The association of nausea and vomiting of pregnancy, its treatments, and select birth defects: Findings from the National Birth Defect Prevention Study.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) occurs in approximately 70% of pregnant people. Treatments include pharmacologic and herbal/natural products. Research on the associations between NVP and its treatments and birth defects is limited. METHODS: We used data from the case-control National Birth Defects Prevention Study (1997-2011) to examine whether first-trimester NVP or its specific treatments were associated with 37 major birth defects. Odds ratios (aOR) and 95% confidence intervals (CIs) were adjusted for sociodemographic and reproductive factors. RESULTS: Mothers of 66.6% of 28,628 cases and 69.9% of 11,083 controls reported first-trimester NVP. Compared to no NVP, mothers with NVP had ≥10% reduction in risk of cardiac and noncardiac defects overall, and of 18 specific defects. Over-the-counter antiemetic use, compared to untreated NVP, was associated with ≥10% increase in risk for nine defect groups (heterotaxy, hypoplastic left heart syndrome [HLHS], aortic stenosis, cataracts, anophthalmos/microphthalmos, biliary atresia, transverse limb deficiency, omphalocele, and gastroschisis), whereas use of prescription antiemetics increased risk ≥10% for seven defect groups (tetralogy of Fallot, HLHS, spina bifida, anopthlamos/microphthalmos, cleft palate, craniosynostosis, and diaphragmatic hernia). We observed increased risks for promethazine and tetralogy of Fallot (aOR: 1.49, 95% CI: 1.05-2.10), promethazine and craniosynostosis (1.44, 1.08-1.92), ondansetron and cleft palate (1.66, 1.18-2.31), pyridoxine and heterotaxy (3.91, 1.49-10.27), and pyridoxine and cataracts (2.57, 1.12-5.88). CONCLUSIONS: NVP does not increase risks of birth defects. Our findings that some treatments for NVP increase risk of specific birth defects should be investigated further before clinical recommendations are made.

Chemotherapy-Associated nausea and vomiting: A cross-sectional survey of occurrence and management patterns at jos university teaching hospital, Nigeria.

Background: The management patterns for chemotherapy-associated nausea and vomiting (CANV) in Sub-Saharan African settings have not been previously reported. The objectives of this study were to describe the prescribing pattern of antiemetics for CANV, to assess their adherence to guidelines, and to determine the occurrence of CANV. Subjects and Methods: This was a cross-sectional study, with data extracted from the records of adult patients who received chemotherapy from 2015 to 2018 at Jos University Teaching Hospital, Nigeria. The National Comprehensive Cancer Network Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis Version 3.2018 was used to determine the extent of guideline adherence. Results: Records of 165 patients were analyzed. Majority of the patients (76.4%, n = 126) received moderate-to-high emetic risk intravenous (IV) chemotherapy. Out of 129 antiemetic prescriptions for acute-phase prophylaxis, ondansetron (75.2%), corticosteroids (61.2%), and promethazine (24.8%) were the most prescribed agents. In the delayed phase, 50 patients received prophylactic antiemetics in the order of corticosteroids, ondansetron, and promethazine at 74%, 34%, and 26%, respectively. Guideline adherence was low for the acute-phase (23.6%), delayed-phase (20.6%), and overall period (17.6%). Among inpatients (n = 85), occurrences of nausea were negligible, whereas acute vomiting (9%) and delayed vomiting (15%) levels were considerable. Not receiving highly emetogenic IV chemotherapy was associated with significantly lower odds for nausea or vomiting occurrence, odds ratio 0.228 (95% confidence interval 0.054-0.967). Conclusions: Antiemetic guideline adherence was low due to antiemetic under-prescribing. A few nausea and vomiting events were recorded predominantly among patients who received highly emetogenic IV chemotherapy.

RésuméContexte: Les schémas de prise en charge des nausées et vomissements associés à la chimiothérapie (CANV) en Afrique subsaharienne n'ont pas Été signalée précédemment. Les objectifs de cette étude étaient de décrire le schéma de prescription des antiémétiques pour le CANV, d'évaluer leur adhésion Aux lignes directrices et pour déterminer l'occurrence du CANV. Subjets et méthodes: Il s'agissait d'une étude transversale, avec des données extraites de Les dossiers des patients adultes ayant reçu une chimiothérapie de 2015 à 2018 à l'hôpital universitaire de Jos, au Nigéria. Le global national Cancer Network Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis Version 3.2018 a été utilisé pour déterminer l'étendue de la directive Adhérence. Résultats: Les dossiers de 165 patients ont été analysés. La majorité des patients (76,4 %, n = 126) ont présenté un risque émétique modéré à élevé Chimiothérapie intraveineuse (IV). Sur 129 prescriptions d'antiémétiques en prophylaxie de phase aiguë, ondansétron (75,2 %), corticoïdes (61,2 %), Et la prométhazine (24,8 %) étaient les agents les plus prescrits. Dans la phase retardée, 50 patients ont reçu des antiémétiques prophylactiques de l'ordre de Corticostéroïdes, ondansétron et prométhazine à 74 %, 34 % et 26 %, respectivement. Le respect des lignes directrices était faible pour la phase aiguë (23,6 %), Phase retardée (20,6 %) et période globale (17,6 %). Parmi les patients hospitalisés (n = 85), les occurrences de nausées étaient négligeables, alors que Les taux de vomissements (9 %) et de vomissements retardés (15 %) étaient considérables. Le fait de ne pas recevoir de chimiothérapie IV hautement émétisante était associé àProbabilités significativement plus faibles de survenue de nausées ou de vomissements, rapport de cotes 0,228 (intervalle de confiance à 95 % 0,054-0,967). Conclusions : Antiémétique Le respect des lignes directrices était faible en raison de la sous-prescription des antiémétiques. Quelques nausées et vomissements ont été enregistrés principalement chez les Patients ayant reçu une chimiothérapie IV hautement émétisante. Mots-clés: Antiémétique, chimiothérapie, nausées, Nigéria, vomissements.

Chlorpromazine and Promethazine (C+P) Reduce Brain Injury after Ischemic Stroke through the PKC-δ/NOX/MnSOD Pathway.

Cerebral ischemia-reperfusion (I/R) incites neurologic damage through a myriad of complex pathophysiological mechanisms, most notably, inflammation and oxidative stress. In I/R injury, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) produces reactive oxygen species (ROS), which promote inflammatory and apoptotic pathways, augmenting ROS production and promoting cell death. Inhibiting ischemia-induced oxidative stress would be beneficial for reducing neuroinflammation and promoting neuronal cell survival. Studies have demonstrated that chlorpromazine and promethazine (C+P) induce neuroprotection. This study investigated how C+P minimizes oxidative stress triggered by ischemic injury. Adult male Sprague-Dawley rats were subject to middle cerebral artery occlusion (MCAO) and subsequent reperfusion. 8 mg/kg of C+P was injected into the rats when reperfusion was initiated. Neurologic damage was evaluated using infarct volumes, neurological deficit scoring, and TUNEL assays. NOX enzymatic activity, ROS production, protein expression of NOX subunits, manganese superoxide dismutase (MnSOD), and phosphorylation of PKC-δ were assessed. Neural SHSY5Y cells underwent oxygen-glucose deprivation (OGD) and subsequent reoxygenation and C+P treatment. We also evaluated ROS levels and NOX protein subunit expression, MnSOD, and p-PKC-δ/PKC-δ. Additionally, we measured PKC-δ membrane translocation and the level of interaction between NOX subunit (p47phox) and PKC-δ via coimmunoprecipitation. As hypothesized, treatment with C+P therapy decreased levels of neurologic damage. ROS production, NOX subunit expression, NOX activity, and p-PKC-δ/PKC-δ were all significantly decreased in subjects treated with C+P. C+P decreased membrane translocation of PKC-δ and lowered the level of interaction between p47phox and PKC-δ. This study suggests that C+P induces neuroprotective effects in ischemic stroke through inhibiting oxidative stress. Our findings also indicate that PKC-δ, NOX, and MnSOD are vital regulators of oxidative processes, suggesting that C+P may serve as an antioxidant.

Psychopharmacology of agitation in acute psychotic and manic episodes.

PURPOSE OF REVIEW: To provide updated guidance for the medication treatment of acute agitation in the setting of psychosis or mania on inpatient psychiatric units. RECENT FINDINGS: This topic presented challenges: studies are sparse, tend to be under-powered, and are difficult to compare. Though there have been few recent studies, there have been several recent meta-analyses, Cochrane reviews, and published guidelines that sift through the primarily older evidence as well as more recent trials. The reviewers often do not agree on what seems to have the best evidence for efficacy and safety. SUMMARY: We conclude that the best approach is to summarize in some detail the evidence for each possible treatment and the interpretations published recently on each of those treatments, and then present recommendations for medication management in tiered rankings, based on the authors' qualitative review of the data and opinions. For oral treatment, the first-tier options are (alphabetically) haloperidol with lorazepam, lorazepam alone, and olanzapine. The second tier includes haloperidol with promethazine, loxapine inhaler, and risperidone alone. Tier 3 includes asenapine and quetiapine. For intramuscular treatment, the first-tier includes haloperidol plus promethazine, and olanzapine alone, and the second-tier includes haloperidol with lorazepam, and lorazepam alone.

Rapid tranquillisation in a psychiatric emergency hospital in Lebanon: TREC-Lebanon - a pragmatic randomised controlled trial of intramuscular haloperidol and promethazine v. intramuscular haloperidol, promethazine and chlorpromazine.

BACKGROUND: Agitated patients constitute 10% of all emergency psychiatric treatment. Management guidelines, the preferred treatment of clinicians differ in opinion and practice. In Lebanon, the use of the triple therapy haloperidol plus promethazine plus chlorpromazine (HPC) is frequently used but no studies involving this combination exists. METHOD: A pragmatic randomised open trial (September 2018-July 2019) in the Lebanese Psychiatric Hospital of the Cross in Beirut Lebanon involving 100 people requiring urgent intramuscular sedation due to aggressive behaviour were given intramuscular chlorpromazine 100 mg plus haloperidol 5 mg plus promethazine 25 mg (HPC) or intramuscular haloperidol 5 mg plus promethazine 25 mg. RESULTS: Primary outcome data were available for 94 (94%) people. People allocated to the haloperidol plus promethazine (HP) group showed no clear difference at 20 min compared with patients allocated to the HPC group [relative risk (RR) 0.84, 95% confidence interval (CI) 0.47-1.50]. CONCLUSIONS: Neither intervention consistently impacted the outcome of 'calm', or 'asleep' and had no discernible effect on the use of restraints, use of additional drugs or recurrence. If clinicians are faced with uncertainty on which of the two intervention combinations to use, the simpler HP is much more widely tested and the addition of chlorpromazine adds no clear benefit with a risk of additional adverse effects.

An inhibitory and beneficial effect of chlorpromazine and promethazine (C + P) on hyperglycolysis through HIF-1α regulation in ischemic stroke.

BACKGROUND: After ischemic stroke, the increased catabolism of glucose (hyperglycolysis) results in the production of reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). A depressive or hibernation-like effect of C + P on brain activity was reported to induce neuroprotection. The current study assesses the effect of C + P on hyperglycolysis and NOX activation. METHODS: Adult male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion. At the onset of reperfusion, rats received C + P with or without temperature control, or phloretin [glucose transporter (GLUT)-1 inhibitor], or cytochalasin B (GLUT-3 inhibitor). We detected brain ROS, apoptotic cell death, and ATP levels along with HIF-1α expression. Cerebral hyperglycolysis was measured by glucose, protein expression of GLUT-1/3, and phosphofructokinase-1 (PFK-1), as well as lactate and lactate dehydrogenase (LDH) at 6 and 24 h of reperfusion. The enzymatic activity of NOX and protein expression of its subunits (gp91phox) were detected. Neural SHSY5Y cells were placed under 2 h of oxygen-glucose deprivation (OGD) followed by reoxygenation for 6 and 24 h with C + P treatment. Cell viability and protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured. A HIF-1α overexpression vector was transfected into the cells, and then protein levels of HIF-1α, GLUT-1/3, PFK-1, and LDH were quantitated. In sham-operated rats and control cells, the protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured at 6 and 24 h after C + P administration. RESULTS: C + P reduced the protein elevations after stroke in HIF-1α, glycolytic enzymes, as well as in ROS, cell death, glucose and lactate, but raised ATP levels in the brain. In ischemic rats exposed to GLUT-1/3 inhibitors, ROS, cell death, glucose, and lactate were all decreased, as well as GLUT-1, GLUT-3, LDH, and PFK-1 protein levels. C + P decreased ischemia-induced NOX activation by reducing the enzymatic activity and protein expression of the NOX subunit gp91phox, as was observed in the presence of GLUT-1/3 inhibitors. These markers were significantly decreased following C + P administration with the induced hypothermia, while C + P administration with temperature control at 37 °C induced lesser protection after ischemia stroke. In the OGD/reoxygenation model, C + P treatment increased cell viability and diminished protein levels of HIF-1α, GLUT-1, GLUT-3, PFK-1, LDH, and gp91phox. However, in OGD with HIF-1α overexpression, C + P was unable to effectively reduce the upregulated GLUT-1, GLUT-3, and LDH. In normal conditions, C + P reduced HIF-1α and the levels of key glycolytic enzymes depending on its pharmacological effect. CONCLUSION: C + P, partially depending on hypothermia, attenuates hyperglycolysis and NOX activation through HIF-1α regulation.

Paracervical blocks facilitate timely brachytherapy amidst COVID-19.

PURPOSE: The COVID-19 pandemic presents serious challenges for brachytherapists, and in the time-sensitive case of locally advanced cervical cancer, the need for curative brachytherapy (BT) is critical for survival. Given the high-volume of locally advanced cervical cancer in our safety-net hospital, we developed a strategy in close collaboration with our gynecology oncology and anesthesia colleagues to allow for completely clinic-based intracavitary brachytherapy (ICBT). METHODS AND MATERIALS: This technical report will highlight our experience with the use of paracervical blocks (PCBs) and oral multimodal analgesia (MMA) for appropriately selected cervical ICBT cases, allowing for completely clinic-based treatment. RESULTS: 18 of 19 (95%) screened patients were eligible for in-clinic ICBT. The excluded patient had significant vaginal fibrosis. 38 of 39 intracavitary implants were successfully transitioned for entirely in-clinic treatment utilizing PCBs and oral MMA (97% success rate). One case was aborted due to inadequate analgesia secondary to a significantly delayed case start time (PO medication effect diminished). 95% of patients reported no pain at the conclusion of the procedure. The median (IQR) D2cc for rectum and bladder were 64.8 (58.6-70.2) Gy and 84.1 (70.9-89.4) Gy, respectively. Median (IQR) CTV high-risk D90 was 88.0 (85.6-89.8) Gy. CONCLUSIONS: In a multidisciplinary effort, we have successfully transitioned many ICBT cases to the clinic with the use of PCB local anesthesia and oral multimodality therapy in direct response to the current pandemic, thereby mitigating exposure risk to patients and staff as well as reducing overall health care burden.

Preliminary experience with promethazine hydrochloride injection in the sclerotherapy of oral mucocele.

Mucoceles are common in the minor salivary and sublingual glands. Sclerotherapy is a possible treatment strategy for mucoceles. The purpose of this study was to evaluate the clinical outcomes of sclerotherapy with promethazine hydrochloride injection in treating mucoceles. Thirty-seven patients were enrolled. Sclerotherapy was performed with promethazine hydrochloride injection (25mg/ml) through the mucosa. Patients were followed up at 1, 3, and 6 months after the last sclerotherapy. Clinical data were reviewed. The lesions (range 2-30mm in diameter) occurred on the ventral tongue tip (20 patients), lower lip (11 patients), and floor of the mouth (six patients). The amount of sclerosant per injection ranged from 0.2ml to 1ml. At the 6-month follow-up, 33 patients showed resolution with no recurrence. One patient showed a significant response with a 5-mm-diameter nodule remaining after two sclerotherapies. Three patients who underwent two or more sclerotherapies failed to show an improvement. The overall cure rate was 91.9% (96.8% for mucoceles of the minor salivary gland, 66.7% for ranulas). Complications were rare and mild. Sclerotherapy with promethazine hydrochloride injection for the treatment of mucoceles is safe. It is effective for mucoceles of the minor salivary glands, but its application for ranulas requires further investigation.

Marijuana, Ondansetron, and Promethazine Are Perceived as Most Effective Treatments for Gastrointestinal Nausea.

BACKGROUND: Many anti-nausea treatments are available for chronic gastrointestinal syndromes, but data on efficacy and comparative effectiveness are sparse. AIMS: To conduct a sectional survey study of patients with chronic nausea to assess comparative effectiveness of commonly used anti-nausea treatments. METHODS: Outpatients at a single center presenting for gastroenterology evaluation were asked to rate anti-nausea efficacy on a scale of 0 (no efficacy) to 5 (very effective) of 29 commonly used anti-nausea treatments and provide other information about their symptoms. Additional information was collected from the patients' chart. The primary outcome was to determine which treatments were better or worse than average using a t test. The secondary outcome was to assess differential response by individual patient characteristics using multiple linear regression. RESULTS: One hundred and fifty-three patients completed the survey. The mean efficacy score of all anti-nausea treatments evaluated was 1.73. After adjustment, three treatments had scores statically higher than the mean, including marijuana (2.75, p < 0.0001), ondansetron (2.64, p < 0.0001), and promethazine (2.46, p < 0.0001). Several treatments, including many neuromodulators, complementary and alternative treatments, erythromycin, and diphenhydramine had scores statistically below average. Patients with more severe nausea responded better to marijuana (p = 0.036) and diphenhydramine (p < 0.001) and less so to metoclopramide (p = 0.020). There was otherwise no significant differential response by age, gender, nausea localization, underlying gastrointestinal cause of nausea, and GCSI. CONCLUSIONS: When treating nausea in patients with chronic gastrointestinal syndromes, clinicians may consider trying higher performing treatments first, and forgoing lower performing treatments. Further prospective research is needed, particularly with respect to highly effective treatments.

Antifungal activity of promethazine and chlorpromazine against planktonic cells and biofilms of Cryptococcus neoformans/Cryptococcus gattii complex species.

Cryptococcus neoformans/Cryptococcus gattii are fungal pathogens that affect the central nervous system, mainly in immunocompromised individuals. Due to the limited pharmacological arsenal available for the treatment of cryptococcosis associated with cases of antifungal resistance of Cryptococcus spp. reported in some studies, the search for new compounds with antifungal potential becomes relevant. Thus, the objective of this study was to evaluate the inhibitory effect of phenothiazines (promethazine and chlorpromazine) on C. neoformans/C. gattii planktonic cells and biofilms. In vitro planktonic susceptibility testing was performed using the broth microdilution assay. The effect of phenothiazines was evaluated against biofilm formation and mature Cryptococcus biofilms. Biofilm morphology and ultrastructure were also evaluated by scanning electron microscopy. Promethazine and chlorpromazine showed antifungal activity against planktonic cells, with minimum inhibitory concentrations of 8-32 µg/ml and 4-16 µg/ml, respectively. As for biofilm formation, phenothiazines reduced biomass by 60% and metabolic activity by 90% at 64 µg/ml; while in mature biofilms, reductions of 85% and 90% in biomass and metabolic activity, respectively, were observed at 1024 µg/ml. Promethazine and chlorpromazine were also able to disrupt and fragment biofilms. In conclusion, promethazine and chlorpromazine have antifungal activity against planktonic cells and biofilms of Cryptococcus spp. These data show the potential of promethazine and chlorpromazine as antibiofilm drugs.

Rapid transition from methadone to buprenorphine using naltrexone-induced withdrawal: A case report.

Background: Patients taking methadone for opioid use disorder may desire transition to buprenorphine for a number of reasons. However, the current recommended approach for this transition generally takes weeks to months as an outpatient, causing considerable discomfort to the patient and a heightened risk of relapse during the transition period. Case: We describe the case of a patient on methadone maintenance who was rapidly transitioned to buprenorphine because of her desire to not return to her methadone clinic. In order to rapidly transition the patient from methadone to buprenorphine, naltrexone was administered to precipitate acute opioid withdrawal, which was followed soon after by buprenorphine induction. Discussion: Rapid transition from methadone maintenance to buprenorphine can be accomplished in inpatients by precipitating acute withdrawal with naltrexone, providing an effective alternative for patients who cannot tolerate the typical protracted methadone taper required prior to buprenorphine induction as an outpatient.

The pharmacological management of agitated and aggressive behaviour: A systematic review and meta-analysis.

INTRODUCTION: Non-pharmacological interventions preferably precede pharmacological interventions in acute agitation. Reviews of pharmacological interventions remain descriptive or compare only one compound with several other compounds. The goal of this study is to compute a systematic review and meta-analysis of the effect on restoring calmness after a pharmacological intervention, so a more precise recommendation is possible. METHOD: A search in Pubmed and Embase was done to isolate RCT's considering pharmacological interventions in acute agitation. The outcome is reaching calmness within maximum of 2 h, assessed by the psychometric scales of PANSS-EC, CGI or ACES. Also the percentages of adverse effects was assessed. RESULTS: Fifty-three papers were included for a systematic review and meta-analysis. Most frequent studied drug is olanzapine. Changes on PANNS-EC and ACES at 2 h showed the strongest changes for haloperidol plus promethazine, risperidon, olanzapine, droperidol and aripiprazole. However, incomplete data showed that the effect of risperidon is overestimated. Adverse effects are most prominent for haloperidol and haloperidol plus lorazepam. CONCLUSION: Olanzapine, haloperidol plus promethazine or droperidol are most effective and safe for use as rapid tranquilisation. Midazolam sedates most quickly. But due to increased saturation problems, midazolam is restricted to use within an emergency department of a general hospital.

Prevention of Opioid-Induced Nausea and Vomiting During Treatment of Moderate to Severe Acute Pain: A Randomized Placebo-Controlled Trial Comparing CL-108 (Hydrocodone 7.5 mg/Acetaminophen 325 mg/Rapid-Release, Low-Dose Promethazine 12.5 mg) with Conventional Hydrocodone 7.5 mg/Acetaminophen 325 mg.

OBJECTIVES: To evaluate the prevention of opioid-induced nausea and vomiting (OINV) and the relief of moderate to severe acute pain by CL-108, a novel drug combining a low-dose antiemetic (rapid-release promethazine 12.5 mg) with hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) was used. METHODS: This was a multicenter, randomized, double-blind, placebo- and active-controlled multidose study. After surgical extraction of two or more impacted third molar teeth (including at least one mandibular impaction), 466 patients with moderate to severe pain (measured on a categorical pain intensity scale [PI-CAT]) were randomized to CL-108, HC/APAP, or placebo. Over the next 24 hours, patients used the PI-CAT to assess pain at regular intervals whereas nausea, vomiting, and other opioid-related side effects were also assessed prospectively. Study medications were taken every four to six hours as needed; supplemental rescue analgesic and antiemetic medications were permitted. Co-primary end points were the incidence of OINV and the time-weighted sum of pain intensity differences over 24 hours (SPID24). RESULTS: Relative to HC/APAP treatment alone, CL-108 treatment reduced OINV by 64% (P < 0.001). Treatment with CL-108 significantly reduced pain intensity compared with placebo (SPID24 = 16.2 vs 3.5, P < 0.001). There were no unexpected or serious adverse events. CONCLUSIONS: CL-108 is a safe and effective combination analgesic/antiemetic for the prevention of OINV during treatment of moderate to severe acute pain.