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JAMA Internal Medicine Jun 2024Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size...
IMPORTANCE
Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure.
OBJECTIVE
To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports.
DESIGN, SETTING, AND PARTICIPANTS
This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023.
EXPOSURES
Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity.
MAIN OUTCOMES AND MEASURES
Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports.
RESULTS
The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports.
CONCLUSIONS AND RELEVANCE
In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.
PubMed: 38913369
DOI: 10.1001/jamainternmed.2024.1836 -
Expert Opinion on Drug Metabolism &... Jun 2024Dopamine (D)-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). (Review)
Review
INTRODUCTION
Dopamine (D)-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV).
AREAS COVERED
Eight D-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects.
EXPERT OPINION
Since the introduction of D-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)-RAs and neurokinin (NK)-RAs have been developed. The classical D-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT-RA, dexamethasone and a NK-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.Side effects differ among various D-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.
Topics: Humans; Nausea; Vomiting; Antiemetics; Antineoplastic Agents; Dopamine Antagonists; Animals; Dopamine D2 Receptor Antagonists; Receptors, Dopamine D3
PubMed: 38878283
DOI: 10.1080/17425255.2024.2367593 -
European Journal of Hospital Pharmacy :... Jun 2024Prochlorperazine is a commonly used medicine to treat nausea and vomiting. The only liquid formulation in the UK was discontinued in November 2022 due to safety...
Prochlorperazine is a commonly used medicine to treat nausea and vomiting. The only liquid formulation in the UK was discontinued in November 2022 due to safety concerns. One alternative option available is to use crushed tablets instead. Crushing and mixing tablets in water to produce a liquid is a widespread practice in paediatrics. However, there is often little evidence to support this practice.In this case report, a patient established on liquid prochlorperazine mesilate who was switched to crushed prochlorperazine maleate tablets experienced significant harm. The child's vomiting became uncontrolled and led to multiple healthcare attendances and a prolonged hospital admission. Control was re-established by increasing the prochlorperazine dose to accommodate for loss of drug during preparation. Care should be taken when converting prochlorperazine mesilate liquid doses to crushed prochlorperazine maleate tablets, and the doses used should not be treated as equivalent.
PubMed: 38876766
DOI: 10.1136/ejhpharm-2023-003791 -
Prescribed Drug Use and Aneurysmal Subarachnoid Hemorrhage Incidence: A Drug-Wide Association Study.Neurology Jun 2024Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial...
BACKGROUND AND OBJECTIVES
Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial aneurysms thus remain untreated. Commonly prescribed drugs reducing aSAH incidence may provide leads for drug repurposing. We performed a drug-wide association study (DWAS) to systematically investigate the association between commonly prescribed drugs and aSAH incidence.
METHODS
We defined all aSAH cases between 2000 and 2020 using codes from the Secure Anonymised Information Linkage databank. Each case was matched with 9 controls based on age, sex, and year of database entry. We investigated commonly prescribed drugs (>2% in study population) and defined 3 exposure windows relative to the most recent prescription before index date (i.e., occurrence of aSAH): current (within 3 months), recent (3-12 months), and past (>12 months). A logistic regression model was fitted to compare drug use across these exposure windows vs never use, controlling for age, sex, known aSAH risk factors, and health care utilization. The family-wise error rate was kept at < 0.05 through Bonferroni correction.
RESULTS
We investigated exposure to 205 commonly prescribed drugs between 4,879 aSAH cases (mean age 61.4, 61.2% women) and 43,911 matched controls. We found similar trends for lisinopril and amlodipine, with a decreased aSAH risk for current use (lisinopril odds ratio [OR] 0.63, 95% CI 0.44-0.90, amlodipine OR 0.82, 95% CI 0.65-1.04) and an increased aSAH risk for recent use (lisinopril OR 1.30, 95% CI 0.61-2.78, amlodipine OR 1.61, 95% CI 1.04-2.48). A decreased aSAH risk in current use was also found for simvastatin (OR 0.78, 95% CI 0.64-0.96), metformin (OR 0.58, 95% CI 0.43-0.78), and tamsulosin (OR 0.55, 95% CI 0.32-0.93). By contrast, an increased aSAH risk was found for current use of warfarin (OR 1.35, 95% CI 1.02-1.79), venlafaxine (OR 1.67, 95% CI 1.01-2.75), prochlorperazine (OR 2.15, 95% CI 1.45-3.18), and co-codamol (OR 1.31, 95% CI 1.10-1.56).
DISCUSSION
We identified several drugs associated with aSAH, of which 5 drugs (lisinopril and possibly amlodipine, simvastatin, metformin, and tamsulosin) showed a decreased aSAH risk. Future research should build on these signals to further assess the effectiveness of these drugs in reducing aSAH incidence.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that some commonly prescribed drugs are associated with subsequent development of aSAH.
Topics: Humans; Subarachnoid Hemorrhage; Female; Male; Middle Aged; Incidence; Adult; Aged; Prescription Drugs; Case-Control Studies; Intracranial Aneurysm; Risk Factors
PubMed: 38838229
DOI: 10.1212/WNL.0000000000209479 -
Obstetric Medicine Jun 2024Hyperemesis gravidarum complicates 0.5-2% of pregnancies. HG is associated with insomnia, significantly increased risks of anxiety and depression, and may be associated...
Hyperemesis gravidarum complicates 0.5-2% of pregnancies. HG is associated with insomnia, significantly increased risks of anxiety and depression, and may be associated with feelings of guilt, social isolation and thoughts of suicidal ideation or termination of pregnancy. Anti-emetic therapy may be complicated by akathisia and dystonic reactions, which may affect the ongoing management of nausea and vomiting. A case of akathisia and oculogyric crisis following the addition of parenteral prochlorperazine to ondansetron and metoclopramide is presented. The treatment options for extrapyramidal side effects with anti-emetics in pregnancy and for ongoing treatment of nausea and vomiting are discussed.
PubMed: 38784181
DOI: 10.1177/1753495X221137942 -
Pediatric Emergency Care May 2024The objective are to determine whether diphenhydramine coadministered with prochlorperazine versus prochlorperazine only is associated with a difference in the risk of...
OBJECTIVES
The objective are to determine whether diphenhydramine coadministered with prochlorperazine versus prochlorperazine only is associated with a difference in the risk of migraine treatment failure, as measured by the need for additional therapy, hospitalization rates, and 72-hour return rates, and to compare extrapyramidal adverse effects between groups.
METHODS
Retrospective cohort of patients aged 7 to 18 years treated in the emergency department for migraines using prochlorperazine with or without diphenhydramine between 2013 and 2019. Patients were included if they had International Classification of Diseases, Ninth or Tenth Revision, codes for migraine or unspecified headache and were treated with prochlorperazine as part of their initial migraine therapy. Data collected included demographics, medications administered, pain scores, neuroimaging, disposition, return visits, and documentation of extrapyramidal adverse effects. Multivariable logistic regression was used to estimate the association between diphenhydramine coadministration and each of the outcomes.
RESULTS
A total of 1683 patients were included. Overall, 13% required additional therapy with a 16.7% admission rate and a 72-hour return rate of 5.3%. There was no association between initial treatment with diphenhydramine and the odds of additional therapy (adjusted odds ratio [aOR], 0.74 [95% confidence interval {CI}, 0.53-1.03]), admission rates (aOR, 1.22 [95% CI, 0.89-1.67]), or return visit rates (aOR, 0.91 [95% CI, 0.55-1.51]). Extrapyramidal adverse effects occurred in 2.4% of patients in the prochlorperazine group and 0% in the prochlorperazine with diphenhydramine group.
CONCLUSIONS
There was no association between diphenhydramine coadministration and the need for additional therapy, 72-hour return visit rates or admission rates. Extrapyramidal effects did not occur in patients treated with diphenhydramine.
PubMed: 38718751
DOI: 10.1097/PEC.0000000000003202 -
The American Journal of Emergency... Jul 2024Neuroleptic malignant syndrome (NMS) is a rare yet severe condition typically associated with antipsychotic medications. Here, we present a case of NMS induced by...
Neuroleptic malignant syndrome (NMS) is a rare yet severe condition typically associated with antipsychotic medications. Here, we present a case of NMS induced by prochlorperazine in a 76-year-old male with multiple comorbidities, aiming to delineate its clinical manifestation, diagnostic complexities, and treatment approaches. Our methodology involved a thorough documentation of the patient's medical history, initial symptoms, physical examination findings, laboratory results, diagnostic processes, and subsequent therapeutic interventions. The patient exhibited classic NMS symptoms, including fever, altered mental status, autonomic dysregulation, and generalized rigidity, consistent with diagnostic criteria. Notably, laboratory investigations failed to reveal the typical abnormalities often seen in NMS cases, highlighting the diverse presentation of this syndrome. Management strategies primarily focused on benzodiazepines and amantadine, leading to a gradual improvement in symptoms and eventual resolution of NMS. This underscores the critical role of early recognition and appropriate pharmacotherapy in managing prochlorperazine-induced NMS, even at standard dosage levels. The absence of characteristic laboratory findings in NMS poses challenges in diagnosis, necessitating a comprehensive clinical assessment for accurate identification. Moreover, this case emphasizes the need for further research to better understand the pathophysiology of prochlorperazine-induced NMS and optimize treatment protocols. In conclusion, our case report sheds light on the complexities surrounding NMS induced by prochlorperazine, emphasizing the importance of vigilant monitoring and tailored therapeutic strategies in mitigating its potentially life-threatening consequences.
Topics: Humans; Neuroleptic Malignant Syndrome; Male; Prochlorperazine; Aged; Antipsychotic Agents
PubMed: 38575461
DOI: 10.1016/j.ajem.2024.03.032 -
Bioelectrochemistry (Amsterdam,... Aug 2024We present a novel application of a nanocrystalline boron-doped diamond electrode (B-NCDE) for the construction of an electrochemical DNA biosensor based on...
We present a novel application of a nanocrystalline boron-doped diamond electrode (B-NCDE) for the construction of an electrochemical DNA biosensor based on double-stranded DNA (dsDNA) for various bioanalytical applications. Surface characterization of the transducer surface (prior and after the fabrication of negatively charged O-terminated surface - O-B-NCDE) was performed by scanning electron microscopy (SEM), Raman spectroscopy, and linear sweep voltammetry (LSV) that was further used for the voltammetric determination, scan rate dependence investigation, and repeatability examination of dsDNA electrochemical oxidation at the O-B-NCDE. The fabrication of a dsDNA/O-B-NCDE biosensor via electrostatic adsorption of dsDNA involved a thorough optimization process of deposition potential (E), deposition time (t), and optimal saturation concentration (c) with optimal values of 0.3 V, 3 min, and 10 mg/mL. The bioanalytical applicability of the fabricated dsDNA/O-B-NCDE biosensor was verified by examining the nature of the interaction between dsDNA and five selected DNA intercalators - namely thioridazine hydrochloride (TR), trimipramine maleate (TRIM), levomepromazine maleate (LEV), imipramine hydrochloride (IMI), and prochlorperazine maleate (PER) - where intercalation was proven for all of the five tested compounds. Moreover, the proposed novel bioanalytical test offers the possibility to selectively distinguish between the phenothiazine representatives (TR, LEV, and PER) and representatives of tricyclic antidepressants group (TRIM and IMI).
Topics: Biosensing Techniques; DNA; Diamond; Boron; Electrodes; Electrochemical Techniques; Nanoparticles
PubMed: 38574451
DOI: 10.1016/j.bioelechem.2024.108691 -
Journal of the American Society of... Jun 2024In hemodialysis, ondansetron initiation versus initiation of lesser QT-prolonging antiemetics associated with higher 10-day sudden cardiac death risk. Analyses...
KEY POINTS
In hemodialysis, ondansetron initiation versus initiation of lesser QT-prolonging antiemetics associated with higher 10-day sudden cardiac death risk. Analyses considering additional cardiac outcomes had consistent findings.
BACKGROUND
Individuals receiving hemodialysis have a high incidence of sudden cardiac death and are susceptible to QT interval–prolonging medication–related cardiac complications. Ondansetron, an antiemetic with known QT-prolonging potential, is associated with fatal arrhythmias in the general population when administered intravenously. The cardiac safety of ondansetron in the hemodialysis population is unknown.
METHODS
We conducted a new-user, active-comparator, cohort study using United States Renal Data System data (2012–2019) to examine the association between the initiation of oral ondansetron versus antiemetics with lesser QT-prolonging potential (promethazine, metoclopramide, or prochlorperazine) and the 10-day risk of sudden cardiac death among individuals receiving hemodialysis. We used inverse probability of treatment-weighted survival models to estimate adjusted hazard ratios, risk differences, and 95% confidence intervals (CIs). We used an intention-to-treat approach in which non-sudden cardiac death was considered a competing event. We examined additional cardiac outcomes in secondary analyses.
RESULTS
Of 119,254 study patients, 64,978 (55%) initiated ondansetron and 54,276 (45%) initiated a comparator antiemetic. Initiation of ondansetron versus a comparator antiemetic was associated with higher relative and absolute 10-day risks of sudden cardiac death (adjusted hazard ratio, 1.44 [95% CI, 1.08 to 1.93]; adjusted risk difference, 0.06% [95% CI, 0.01% to 0.11%]). The number needed to harm was 1688. Analyses of additional cardiac outcomes yielded similar findings.
CONCLUSIONS
Compared with initiation of antiemetics with lesser QT-prolonging potential, initiation of ondansetron was associated with higher short-term cardiac risks among people receiving hemodialysis.
Topics: Humans; Renal Dialysis; Death, Sudden, Cardiac; Ondansetron; Male; Female; Middle Aged; Kidney Failure, Chronic; Antiemetics; Aged
PubMed: 38409683
DOI: 10.1681/ASN.0000000000000336 -
Handbook of Clinical Neurology 2024The acute treatment of migraine attacks should provide rapid, effective, and long-lasting symptom relief, causing minimal adverse effects. For this purpose, there are... (Review)
Review
The acute treatment of migraine attacks should provide rapid, effective, and long-lasting symptom relief, causing minimal adverse effects. For this purpose, there are several specific and nonspecific acute treatments. In this chapter, we focus on molecules not specifically designed for migraines, including anti-inflammatory not specific analgesics, such as acetaminophen, acetylsalicylic acid, and other non-steroidal anti-inflammatory drugs (or COX-2 inhibitors); antinausea medications like metoclopramide or prochlorperazine, which can alleviate sickness and vomiting associated with migraines, and may also have a direct painkiller effect; combinations of simple analgesics or association of a painkiller with caffeine. This stimulant can help enhance the pain-relieving effects of some headache medications and provide its own analgesic effect; physical approaches: applying cold packs or heating pads on the forehead or neck, can help relieve migraine pain; other classes with limited to no evidence to support their use, such as intravenous corticosteroids or antiepileptic drugs as sodium valproate. Finally, we will briefly mention opioids, barbiturates, or medical cannabis, bearing in mind that their use is not recommended by current guidelines.
Topics: Humans; Antiemetics; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Migraine Disorders; Anti-Inflammatory Agents; Pain; Analgesics, Opioid
PubMed: 38307653
DOI: 10.1016/B978-0-12-823357-3.00035-5