomatic fibroids. Ulipristal acetate (UPA) is a “selective progesterone receptor modulator” in which mixed agonist and antagonist activity appears to offer a novel approach to medical management of symptomatic uterine fibroids. There are currently no studies that have assessed its effect on the mammary gland in humans. MethodsProspective observational study conducted in a tertiary hospital, in which 14 consecutive patients diagnosed with uterine fibroids by transvaginal ultrasound were included. The patients received two cycles of UPA 5mg/day for 3 months each, with a rest period of two months between both cycles. To assess the safety on the mammary gland, 3 mammary ultrasounds were performed at three different points: prior to the first cycle of UPA, between the two cycles and at the end of the second cycle. ResultsOf the 14 recruited patients, 9 completed the study period. Breast ultrasound reports were normal in all patients. In 4 patients (44.4%), the 3 breast ultrasounds were classified as BI-RADS 2. In 2 patients (22.2%) the 3 breast ultrasounds were classified as BI_RADS1; and in 3 patients (33.3%), the first breast ultrasound was classified as BI-RADS 3 and the last two as BI-RADS 2. ConclusionIn conclusion, our study showed that 2 cycles of treatment with UPA in patients with symptomatic uterine fibroids is safe for normal breast tissue with an acceptable adverse effects profile. Nonetheless, further research is required to confirm our findings.

Possible Protective Effect of Endothelin-1 Receptor Antagonist on Renal Impairment in Type 2 Diabetic Rats

Background: Diabetic nephropathy (DN) is characterized by persistent albuminuria and progressive decline in glomerular filtration rate (GFR). Bosentan is a non-peptide mixed antagonist of ET-1. Aim: To investigate the possible protective role of bosentan on renal impairment in T2DM rats and the mechanisms concerned. Materials: Fifty rats were randomly divided into five equal groups; Non-Diabetic (ND), Diabetic non-treated (DN), Diabetic Bosentan-treated (D-Bos.), Diabetic Metformin-treated (D-Met.), Diabetic combined Bosentan and Metformin-treated groups (D-Bos& Met.). T2DM was induced by Streptozotocin (STZ) (35mg/kg) and high fat diet (HFD) for 3 weeks. Both Bosentan and metformin were given orally for 4 weeks. At the end of the experiment, 24hrs urine samples were collected to measure urine (volume, albumin, NAG and creatinine), renal blood flow velocity (RBFV) and peripheral renal resistance (RVR) were measured using Doppler technique. Blood was collected directly from abdominal aorta to estimate fasting serum glucose, glycosylated hemoglobin (HBA1c), serum insulin, complete lipid profile, renal function tests and parameters of oxidative stress: malondialdehyde (MDA), total antioxidant capacity (TAC) and tumor necrosis factor-α (TNFα). Insulin resistance, serum LDL-cholesterol, urinary albumin creatinine ratio (UACR) and creatinine clearance (CC) were calculated. Results: Serum cysteine c, BUN, urinary albumin and UACR were significantly lowered in both D-Bos. & D-Met when compared to the corresponding values in DN while urinary volume, urinary creatinine, CC and RBFV were significantly elevated but serum creatinine, NAG & RVR were significantly lowered in D-Bos. only. Conclusion: Bosentan and metformin treatment both have a renoprotective effect. Combined treatment showed better results.

Cytokine Profile in Children with Severe Multisystem Inflammatory Syndrome Related to the Coronavirus Disease 2019.

The multisystem inflammatory syndrome in children (MIS-C) is a novel and concerning entity related to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Although MIS-C has been the subject of intensive research efforts, its pathophysiology and optimal treatment remain elusive. We studied the clinical features, laboratory findings, and immunoinflammatory profiles of seven children prospectively admitted to a pediatric intensive care unit (PICU) during the first wave of the pandemic. All patients had immunoglobulin (Ig)-G against SARS-CoV-2, four of seven patients had both IgM and IgG, and in one of the 7 SARS-CoV-2 was detected in a respiratory sample. All patients received intravenous fluid boluses (median: 15 mL/kg) and norepinephrine. The most common form of respiratory support was supplemental oxygen via nasal cannula. None of the patients needed mechanical ventilation. The cardiovascular system was frequently involved. All patients had an elevated troponin-I (median: 107.3 ng/L). Four out of seven patients had coronary artery abnormalities, and two of seven had both abnormal electrocardiogram (EKG) findings and evidence of left ventricular dysfunction on echocardiogram. Ig levels and complement function were normal. Peripheral blood phenotyping with flow cytometry showed decreased T-cell numbers at the expense of CD8+ T-cells. Cytokine profiling showed a heterogeneous increase in interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-18, IL-2Ra, IL-10, and IL-1Ra that tended to normalize after treatment. Our study shows that children with MIS-C have elevated plasma levels of pro- and anti-inflammatory cytokines in the acute phase of the disease without other relevant immunologic disturbances. These findings suggest the presence of a mixed antagonist response syndrome (MARS) similar to that present in pediatric sepsis. Combining a meticulous differential diagnosis with cautiously coordinated immunomodulatory therapy and high-quality supportive care can help clinicians avoid causing iatrogenic harm in patients with MIS-C.

The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Evaluation of Adjuvant Effectiveness of Alum-Propranolol Mixture on the Immunogenicity of Excreted/Secreted Antigens of Toxoplasma gondii RH Strain.

Purpose: The introduction of novel adjuvants is an important step in attempts to develop a safe and more efficient vaccine. The present study was performed to determine whether the use of a mixed beta-adrenergic receptor antagonist propranolol (PRP) and aluminum (alum), as an adjuvant, have efficacy for Toxoplasma gondii vaccine to induce protective immunity in a mouse model.Methods: Female BALB/c mice divided into five groups were immunized with excretorys-ecretory antigens (ESA) vaccine, alum-ESA vaccine, PRP-ESA vaccine, and alum-PRP ESA vaccine, as well as with phosphate buffered saline (PBS), as a negative control group. The immune responses were evaluated by lymphocyte proliferation assay for measuring delayedtype hypersensitivity (DTH) response and by cytokine assay for evaluating IFN-γ and IL-5 levels. The survival rate of mice in all groups was assessed during a three-week monitoring period after an intraperitoneal challenge with T. gondii tachyzoites. Results: The results showed that mice immunized with PRP, as an adjuvant, could secret a higher level of IFN-γ, which was significant in comparison to other groups. However, mice vaccinated with alum-precipitated ESA antigen had ability to produce an elevated level of IL-5 compared to other mouse groups (P ≤ 0.05). Moreover, alum-PRP co-administration together with ESA vaccine resulted in the longer survival of mice.Conclusion: The findings of this study revealed that the combination of alum-PRP adjuvants and ESA vaccine of T. gondii elicits both humoral and cellular immune responses, which are comparable to either alum or PRP alone.

Treatment-Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance.

Objective: To describe the clinical characteristics of adolescents with antidepressant treatment-resistant major depressive disorder (MDD) and to examine the utility of the Antidepressant Treatment Record (ATR) in categorizing treatment resistance in this population. Methods: Adolescents with treatment-resistant MDD enrolled in an interventional study underwent a baseline evaluation with the ATR, Children's Depression Rating Scale-Revised (CDRS-R), and Clinical Global Impressions-Severity (CGI-S) scales. Demographic and clinical characteristics were examined with regard to ATR-defined level of resistance (level 1 to ≥3) using analysis of variance and χ2 tests. Results: In adolescents with treatment-resistant MDD (N = 97), aged 12-21 years, most were female (65%), white (89%), and had recurrent illness (78%). Patients were severely ill (median CGI-S score of 5), had a mean CDRS-R score of 63 ± 10, and 17.5% had been hospitalized for depression-related symptoms. Fifty-two patients were classified as ATR 1, whereas 32 were classified as ATR level 2 and 13 patients as ≥3, respectively. For increasing ATR-defined levels, illness duration increased from 12.0 (range: 1.5-31.9) to 14.8 (range: 1.8-31.7) to 19.5 (range: 2.5-36.2) months and the likelihood of treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs) similarly increased (p = 0.006 for both SNRIs and DNRIs) as did the likelihood of treatment with mixed dopamine serotonin receptor antagonists (χ2 = 17, p < 0.001). Conclusions: This study underscores the morbidity and chronicity of treatment-resistant MDD in adolescents. The present characterization of related clinical features describes the use of nonselective serotonin reuptake inhibitors in adolescents with treatment-resistant depression and raises the possibility that those with the greatest medication treatment resistance are less likely to have had recurrent episodes. The study also demonstrates the utility of the ATR in categorizing treatment resistance in adolescents with MDD.

Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders.

Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.

The effects of flutamide on the neonatal rat hypothalamic-pituitary-adrenal and gonadal axes in response to hypoxia.

Hypoxia is common with preterm birth and may lead to long‐term effects on the adult hypothalamic–pituitary–adrenal (HPA) axis that are sexually dimorphic due to neonatal androgens. Although the adult rat adrenal does not express appreciable CYP17 activity, the neonatal rat adrenal may synthesize androgens that could be a critical local factor in the development of adrenal function. We evaluated these phenomena by pretreating the neonatal rats on postnatal days (PD) 1, 6, 13, 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 mg/kg or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to acute hypoxia and blood was sampled. We found that (a) in PD2 pups, flutamide augmented corticosterone responses in a sexually dimorphic pattern and without an increase in ACTH, (b) PD7 and PD14 pups had the smallest corticosterone response to hypoxia (c) PD21 pups had an adult‐like corticosterone response to hypoxia that was sexually dimorphic, (d) flutamide attenuated ACTH responses in PD7 hypoxic pups, and (e) high‐dose flutamide suppressed the HPA axis, FSH, and estradiol. Flutamide demonstrated mixed antagonist and agonist effects that changed during the first three weeks of neonatal life. We conclude that the use of flutamide in neonatal rats to evaluate androgen‐induced programming of subsequent adult behavior is not optimal. However, our studies suggest neonatal androgens play a role in regulation of adrenal function that is sexually dimorphic and changes during early development.

Implementation and evaluation of Missouri's Medication First treatment approach for opioid use disorder in publicly-funded substance use treatment programs

BackgroundLeaders of Missouri's State Targeted Response to the opioid crisis (STR) grant have prioritized increasing access to treatment medications for opioid use disorder (MOUD) through a “Medication First” approach. This conceptual framework prioritizes rapid, sustained, low-barrier access to MOUD for optimal impact on decreased illicit drug use and mortality. Medication First principles and practices were facilitated through state-level structural changes and disseminated to participating community treatment programs via a multi-pronged, multi-disciplinary approach. In the first nine months of STR, 14 state-contracted treatment agencies operating 38 sites used STR funding to implement the Medication First model. MethodsWe utilized state billing and service data to make comparisons before and during STR on the following outcomes: MOUD utilization, timely access to MOUD, amount of psychosocial services delivered, treatment retention at 1, 3, and 6 months, and monthly price of treatment. We conducted follow-up analyses examining differences across MOUD types (no medication, methadone, buprenorphine, oral naltrexone, mixed antagonist + agonist, and extended release naltrexone). ResultsDuring STR, MOUD utilization increased (44.8% to 85.3%), timeliness of MOUD receipt improved (Median of 8 days vs. 0 days), there were fewer psychosocial services delivered, treatment retention improved at one, three, and six month timeframes, and the median cost per month was 21% lower than in the year prior to STR. All differences were driven by increased utilization of buprenorphine. ConclusionsFindings suggest Medication First implementation through STR was successful in all targeted domains. Though much more work is needed to further reduce logistical, financial, and cultural barriers to improved access to maintenance MOUD, the steps taken through Missouri's STR grant show significant promise at making swift and drastic transformations to a system of care in response to a growing public health emergency.