Emetic Effects Research Articles

Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome

Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- “off” agent for Parkinson’s disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.

Amelioration of functional and histopathological consequences after spinal cord injury through phosphodiesterase 4D (PDE4D) inhibition

Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, even when starting 2 dpi, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.

Opioid Prescribing for Noncancer Patients—Issues of Drug Therapy Safety: Results from a German Study Based on Routine Data

Opioids are highly effective drugs but need close monitoring to avoid harm to patients. The aim of this study was to analyze how guideline recommendations are met for (i) the avoidance of the concomitant use of anxiolytics, hypnotics, or sedatives; (ii) the prescribing of laxatives in long-term opioid treatment; (iii) the co-prescribing of drugs to control the emetic effect of opioids; (iv) pretreatment with non-opioids; and (v) screening for depression when initiating opioids. The results are based on a routine data analysis of a large German health insurance fund. Different study populations of noncancer patients (18+ years old) treated with opioids were analyzed: 10.4% of the opioid recipients in 2021 received at least one concomitant prescription with anxiolytics, hypnotics, or sedatives; 69.3% of those with long-term opioid treatment received at least one laxative prescription. Of those with first-time opioid prescriptions, 4.8% received an antiemetic drug; 47.3% of those with a newly initiated opioid therapy received a non-opioid prescription within three months before the start of the opioid therapy; and 22.0% of patients with incident opioid prescription had at least one documentation of a depression diagnosis within three months of the first prescription. There is an urgent need to improve opioid prescribing to avoid risky combinations and adverse effects.

Role of Sapindus emarginatus Pericarp Extract in Gut Serotonin Level and its Emetic Activity in Animal Models

Background: Emesis is a complex and distressing protective mechanism that helps to remove toxic substances from the stomach and prevent further ingestion. The emetics and cathartics are predominantly used for accidental and intentional ingestion of poisons or toxins. The availability and usage of emetics in humans are limited because of their side effects. Therefore, to treat poisoned people, we need effective medications. Sapindus emarginatus Vahl., often called soapnut, is a member of the Sapindaceae family. They have historically been used as emetic, antipruritic, laxative, antifertility, and anti-inflammatory medicines. Objective: This study aims to assess the gut serotonin level and emetic effect of Sapindus emarginatus hydroethanolic pericarp extract (HESE) by using animal models. Methods: Gravimetric analysis was used to determine the HESE's saponin content. The emetic effect of the HESE at a dose of 250, 500, 1000, and 2000 mg/kg was evaluated by copper sulfateinduced emesis in the chick model and cisplatin-induced emesis in the rat-pica model. The serotonin level in rat intestinal mucosa was measured by spectrofluorimetry. Results: HESE was estimated to contain 11.92% saponin. The extract at high doses of 1000 and 2000 mg/kg showed emetic activity evidenced by increased frequency of retching in chick, increased kaolin intake, and anorexia in the rat-pica model. The extract showed a significant increase in serotonin levels in the proximal part of the small intestine in comparison with normal animals. Conclusion: According to the results of the current investigation, which employed various animal models, the HESE demonstrated appreciable emetic activity. The extract at a high dose showed a significant emetic effect due to increased serotonin levels in the gut. The HESE was discovered to be a strong contender for the treatment of poisoned patients. More research are required to validate their adverse effects of frequent usage.

The use of cannabinoids in the treatment of multiple sclerosis

Cannabis sativa is a component of the group of psychotropic cannabinoids and its main active component is tetrahydrocannabinol (THC). Its influence on the medial prefrontal cortex is complex, and its dose-dependency is high. Cannabis sativa is the third most used substance in the world, after cigarettes and alcohol. Currently, it is being used for illegal recreational purposes and medicinal purposes in complementary therapy. Cannabidiol (CBD) can be found in 60 subtypes of Cannabis sativa and has a therapeutic effect, being used to treat various diseases. In patients with multiple sclerosis, it causes a reduction in pain crises through the release of neurotransmitters that generate emetic, anesthetic, anti-inflammatory and analgesic effects. The aim of this review is to present the mechanisms of potentiating herbal treatment, highlighting the immunological response after the action of cannabinoids on human physiology.

Utility of Prophylactic Percutaneous Gastrostomy in Patients With Head and Neck Cancer Receiving Concurrent Chemoradiotherapy: A Multicenter Analysis.

Patients with head and neck cancer (HNC) have an elevated incidence of cachexia and malnutrition due to the tumor's location interfering with oral feeding. Concurrent chemoradiation (CCRT) can have an emetic effect and cause dysphagia and oral mucositis. Adequate nutrition improves immunity, raises the response to therapy, reduces adverse effects, and improves survival. Numerous studies have suggested the utility of nutritional support from percutaneous endoscopic gastrostomy (PEG) in HNC patients. Although PEG is usually considered a safe procedure, it has a mortality rate of 0-2.2% and a risk of other procedure-related complications of 17-40%. Our work intends to evaluate the utility of PEG in patients with locally advanced HNC who underwent CCRT. We performed a cohort study at three institutions. We included patients with HNC who underwent definitive CCRT treatment from January 2013 to December 2022.The study consisted of an observational, descriptive, retrospective analysis of prespecified clinical data. Descriptive statistics were used to compare the data between the PEG group and the non-PEG group. Analysis of covariance (ANCOVA) was used forcovariance analysis. Fisher's exact test was used to compare proportional data and Student's t-test was used to assess the differences in continuous data. Survival analysis was performed using the Kaplan-Meier estimator. P-values of<0.05 were considered to be indicative of statistical significance. The SPSS Statisticsversion 28.0 (Armonk, NY: IBM Corp.) was used to perform all statistical evaluations. We identified 90 eligible patients diagnosed with local advanced HNC who had received definitive CCRT with three weekly cycles of cisplatin as follows: 44 with a prophylactic PEG tube and 46 without a prophylactic PEG tube. Most patients were male (84.4%) and 50% of patients were diagnosed with stage IVa HNC at the time of diagnosis. There wasn't an effect of PEG placement on BMI at the end of CCRT after controlling for the effect ofbaseline BMI (F {1.84}=0.065 {p=0.799}).In the study population, BMI was significantly lower after CCRT (21.30 kg/m2 vs. 23.97 kg/m2), t (86)=12.389, p<0.001. In the subgroup with baseline BMI <18.5 kg/m2 (15 patients), 90% of patients with prophylactic PEG were able to complete the three planned cycles of chemotherapy vs. 66.7% in the non-PEG group. Ten patients in the PEG group (22.7%) referredfeeding tube dependency. Patients with dysphagia were 3.2 times more likely to have placed prophylactic PEG (p=0.007). The difference in overall survivaland progression-free survivalbetween the two groups was not statistically significant (p=0.57 and p=0.497, respectively). In this study using real-world data, we found a potentially protective effect of PEG in underweight patients with locally advanced HNC performing CCRT in order to complete three cycles of treatment.

Pharmacokinetics of intramuscular maropitant in pigs (Sus scrofa domesticus).

Pigs are at risk of vomiting from medical conditions as well as the emetic side effects of drugs administered for peri-operative manipulations, but there is a lack of pharmacokinetic data for potential anti-emetic therapies, such as maropitant, in this species. The main objective of this study was to estimate plasma pharmacokinetic parameters for maropitant in pigs after a single intramuscular (IM) administration dosed at 1.0mg/kg. A secondary objective was to estimate pilot pharmacokinetic parameters in pigs after oral (PO) administration at 2.0mg/kg. Maropitant was administered to six commercial pigs at a dose of 1.0mg/kg IM. Plasma samples were collected over 72 h. After a 7-day washout period, two pigs were administered maropitant at a dose of 2.0mg/kg PO. Maropitant concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive pharmacokinetics parameters. No adverse events were noted in any of the study pigs after administration. Following single IM administration, maximum plasma concentration was estimated at 412.7 ± 132.0ng/mL and time to maximum concentration ranged from 0.083 to 1.0h. Elimination half-life was estimated at 6.7 ± 1.28 h, and mean residence time was 6.1 ± 1.2h. Volume of distribution after IM administration was 15.9L/kg. Area under the curve was 1336 ± 132.0h*ng/mL. The relative bioavailability of PO administration was noted to be 15.5% and 27.2% in the two pilot pigs. The maximum systemic concentration observed in the study pigs after IM administration was higher than what was observed after subcutaneous administration in dogs, cats, or rabbits. The achieved maximum concentration exceeded the concentrations for anti-emetic purposes in dogs and cats; however, a specific anti-emetic concentration is currently not known for pigs. Further research is needed into the pharmacodynamics of maropitant in pigs to determine specific therapeutic strategies for this drug.

A Comparative Study of Propofol Vs Midazolam for Sedation and Anti Emetic Effect in Spinal Anesthesia

A Comparative Study of Propofol Vs Midazolam for Sedation and Anti Emetic Effect in Spinal Anesthesia

Patient-controlled sublingual sufentanil tablet system versus intravenous opioid analgesia for postoperative pain management after lumbar spinal fusion surgery

PurposeThis retrospective cohort study investigated the efficacy of a sublingual sufentanil tablet system (SSTS) in comparison to intravenous patient-controlled analgesia (IV-PCA) with piritramide for the management of postoperative pain following lumbar spinal fusion surgery.MethodsThis was a retrospective analysis of patients undergoing single- or two-level lumbar spinal fusion surgery and receiving the SSTS or IV-PCA for postoperative pain relief as part of multimodal pain management that included IV paracetamol and oral metamizole. The following variables were collected: postoperative pain intensity and frequency scores using the numerical rating scale (NRS), hospital anxiety and depression scale (HADS), occurrence of nausea, postoperative mobilization, and patient satisfaction (MacNab criteria).ResultsSixty-four patients were included. Those receiving the SSTS (n = 30) had significantly lower pain intensities on the operative day (NRS: 4.0, CI: 3.6–4.3 vs. 4.5, CI: 4.2–4.9; p < 0.05) and one day postoperatively (NRS: 3.4, CI: 3.1–3.8 vs. 3.9 CI: 3.6–4.3; p < 0.05) compared to patients receiving IV-PCA (n = 34). No differences were observed on postoperative days 2 to 5. SSTS patients experienced more nausea than IV-PCA patients (p = 0.027). Moreover, SSTS patients had a higher percentage of early mobilization following surgery than IV-PCA patients (p = 0.040). Regarding patient satisfaction, no significant differences were seen between the groups.ConclusionThe SSTS is a potentially advantageous alternative to opioid IV-PCA for use within a multimodal approach to managing postoperative pain after lumbar fusion surgery. Furthermore, the potentially higher emetic effect of SSTS should be considered, and the patient should be able to perform the application.

Glucose-Dependent Insulinotropic Polypeptide and Substance P Mediate Emetic Response Induction by Masked Trichothecene Deoxynivalenol-3-Glucoside through Ca2+ Signaling.

Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G’s emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.

Selective Inhibition of PDE4B Reduces Methamphetamine Reinforcement in Two C57BL/6 Substrains.

Methamphetamine (MA) is a highly addictive psychostimulant drug, and the number of MA-related overdose deaths has reached epidemic proportions. Repeated MA exposure induces a robust and persistent neuroinflammatory response, and the evidence supports the potential utility of targeting neuroimmune function using non-selective phosphodiesterase 4 (PDE4) inhibitors as a therapeutic strategy for attenuating addiction-related behavior. Off-target, emetic effects associated with non-selective PDE4 blockade led to the development of isozyme-selective inhibitors, of which the PDE4B-selective inhibitor A33 was demonstrated recently to reduce binge drinking in two genetically related C57BL/6 (B6) substrains (C57BL/6NJ (B6NJ) and C57BL/6J (B6J)) that differ in their innate neuroimmune response. Herein, we determined the efficacy of A33 for reducing MA self-administration and MA-seeking behavior in these two B6 substrains. Female and male mice of both substrains were first trained to nose poke for a 100 mg/L MA solution followed by a characterization of the dose–response function for oral MA reinforcement (20 mg/L–3.2 g/L), the demand-response function for 400 mg/L MA, and cue-elicited MA seeking following a period of forced abstinence. During this substrain comparison of MA self-administration, we also determined the dose–response function for A33 pretreatment (0–1 mg/kg) on the maintenance of MA self-administration and cue-elicited MA seeking. Relative to B6NJ mice, B6J mice earned fewer reinforcers, consumed less MA, and took longer to reach acquisition criterion with males of both substrains exhibiting some signs of lower MA reinforcement than their female counterparts during the acquisition phase of the study. A33 pretreatment reduced MA reinforcement at all doses tested. These findings provide the first evidence that pretreatment with a selective PDE4B inhibitor effectively reduces MA self-administration in both male and female mice of two genetically distinct substrains but does not impact cue-elicited MA seeking following abstinence. If relevant to humans, these results posit the potential clinical utility of A33 or other selective PDE4B inhibitors for curbing active drug-taking in MA use disorder.

Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva).

Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.5, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) of temsirolimus in the least shrew. Temsirolimus caused a bell-shaped and dose-dependent increase in both the mean vomit frequency and the number of shrews vomiting with maximal efficacy at 10 mg/kg (p < 0.05 and p < 0.02, respectively). Its larger doses (20 or 40 mg/kg) had no significant emetic effect. We also evaluated the emetic potential of its analogs (5, 10, and 20 mg/kg, i.p.), all of which exhibited a similar emetic profile. Our observational studies indicated that temsirolimus can reduce the shrew motor activity at 40 mg/kg, and subsequently, we examined the motor effects of its lower doses. At 10 and 20 mg/kg, it did not affect the spontaneous locomotor activity (distance moved) but attenuated the mean rearing frequency in a U-shaped manner at 10 mg/kg (p < 0.05). We then determined the broad-spectrum antiemetic potential of a 20 mg/kg (i.p.) dose of temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D2/3 receptors (apomorphine and quinpirole); 2) serotonergic 5-HT3 receptors [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M1 receptors (pilocarpine and McN-A-343); 4) substance P neurokinin NK1 receptors (GR73632); 5) the L-type calcium (Ca2+) channel (LTCC) (FPL64176); 6) the sarcoplasmic endoplasmic reticulum Ca2+ ATPase inhibitor, thapsigargin; 7) the CB1 receptor inverse agonist/antagonist, SR141716A; and 8) the chemotherapeutic cisplatin. Temsirolimus prevented vomiting evoked by the aforementioned emetogens with varying degrees. The mechanisms underlying the pro- and antiemetic effects of temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a c-fos induction in the AP and NTS, but not DMNX with the 10 mg/kg emetic dose of temsirolimus, whereas its larger antiemetic dose (20 mg/kg) had no significant effect. Our study is the first to provide preclinical evidence demonstrating the promising antiemetic potential of high doses of temsirolimus and possibly its analogs in least shrews.

Beyond the Psychoactive Effects of Ayahuasca: Cultural and Pharmacological Relevance of Its Emetic and Purging Properties

The herbal preparation ayahuasca has been an important part of ritual and healing practices, deployed to access invisible worlds in several indigenous groups in the Amazon basin and among mestizo populations of South America. The preparation is usually known to be composed of two main plants, Banisteriopsis caapi and Psychotria viridis, which produce both hallucinogenic and potent purging and emetic effects; currently, these are considered its major pharmacological activities. In recent decades, the psychoactive and visionary effect of ayahuasca has been highly sought after by the shamanic tourism community, which led to the popularization of ayahuasca use globally and to a cultural distancing from its traditional cosmological meanings, including that of purging and emesis. Further, the field of ethnobotany and ethnopharmacology has also produced relatively limited data linking the phytochemical diversity of ayahuasca with the different degrees of its purging and emetic versus psychoactive effects. Similarly, scientific interest has also principally addressed the psychological and mental health effects of ayahuasca, overlooking the cultural and pharmacological importance of the purging and emetic activity. The aim of this review is therefore to shed light on the understudied purging and emetic effect of ayahuasca herbal preparation. It firstly focuses on reviewing the cultural relevance of emesis and purging in the context of Amazonian traditions. Secondly, on the basis of the main known phytochemicals described in the ayahuasca formula, a comprehensive pharmacological evaluation of their emetic and purging properties is presented.

Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of 18a (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety.

Glucagon-like peptide-1 in diabetes care: Can glycaemic control be achieved without nausea and vomiting?

Introduced less than two decades ago, glucagon-like peptide-1 receptor agonists rapidly reshaped the field of Type 2 diabetes mellitus (T2DM) care by providing glycaemic control in tandem with weight loss. However, FDA-approved GLP-1 receptor agonists are often accompanied by nausea and emesis and, in some lean T2DM patients, by undesired anorexia. Importantly, the hypophagic and emetic effects of GLP-1 receptor agonists are caused by activation of central GLP-1 receptors. This review summarizes two different approaches to mitigate the incidence and severity of nausea and emesis related to GLP-1 receptor agonists: conjugation with vitamin B12 , or related corrin ring-containing compounds ('corrination'), and development of dual agonists of GLP-1 receptors with glucose-dependent insulinotropic polypeptide (GIP). Such approaches could lead to the generation of GLP-1 receptor agonists with improved therapeutic efficacy, thus decreasing treatment attrition, increasing patient compliance and extending treatment to a broader population of T2DM patients. The data reviewed show that it is possible to pharmacologically separate the emetic effects of GLP-1 receptor agonists from their glucoregulatory action. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

The Potential of Medicinal Plants and Bioactive Compounds in the Fight Against COVID-19

The Potential of Medicinal Plants and Bioactive Compounds in the Fight Against COVID-19

Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains.

Cyclic AMP (cAMP)-dependent signaling is highly implicated in the pathophysiology of alcohol use disorder (AUD), with evidence supporting the efficacy of inhibiting the cAMP hydrolyzing enzyme phosphodiesterase 4 (PDE4) as a therapeutic strategy for drinking reduction. Off-target emetic effects associated with non-selective PDE4 inhibitors has prompted the development of selective PDE4 isozyme inhibitors for treating neuropsychiatric conditions. Herein, we examined the effect of a selective PDE4B inhibitor A33 (0–1.0 mg/kg) on alcohol drinking in both female and male mice from two genetically distinct C57BL/6 substrains. Under two different binge-drinking procedures, A33 pretreatment reduced alcohol intake in male and female mice of both substrains. In both drinking studies, there was no evidence for carry-over effects the next day; however, we did observe some sign of tolerance to A33’s effect on alcohol intake upon repeated, intermittent, treatment (5 injections of 1.0 mg/kg, every other day). Pretreatment with 1.0 mg/kg of A33 augmented sucrose intake by C57BL/6NJ, but not C57BL/6J, mice. In mice with a prior history of A33 pretreatment during alcohol-drinking, A33 (1.0 mg/kg) did not alter spontaneous locomotor activity or basal motor coordination, nor did it alter alcohol’s effects on motor activity, coordination or sedation. In a distinct cohort of alcohol-naïve mice, acute pretreatment with 1.0 mg/kg of A33 did not alter motor performance on a rotarod and reduced sensitivity to the acute intoxicating effects of alcohol. These data provide the first evidence that selective PDE4B inhibition is an effective strategy for reducing excessive alcohol intake in murine models of binge drinking, with minimal off-target effects. Despite reducing sensitivity to acute alcohol intoxication, PDE4B inhibition reduces binge alcohol drinking, without influencing behavioral sensitivity to alcohol in alcohol-experienced mice. Furthermore, A33 is equally effective in males and females and exerts a quantitatively similar reduction in alcohol intake in mice with a genetic predisposition for high versus moderate alcohol preference. Such findings further support the safety and potential clinical utility of targeting PDE4 for treating AUD.

The trichothecene neosolaniol stimulates an emetic response through neuropeptide Y2 and serotonin 3 receptors in mink

Type A trichothecene neosolaniol (NEO) is considered a potential risk to human and animal health by the European Food Safety Authority (EFSA). To date, available data do not allow making conclusions about the toxicological properties of this toxin. Trichothecenes have been previously demonstrated to induce emetic responses in mink, and this response has been associated with neurotransmitter peptide YY (PYY) and serotonin (5-hydroxytryptamine, 5-HT). The goal of this study was to compare emetic effects of NEO administered by intraperitoneal and oral routes and relate these effects to PYY and 5-HT. The effective doses resulting in emetic events in 50% of the animals following intraperitoneal and oral exposure to NEO were 0.4 and 0.09 mg/kg bw, respectively. This emetic response corresponded to elevated PYY and 5-HT levels. Blocking the neuropeptide Y2 receptor diminished emesis induction by PYY and NEO. The 5-HT3 receptor inhibitor granisetron completely restrained the induction of emesis by 5-HT and NEO. To summarize, our findings demonstrate that PYY and 5-HT play important roles in the NEO-induced emetic response.

Sedation in obstetrics and gynecology

Background. Sedation is a controlled medical depression of consciousness with the preservation of protective reflexes, independent effective breathing and response to physical stimulation and verbal commands. Requirements for sedation include rapid onset of effect, short action, minimal impact on the cardiorespiratory system, lack of delirium and emetic effect. The goals of sedation include patient comfort, minimization of pain and discomfort, anxiolysis, amnesia, control of patient behavior, rapid recovery.&#x0D; Objective. To describe the features of sedation in obstetrics and gynecology.&#x0D; Materials and methods. Analysis of literature data on this topic; own research. The study included 64 women with gynecological diseases who underwent elective surgery under regional anesthesia. Longocaine and Longocaine Heavy (“Yuria-Pharm”) were used as local anesthetics. Sedation by dexmedetomidine ("Yuria-Pharm") was used in group 1, and by propofol in group 2.&#x0D; Results and discussion. Cesarean section is characterized by high levels of stress. The main requirements for sedation during caesarean section include the preservation of consciousness, self-breathing and protective reflexes of the respiratory tract, minimal impact on hemodynamics, short duration of action of drugs. Subjective methods (different scales, verbal contact with the patient, assessment of pupil dilation, pulse, respiratory rate, blood pressure) and objective methods (electroencephalography, BIS spectral index) are used to determine the degree of sedation. Mandatory monitoring during sedation includes non-invasive blood pressure measurement, pulse oximetry, electrocardiography, capnography, BIS monitoring. Capnography is the most effective type of monitoring. For the safety of procedure carefully trained personnel, the device for mechanical lung ventilation, a set for ensuring passability of respiratory tracts, a defibrillator, and drugs for emergency medical care are necessary. For procedural sedation, drugs such as propofol, barbiturates, benzodiazepines, dexmedetomidine, ketamine, and inhalation anesthetics are used. The advantages of benzodiazepines are rapid effect and amnestic action, the disadvantages include the promotion of delirium and respiratory depression, no analgesic effect. The last two effects are also typical for propofol, which also causes pain in the vein during administration and the propofol infusion syndrome. The advantages of propofol include rapid onset of effect and rapid awakening, ease of titration, amnestic and antiemetic action. Ketamine also provides a rapid onset of effect and rapid awakening, and has an analgesic effect, however, causes hallucinations and hypersalivation, increased motor activity. Dexmedetomidine is an analgesic, has a sedative effect and a minimal effect on respiratory status. Disadvantages of dexmedetomidine include slow onset of effect and dose-dependent decrease in blood pressure. A number of scientific studies indicate the absence of adverse effects of dexmedetomidine during cesarean section under regional anesthesia. According to our own study, sedation with dexmedetomidine caused hypotension 26.5 % less often than sedation with propofol. Targeted sedation with dexmedetomidine caused almost no respiratory depression, whereas sedation with propofol led to moderate hypoxemia in 21 % of patients and severe hypoxemia in 35.9 % of patients. Dexmedetomidine contributed to a more pronounced reduction in pain, which can be explained by its own analgesic effect.&#x0D; Conclusions. 1. The goals of sedation include patient comfort, minimization of pain and discomfort, anxiolysis, amnesia, control of patient behavior, rapid recovery. 2. The main requirements for sedation during caesarean section include the preservation of consciousness, independent breathing and protective reflexes of the respiratory tract, minimal impact on hemodynamics, short duration of action of drugs. 3. Capnography is the most effective type of monitoring during sedation. 4. Sedation with dexmedetomidine caused hypotension 26.5 % less often than sedation with propofol. 5. Targeted sedation with dexmedetomidine caused almost no respiratory depression. 6. Dexmedetomidine contributed to a more pronounced reduction in pain than propofol.

The Effect of Zikr Meditation on Post Operative Pain Among Women Post Cesarean Section

Pain is the most common adverse effects in the early postoperative period. Routine pharmacologic Methods may impair the recovery of patients for their sedative and emetic effects. Therefore, patients’ relaxation is necessary for a successful post-operative pain managements and it is among the interventions addressed to improve physiologic response. The aim of this study was to examine the effects of zikr meditation on post-operative pain among post cesarean section women. This is a quasy experimental research with control group pre-test post-test. A total of 30 muslim post cesarean section women were included in the study. Medical information form, Numeric Rating Scale, and Interument Guideline are used to collect the data. The results show that there is a significant difference of pain between experiment and control group (p= .012), there is a significant difference of pain before and after intervention in the experiment group (p= .00).