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BMJ (Clinical Research Ed.) Feb 2022
PubMed: 35144927
DOI: 10.1136/bmj.o359 -
Neuroepidemiology 2022Migraine headache is commonly diagnosed in emergency departments (ED). There is relatively little real-world information about the epidemiology, investigation,...
BACKGROUND AND AIM
Migraine headache is commonly diagnosed in emergency departments (ED). There is relatively little real-world information about the epidemiology, investigation, management, adherence to therapeutic guidelines and disposition of patients treated in ED with a final diagnosis of migraine. The primary aim of the current study is to get a snapshot of assessment and management patterns of acute migraine presentations to the different settings of EDs with a view to raise awareness.
METHODS
This is a planned sub-study of a prospective study conducted in 67 health services in 10 countries including Australia, New Zealand, Southeast Asia, Europe, and the UK investigating the epidemiology and outcome of adult patients presenting to ED with nontraumatic headache. Outcomes of interest for this study are demographics, clinical features (including severity), patterns of investigation, treatment, disposition, and outcome of patients diagnosed as having migraine as their final ED diagnosis.
RESULTS
The cohort comprises 1,101 patients with a mean age of 39 years (SD ± 13.5; 73.7% [811]) were female. Most patients had had migraine diagnosed previously (77.7%). Neuroimaging was performed in 25.9% with a very low diagnostic yield or significant findings (0.07%). Treatment of mild migraine was in accordance with current guidelines, but few patients with moderate or severe symptoms received recommended treatment. Paracetamol (46.3%) and nonsteroidal anti-inflammatory drugs (42.7%) were the most commonly prescribed agents. Metoclopramide (22.8%), ondansetron (19.2%), chlorpromazine (12.8%), and prochlorperazine (12.8%) were also used.
CONCLUSIONS
This study suggests that therapeutic practices are not congruent with current guidelines, especially for patients with severe symptoms. Efforts to improve and sustain compliance with existing management best practices are required.
Topics: Adult; Emergency Service, Hospital; Female; Humans; Metoclopramide; Migraine Disorders; Prochlorperazine; Prospective Studies
PubMed: 35021181
DOI: 10.1159/000520548 -
Journal of Intensive Care Medicine Oct 2022Ondansetron is a preferred anti-emetic in critical care to treat nausea and vomiting, and has historically been considered a largely safe option. A recent...
Ondansetron is a preferred anti-emetic in critical care to treat nausea and vomiting, and has historically been considered a largely safe option. A recent pharmacoepidemiology study reported that ondansetron may be associated with an increased risk for acute kidney injury (AKI). We interrogated the High-Density Intensive Care (HiDenIC-15) database containing intensive care data for 13 hospitals across Western Pennsylvania between Oct 2008-Dec 2014. AKI was defined using the Kidney Disease, Improving Global Outcomes 2012 guidelines. Ondansetron use was considered as receiving any form of ondansetron within 24 h of admission. The subsequent 48 h (hours 25-72 after admission) were analyzed for outcomes. Primary outcome was development of AKI; secondary outcomes included 90-day mortality and time to AKI. Propensity-matched, multivariate logistic regression was applied for both outcomes. Comparator groups were metoclopramide and prochlorperazine using the same exposure criteria. AKI occurred in 965 (5.6%), 12 (3.0%), and 61 (6.5%) patients receiving ondansetron, prochlorperazine, and metoclopramide, respectively. In the adjusted analysis, no anti-emetic was associated with a significant change in the odds of developing AKI. Ondansetron was associated with a 5.48% decrease (CI -6.17--4.79) in death within 90 days of ICU-admission, which was independent of AKI status; an effect not seen with other anti-emetics. Anti-emetic usage was not associated with a change in the time to first AKI. Anti-emetic usage did not alter AKI risk. Ondansetron was associated with a significant decrease in 90-day mortality that was not seen by other anti-emetics, which requires further exploration.
Topics: Acute Kidney Injury; Antiemetics; Critical Illness; Humans; Intensive Care Units; Kidney; Metoclopramide; Ondansetron; Prochlorperazine
PubMed: 35000482
DOI: 10.1177/08850666211073582 -
Life (Basel, Switzerland) Oct 2021A gradual increase in rat soleus muscle electromyographic (EMG) activity is known to occur after 3-4 days of hindlimb suspension/unloading (HS). The physiological...
A gradual increase in rat soleus muscle electromyographic (EMG) activity is known to occur after 3-4 days of hindlimb suspension/unloading (HS). The physiological significance and mechanisms of such activity of motoneurons under unloading conditions are currently unclear. Since hyperactivity of motoneurons and muscle spasticity after spinal cord injury are associated with KCC2 downregulation, we hypothesized that a decrease in potassium (K)/chloride (Cl) co-transporter 2 (KCC2) in motoneurons would be responsible for an increase in soleus muscle EMG activity during HS. We aimed to investigate the effect of prochlorperazine (KCC2 activator) on the electrical activity of rat soleus muscle under HS. Wistar rats were divided into the following groups: (1) vivarium control (C), (2) 7-day HS group (7HS) and (3) 7-day HS group plus intraperitoneal injections of prochlorperazine (10 mg/kg, daily) (7HS + P). Expression of proteins in the motoneurons of the lumbar spinal cord was determined by Western blotting. An electromyogram of the rat soleus muscle was recorded using intramuscular electrodes. KCC2 content after 7-day HS significantly decreased by 34% relative to the control group. HS-induced decrease in KCC2 protein content was prevented by prochlorperazine administration. HS also induced a significant 80% decrease in KCC2 Ser940 phosphorylation; however prochlorperazine did not affect KCC2 phosphorylation. The treatment of the rats with prochlorperazine prevented a HS-induced increase in Na(+)/K(+)/(Cl-) co-transporter 1 (KCC2 antagonist) protein content. In parallel with the restoration of KCC2 content, prochlorperazine administration during HS partially prevented an increase in the soleus muscle tonic EMG activity. Thus, prochlorperazine administration during 7-day HS prevents a decrease in KCC2 protein expression in motoneurons and significantly reduces the level of HS-induced soleus muscle electrical activity.
PubMed: 34833037
DOI: 10.3390/life11111161 -
Headache Nov 2021Millions of patients present to US emergency departments (ED) annually for the treatment of migraine. First-line treatments, including metoclopramide, prochlorperazine,... (Review)
Review
OBJECTIVE
Millions of patients present to US emergency departments (ED) annually for the treatment of migraine. First-line treatments, including metoclopramide, prochlorperazine, and sumatriptan, fail to provide sufficient relief in up to one-third of treated patients. In this narrative review, we discuss the evidence supporting the use of injectable (intravenous, intramuscular, or subcutaneous) medications for patients in the ED who fail to improve sufficiently after treatment with first-line medication.
METHODS
We used the American Headache Society's guideline, "Management of Adults with Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies," published in 2016, to identify first-line medications for migraine. We then conducted a PubMed search to determine whether any evidence supported the use of these medications as second-line therapy and whether any evidence existed to support the use of injectable therapies not discussed in the guideline as second-line therapy.
RESULTS
We identified only scant high-quality randomized data of second-line therapy. Therefore, we based our recommendations on medications that have reliably demonstrated efficacy as first-line treatment of migraine. These medications include injectable non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. Dihydroergotamine and valproic acid have some data supporting efficacy. More recently, greater occipital nerve blocks (GONBs) have been shown to be efficacious. With the exception of meperidine, opioids have been shown to be not efficacious. Most data published to date demonstrate no role for propofol and ketamine.
CONCLUSIONS
There are no evidence-based second-line treatments of migraine in the ED setting. For patients with migraine, who fail to improve after treatment with a first-line medication, it is reasonable to use an intravenous NSAID or intravenous acetaminophen. Alternatively, clinicians adept at performing a GONB may offer this treatment.
Topics: Acetaminophen; Administration, Intravenous; Anti-Inflammatory Agents, Non-Steroidal; Emergency Service, Hospital; Humans; Metoclopramide; Migraine Disorders
PubMed: 34806767
DOI: 10.1111/head.14239 -
Archives of Biochemistry and Biophysics Jan 2022The identification of biomolecules associated with papillary thyroid cancer (PTC) has upmost importance for the elucidation of the disease mechanism and the development... (Meta-Analysis)
Meta-Analysis
The identification of biomolecules associated with papillary thyroid cancer (PTC) has upmost importance for the elucidation of the disease mechanism and the development of effective diagnostic and treatment strategies. Despite particular findings in this regard, a holistic analysis encompassing molecular data from different biological levels has been lacking. In the present study, a meta-analysis of four transcriptome datasets was performed to identify gene expression signatures in PTC, and reporter molecules were determined by mapping gene expression data onto three major cellular networks, i.e., transcriptional regulatory, protein-protein interaction, and metabolic networks. We identified 282 common genes that were differentially expressed in all PTC datasets. In addition, six proteins (FYN, JUN, LYN, PML, SIN3A, and RARA), two Erb-B2 receptors (ERBB2 and ERBB4), two cyclin-dependent receptors (CDK1 and CDK2), and three histone deacetylase receptors (HDAC1, HDAC2, and HDAC3) came into prominence as proteomic signatures in addition to several metabolites including lactaldehyde and proline at the metabolome level. Significant associations with calcium and MAPK signaling pathways and transcriptional and post-transcriptional activities of 12 TFs and 110 miRNAs were also observed at the regulatory level. Among them, six miRNAs (miR-30b-3p, miR-15b-5p, let-7a-5p, miR-130b-3p, miR-424-5p, and miR-193b-3p) were associated with PTC for the first time in the literature, and the expression levels of miR-30b-3p, miR-15b-5p, and let-7a-5p were found to be predictive of disease prognosis. Drug repositioning and molecular docking simulations revealed that 5 drugs (prochlorperazine, meclizine, rottlerin, cephaeline, and tretinoin) may be useful in the treatment of PTC. Consequently, we report here biomolecule candidates that may be considered as prognostic biomarkers or potential therapeutic targets for further experimental and clinical trials for PTC.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Drug Repositioning; Gene Expression; Gene Expression Profiling; Humans; MicroRNAs; Molecular Docking Simulation; Protein Binding; Proteomics; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transcriptome
PubMed: 34800440
DOI: 10.1016/j.abb.2021.109085 -
Frontiers in Pharmacology 2021Understanding the prescription pattern of medications in a population can help reveal the potential usage scenarios, including off-label prescriptions, and the need for...
Understanding the prescription pattern of medications in a population can help reveal the potential usage scenarios, including off-label prescriptions, and the need for precision medicine implementation. Therefore, the aim of this study was to assess the prescription pattern and off-label use of antipsychotics in the Qatari population. We performed a cross-sectional study of Qatari patients who received antipsychotic prescriptions from the major healthcare providers in the country during the 2-year period between June 2018 and May 2020. The number of patients, prescriptions dispensed, and clinical indications were collected and statistical analysis using chi-square test was conducted. Among the 9,349 Qatari patients prescribed with antipsychotics during the study period, the majority were female (57%; < 0.001) and were in the age categories 20-39 and 30-39 years (both 22%; < 0.001). Among the 35,938 antipsychotic prescriptions dispensed, second-generation antipsychotics were the most highly prescribed (59%), specifically, quetiapine (16%) and olanzapine (12%), but the first-generation antipsychotic prochlorperazine (13%) was also highly prescribed. Most of the indications of antipsychotics (69%) were for off-label use such as for controlling chronic diseases, sleeping disorders, benign paroxysmal positional vertigo and irritable bowel syndrome. Non-mental health and off-label prescriptions of several antipsychotics were observed. Integration of this data with pharmacogenomic and clinical outcome data will help in determining the course of action for implementing personalized and precision medicine in the country and beyond.
PubMed: 34790126
DOI: 10.3389/fphar.2021.753845 -
Free Radical Biology & Medicine Dec 2021Lung cancer is considered as leading cancer with the highest mortality. The KRAS-oncogenic mutations are dominant in lung carcinoma leading to poor prognosis and...
Lung cancer is considered as leading cancer with the highest mortality. The KRAS-oncogenic mutations are dominant in lung carcinoma leading to poor prognosis and radioresistance, which is a major impediment to radiotherapy. Thus, KRAS mutant inhibitors that synergistically sensitize tumours to radiation are urgently needed. In pursuance of the search for a novel radiosensitizer, high-throughput screening of FDA-approved drugs was performed at active site of K-Ras. Prochlorperazine (PCZ), an antipsychotic drug, showed good binding affinity with KRAS-mutant proteins. PCZ binds to the GTP-binding pocket of KRAS-mutant protein and inhibits its constitutive activation by stabilizing the GDP-bound conformation of K-Ras mutants by 9 kcal/mol compared to WT. PCZ alongwith radiation decreased the clonogenic survival of KRAS-mutant NSCLC but not KRAS-WT cells. The combination treatment activates p-ATM, p53, and p21 proteins, leading to cell cycle arrest. PCZ with increasing radiation caused a linear increase in γH2AX foci, suggesting enhanced DSBs-associated apoptosis in radioresistant A549 cells. Pharmacokinetics study showed C = 526 ng/ml at 30min, 4.6h half-life in plasma, and highest accumulation in tumours. PCZ and 10Gy irradiation synergistically radiosensitize mice xenografts via downregulation of Ras/Raf/MEK/ERK pathway. Our efforts have led to the discovery of PCZ as a lead compound. In preclinical analyses, treatment with PCZ alone and in combination with radiation led to regression of KRASG12S tumours.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Lung Neoplasms; Mice; Mutation; Prochlorperazine; Proto-Oncogene Proteins p21(ras); Radiation Tolerance
PubMed: 34742922
DOI: 10.1016/j.freeradbiomed.2021.11.001 -
Journal of Dental Anesthesia and Pain... Oct 2021Migraine headaches are the second leading cause of disability worldwide and are responsible for significant morbidity, reduction in the quality of life, and loss of... (Review)
Review
BACKGROUND
Migraine headaches are the second leading cause of disability worldwide and are responsible for significant morbidity, reduction in the quality of life, and loss of productivity on a global scale. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ketamine on migraines and other primary headache disorders compared to placebo and other active interventions, such as midazolam, metoclopramide/diphenhydramine, and prochlorperazine/diphenhydramine.
METHODS
An electronic search of databases published up to February 2021, including Medline via PubMed, EMBASE, Web of Science, and Cochrane Library, a hand search of the bibliographies of the included studies, as well as literature and systematic reviews found through the search was conducted to identify randomized controlled trials (RCTs) investigating ketamine in the treatment of migraine/headache disorders compared to the placebo. The authors assessed the risk of bias according to the Cochrane Handbook guidelines.
RESULTS
The initial search strategy yielded 398 unduplicated references, which were independently assessed by three review authors. After evaluation, this number was reduced to five RCTs (two unclear risk of bias and three high risk of bias). The total number of patients in all the studies was 193. Due to the high risk of bias, small sample size, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups, the quality of the evidence was very low. One RCT reported that intranasal ketamine was superior to intranasal midazolam in improving the aura attack severity, but not duration, while another reported that intranasal ketamine was not superior to metoclopramide and diphenhydramine in reducing the headache severity. In one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, intravenous (I.V.) ketamine was inferior to I.V. prochlorperazine and diphenhydramine in another study.
CONCLUSION
Further double-blind controlled studies are needed to assess the efficacy of ketamine in treating acute and chronic refractory migraines and other primary headaches using intranasal and subcutaneous routes. These studies should include a long-term follow-up and different ketamine dosages in diagnosed patients following international standards for diagnosing headache/migraine.
PubMed: 34703891
DOI: 10.17245/jdapm.2021.21.5.413 -
Journal of Pharmacy Practice Jun 2023Contraction alkalosis is characterized by low serum sodium and chloride and high serum carbon dioxide and bicarbonate levels. A 28-year-old Caucasian active-duty male...
Contraction alkalosis is characterized by low serum sodium and chloride and high serum carbon dioxide and bicarbonate levels. A 28-year-old Caucasian active-duty male with a history of autosomal dominant polycystic kidney disease and diarrhea-predominant Irritable Bowel Syndrome (D-IBS) presented to his primary care provider (PCP) with elevated blood pressure (136/96 mmHg), was diagnosed with stage-2 hypertension, and started oral HCTZ (25 mg/day). His medications included dicyclomine (10 mg oral three times daily). Subsequently, (Visit 1), his blood pressure was 130/91 mmHg and he was started on telmisartan (20 mg/day). At Visit 2, 4 weeks later, his blood pressure improved (121/73 mmHg); however, blood chemistry revealed elevated serum CO2 (32 mEq/L) and chloride (94 mmol/L). Four days later, the patient presented to the Emergency Department with dyspnea and swallowing difficulty. The patient returned to his PCP 3 days later complaining of cough, congestion, vomiting, and mild dyspnea, blood pressure of 124/84 mmHg. Two months later, sudden onset of projectile vomiting and abdominal pain while running was reported, resolved by rehydration and a single oral dose of prochlorperazine 25 mg. Three months later, (Visit 3), he complained of lightheadedness and cloudy judgment, suggesting contraction alkalosis. HCTZ was discontinued and telmisartan was increased to 20 mg twice daily. A follow-up blood chemistry panel 2 weeks later revealed serum chloride and CO2 levels within normal limits and blood pressure under 130/80 mmHg. This is the first known report of contraction alkalosis driven by drug-drug interaction between dicyclomine and HCTZ.
Topics: Humans; Male; Adult; Telmisartan; Hydrochlorothiazide; Dicyclomine; Chlorides; Carbon Dioxide; Hypertension; Blood Pressure; Alkalosis; Antihypertensive Agents; Drug Therapy, Combination
PubMed: 34670427
DOI: 10.1177/08971900211052829