-
Drug Delivery and Translational Research Oct 2021Meclizine hydrochloride (MCZ), a first-generation antihistamine of the piperazine class, is antiemetic and intended for the management of nausea and vomiting with few...
Meclizine hydrochloride (MCZ), a first-generation antihistamine of the piperazine class, is antiemetic and intended for the management of nausea and vomiting with few adverse effects. The introduction of orodispersible tablet (ODT) would solve the problems encountered in the administration of this drug to pediatric, geriatric, and psychiatric patients. It would be even more advantageous if the MCZ tablet could provoke rapid and prolonged efficacy. Achieving concomitant rapid and prolonged drug therapeutic effects in orodissolvable/dispersible dosage forms would be challenging. In this respect, the authors prepared tablets with coats and cores for immediate and prolonged drug absorption. To achieve this goal, nanoparticles of MCZ from chitosan (CS) and shellac (SH) were prepared by ionic crosslinking and then directly compressed with excipients to form the core in a coated tablet. The immediate release coat with MCZ with the same excipients as in the core was amenable by direct compression. MCZ in the coat dissolved in the presence of a superdisintegrant, leading to rapid absorption from the buccal cavity. Meanwhile, enteric-coated nanoparticles were swallowed and dissolved in the GIT. Intuitively, the absorption process was prolonged. The in vitro release characteristics of all the tablets were studied in comparison with a commercial tablet (CT). Additionally, evaluation of the in vivo pharmacokinetic profile of both the prepared and commercial tablets was performed in humans. The dual function tablet disintegrated in 58 s at pH 5.5. In vivo, noncompartmental pharmacokinetic analysis showed concomitant rapid absorption, possibly from the coat, followed by prolonged absorption from the core. Successfully, these good results confirm that combined rapid and prolonged MCZ therapy with the prepared dual function orodissolvable/dispersible tablet could be a promising oral drug delivery system to enhance convenience for patients. Hopefully, dual function tablets will confer a benefit through the accommodation of more than a single medication in the case of multiple therapies.
Topics: Aged; Child; Drug Compounding; Excipients; Healthy Volunteers; Humans; Meclizine; Tablets
PubMed: 33443718
DOI: 10.1007/s13346-020-00889-z -
Clinical Epidemiology 2021To determine antiemetic prescription fill patterns during pregnancy in Norway, with special focus on the use of ondansetron and recurrent use in subsequent pregnancies.
OBJECTIVE
To determine antiemetic prescription fill patterns during pregnancy in Norway, with special focus on the use of ondansetron and recurrent use in subsequent pregnancies.
METHODS
We conducted a population-based registry study based on data from the Medical Birth Registry of Norway linked to the Norwegian Prescription Database for 762,437 pregnancies >12 gestational weeks ending in live or non-live births between 2005 and 2017. Prescription fills of medications used for nausea and vomiting of pregnancy were summarized in treatment pathways to determine drug utilization patterns. Logistic regression analyses were used to estimate associations between maternal and pregnancy characteristics and antiemetic prescription fills.
RESULTS
The prescription fill rate for antiemetic medication during pregnancy was 7.6%. However, prescription fill rates were 35.5% in the second pregnancy after filling an antiemetic prescription in the first pregnancy and 53.5% for women who filled antiemetic prescriptions in the previous 2 pregnancies. Among pregnancies with antiemetic prescription fills, 62.2% were dispensed metoclopramide, 28.2% meclizine, and 17.2% promethazine. First-line treatment started with monotherapy in 97.4% of these pregnancies, which was the only treatment received in 78.7%. Prescriptions for ondansetron were filled in 0.3% of pregnancies, with 76.9% being initially filled in the first trimester. Ondansetron as first-line prescription medication and/or use in the first trimester was associated with proxies for more severe nausea and vomiting of pregnancy, including a diagnosis of hyperemesis gravidarum, multiple gestations, a higher obstetric comorbidity index, and concomitant use of medication for gastroesophageal reflux disease and nervous system medications. Women who filled an antiemetic prescription in their first pregnancy were less likely to have subsequent pregnancies than women who did not fill an antiemetic prescription in their first pregnancy (OR 0.93, 95% CI 0.90-0.96).
CONCLUSION
Complex patterns of antiemetic prescription fills in pregnancy may mirror the challenge of optimal management of nausea and vomiting of pregnancy in clinical practice, especially for women with severe symptoms.
PubMed: 33664595
DOI: 10.2147/CLEP.S287892 -
Biomedicine & Pharmacotherapy =... Jan 2023Translationally controlled tumor protein (TCTP), a highly conserved protein present in most eukaryotes, is involved in numerous biological processes. Only the dimeric...
Translationally controlled tumor protein (TCTP), a highly conserved protein present in most eukaryotes, is involved in numerous biological processes. Only the dimeric form of TCTP (dTCTP) formed during inflammatory conditions exhibits cytokine-like activity. Therefore, dTCTP is considered as a therapeutic target for allergic diseases. Because monomeric TCTP (mTCTP) and dTCTP share a high topological similarity, we hypothesized that small molecules interacting with mTCTP would also bind to dTCTP and interfere with dTCTP-based cellular processes. In this study, nine compounds listed in the literature as interacting with mTCTP were investigated for their ability to suppress the activity of extracellular dTCTP in bronchial epithelial cells. It was found that one of the nine, meclizine, a piperazine-derivative antihistamine, significantly reduced IL-8 release and suppressed the NF-κB pathway. The direct interaction of meclizine with dTCTP was confirmed by surface plasmon resonance (SPR). Also, we found that meclizine can attenuate ovalbumin (OVA)-induced airway inflammation in mice. Therefore, meclizine might be a potential anti-allergic drug as an inhibitor for dTCTP.
Topics: Mice; Animals; Piperazine; Tumor Protein, Translationally-Controlled 1; Meclizine; Biomarkers, Tumor; Hypersensitivity; Disease Models, Animal; Ovalbumin; Histamine Antagonists; Mice, Inbred BALB C
PubMed: 36493627
DOI: 10.1016/j.biopha.2022.114072 -
Academic Emergency Medicine : Official... May 2023Benign paroxysmal positional vertigo (BPPV) is a very common condition in the population and an important cause of acute vertigo or dizziness in patients presenting to...
Benign paroxysmal positional vertigo (BPPV) is a very common condition in the population and an important cause of acute vertigo or dizziness in patients presenting to an emergency department (ED). Despite this, abundant evidence shows that current ED management of patients with BPPV is suboptimal. Common ED management processes include brain imaging and treatment with vestibular suppressant medications such as meclizine, neither of which is recommended by current guidelines. The most efficient management of BPPV is to perform a bedside test (Dix-Hallpike test) and then to treat the patients with a bedside positional (the Epley) maneuver. In this practical review we emphasize the efficient management for the most common form of BPPV-posterior canal BPPV. Using this management will reduce resource utilization (laboratory testing, brain imaging, specialist consultation), reduce ED length of stay, and reduce use of ineffective mediations that have side effects but little therapeutic effect. Application of these practices would improve important patient-centered outcomes such as symptom reduction, radiation exposure, side effects from medications, and less need for urgent follow-up with another health care provider. The article also discusses the approach to patients in whom the Dix-Hallpike and/or Epley maneuvers do not seem to work. This includes a discussion the second most common variant of BPPV (horizontal canal BPPV) and criteria for safe discharge of patients. Another important advantage of learning BPPV best practices is that it is enormously satisfying for the clinician, not unlike treating a child with a nursemaid's elbow.
Topics: Child; Humans; Benign Paroxysmal Positional Vertigo; Patient Positioning; Dizziness; Brain; Physicians
PubMed: 35833326
DOI: 10.1111/acem.14558 -
Aerospace Medicine and Human Performance Nov 2019Exposure to high G force is a known safety hazard in military aviation as well as civilian aerobatic flight. Tolerance to high G forces has been well studied in...
Exposure to high G force is a known safety hazard in military aviation as well as civilian aerobatic flight. Tolerance to high G forces has been well studied in military pilots, but there is little research directed at civilian pilots who may have medications or medical conditions not permitted in military pilots. In this case-control study, we identified 89 fatal high-G aerobatic accidents and 4000 fatal control accidents from 1995 through 2018 from the NTSB accident database and the FAA autopsy database. We retrieved medications and medical conditions from the FAA's pilot medical databases. Logistic regression models were used to explore the associations of drugs, medical conditions, height, and medical waivers with high-G accidents. Seven drugs (alprazolam, clonidine, ethanol, meclizine, phentermine, triamterene, and zolpidem) reached statistical significance in our models, but had such small case counts that we consider these findings to be uncertain, except for ethanol, which was found in seven cases. Of these, only triamterene was known to the FAA. Statistically significant medical predictors included only alcohol abuse (seven cases) and liver disease (only two cases). Our analysis found that the drug ethanol and the condition alcohol abuse are significantly associated with high-G accidents. Seven other factors were statistically significant, but should only be considered as hypothesis generating due to very low case counts. Our study does not suggest that restricting pilots with otherwise permissible medications or medical conditions from aerobatics is warranted.
Topics: Accidents, Aviation; Aerospace Medicine; Alcoholism; Alprazolam; Case-Control Studies; Clonidine; Databases, Factual; Ethanol; Female; Humans; Hypergravity; Liver Diseases; Logistic Models; Male; Meclizine; Middle Aged; Phentermine; Pilots; Triamterene; United States; Zolpidem
PubMed: 31666158
DOI: 10.3357/AMHP.5445.2019 -
Journal of Hepatology Apr 2020Since human induced pluripotent stem cells (iPSCs) develop into hepatic organoids through stages that resemble human embryonic liver development, they can be used to...
BACKGROUND & AIMS
Since human induced pluripotent stem cells (iPSCs) develop into hepatic organoids through stages that resemble human embryonic liver development, they can be used to study developmental processes and disease pathology. Therefore, we examined the early stages of hepatic organoid formation to identify key pathways affecting early liver development.
METHODS
Single-cell RNA-sequencing and metabolomic analysis was performed on developing organoid cultures at the iPSC, hepatoblast (day 9) and mature organoid stage. The importance of the phosphatidylethanolamine biosynthesis pathway to early liver development was examined in developing organoid cultures using iPSC with a CRISPR-mediated gene knockout and an over the counter medication (meclizine) that inhibits the rate-limiting enzyme in this pathway. Meclizine's effect on the growth of a human hepatocarcinoma cell line in a xenotransplantation model and on the growth of acute myeloid leukemia cells in vitro was also examined.
RESULTS
Transcriptomic and metabolomic analysis of organoid development indicated that the phosphatidylethanolamine biosynthesis pathway is essential for early liver development. Unexpectedly, early hepatoblasts were selectively sensitive to the cytotoxic effect of meclizine. We demonstrate that meclizine could be repurposed for use in a new synergistic combination therapy for primary liver cancer: a glycolysis inhibitor reprograms cancer cell metabolism to make it susceptible to the cytotoxic effect of meclizine. This combination inhibited the growth of a human liver carcinoma cell line in vitro and in a xenotransplantation model, without causing significant side effects. This drug combination was also highly active against acute myeloid leukemia cells.
CONCLUSION
Our data indicate that phosphatidylethanolamine biosynthesis is a targetable pathway for cancer; meclizine may have clinical efficacy as a repurposed anti-cancer drug when used as part of a new combination therapy.
LAY SUMMARY
The early stages of human liver development were modeled using human hepatic organoids. We identified a pathway that was essential for early liver development. Based upon this finding, a novel combination drug therapy was identified that could be used to treat primary liver cancer and possibly other types of cancer.
Topics: Adult; Aged; Animals; Carcinoma, Hepatocellular; Cell Survival; Drug Therapy, Combination; Female; Gene Knockout Techniques; Glycolysis; Hep G2 Cells; Humans; Induced Pluripotent Stem Cells; Leukemia, Myeloid, Acute; Liver; Liver Neoplasms; Male; Meclizine; Mice; Middle Aged; Organogenesis; Organoids; Phosphatidylethanolamines; Pyridines; Quinolines; RNA Nucleotidyltransferases; Retrospective Studies; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 31760071
DOI: 10.1016/j.jhep.2019.11.007 -
Biomedical Chromatography : BMC Jun 2022Cyclizine hydrochloride (CYC) and meclozine hydrochloride (MEC) are antihistaminic drugs generally co-formulated with pyridoxine hydrochloride (PYR) to treat nausea and...
Cyclizine hydrochloride (CYC) and meclozine hydrochloride (MEC) are antihistaminic drugs generally co-formulated with pyridoxine hydrochloride (PYR) to treat nausea and vomiting in pregnancy. Several analytical techniques have been applied for the determination of CYC or MEC with PYR, but determination of CYC impurity; benzhydrol (BEH) or MEC impurity; or 4-chlorobenzophenone (BEP) has not been paid attention to. Therefore, micellar UPLC method is introduced for analysis of ternary mixtures containing PYR together with both CYC and BEH (mixture I) or MEC and BEP (mixture II). Chromatographic separation was achieved using a Hypersil gold C column (50 × 2.1 mm, 1.9 μm) using 0.01 M sodium dodecyl sulfate modified to pH 3.5 using phosphoric acid:acetonitrile (45:55 by volume) for mixture I and 0.1% sodium dodecyl sulfate, 0.1% sodium bicarbonate adjusted to pH 2.6 by phosphoric acid:acetonitrile (47:53 by volume) for mixture II as mobile phases. The separated peaks were detected at 230 and 245 nm for mixtures I and II, respectively. The adopted methods were validated in conformance with the International Conference on Harmonization (ICH) recommendations and were properly applied in commercial pharmaceutical formulation analysis. Comprehensive ecological comparison was achieved, confirming a higher ecological value of the presented methods compared to the earlier reported methods.
Topics: Acetonitriles; Antiemetics; Chromatography, High Pressure Liquid; Female; Humans; Pregnancy; Pyridoxine; Sodium Dodecyl Sulfate
PubMed: 35128703
DOI: 10.1002/bmc.5353 -
Frontiers in Cellular and Infection... 2018Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a...
Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a cascade virtual screening campaign combining ligand- and structure-based methods. In order to find novel inhibitors of putrescine uptake in , an ensemble of linear ligand-based classifiers obtained by has been applied as initial screening filter, followed by docking into a homology model of the putrescine permease PAT12. 1,000 individual linear classifiers were inferred from a balanced dataset. Subsequently, different schemes were tested to combine the individual classifiers: MIN operator, average ranking, average score, average voting, with MIN operator leading to the best performance. The homology model was based on the arginine/agmatine antiporter (AdiC) from as template. It showed 64% coverage of the entire query sequence and it was selected based on the normalized Discrete Optimized Protein Energy parameter and the GA341 score. The modeled structure had 96% in the allowed area of Ramachandran's plot, and none of the residues located in non-allowed regions were involved in the active site of the transporter. Positivity Predictive Value surfaces were applied to optimize the score thresholds to be used in the ligand-based virtual screening step: for that purpose Positivity Predictive Value was charted as a function of putative yields of active in the range 0.001-0.010 and the Se/Sp ratio. With a focus on drug repositioning opportunities, DrugBank and Sweetlead databases were subjected to screening. Among 8 hits, cinnarizine, a drug frequently prescribed for motion sickness and balance disorder, was tested against epimastigotes and amastigotes, confirming its trypanocidal effects and its inhibitory effects on putrescine uptake. Furthermore, clofazimine, an antibiotic with already proven trypanocidal effects, also displayed inhibitory effects on putrescine uptake. Two other hits, meclizine and butoconazole, also displayed trypanocidal effects (in the case of meclizine, against both epimastigotes and amastigotes), without inhibiting putrescine uptake.
Topics: Biological Transport; Chagas Disease; Cinnarizine; Clofazimine; Drug Evaluation, Preclinical; Drug Repositioning; Imidazoles; Meclizine; Membrane Transport Proteins; Molecular Docking Simulation; Molecular Dynamics Simulation; Putrescine; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 29888213
DOI: 10.3389/fcimb.2018.00173 -
Free Radical Biology & Medicine Oct 2016To meet energy demands, dorsal root ganglion (DRG) neurons harbor high mitochondrial content, which renders them acutely vulnerable to disruptions of energy homeostasis....
To meet energy demands, dorsal root ganglion (DRG) neurons harbor high mitochondrial content, which renders them acutely vulnerable to disruptions of energy homeostasis. While neurons typically rely on mitochondrial energy production and have not been associated with metabolic plasticity, new studies reveal that meclizine, a drug, recently linked to modulations of energy metabolism, protects neurons from insults that disrupt energy homeostasis. We show that meclizine rapidly enhances glycolysis in DRG neurons and that glycolytic metabolism is indispensable for meclizine-exerted protection of DRG neurons from hypoxic stress. We report that supplementation of meclizine during hypoxic exposure prevents ATP depletion, preserves NADPH and glutathione stores, curbs reactive oxygen species (ROS) and attenuates mitochondrial clustering in DRG neurites. Using extracellular flux analyzer, we show that in cultured DRG neurons meclizine mitigates hypoxia-induced loss of mitochondrial respiratory capacity. Respiratory capacity is a measure of mitochondrial fitness and cell ability to meet fluctuating energy demands and therefore, a key determinant of cellular fate. While meclizine is an 'old' drug with long record of clinical use, its ability to modulate energy metabolism has been uncovered only recently. Our findings documenting neuroprotection by meclizine in a setting of hypoxic stress reveal previously unappreciated metabolic plasticity of DRG neurons as well as potential for pharmacological harnessing of the newly discovered metabolic plasticity for protection of peripheral nervous system under mitochondria compromising conditions.
Topics: Adenosine Triphosphate; Animals; Astrocytes; Cell Hypoxia; Ganglia, Spinal; Glucose; Glycolysis; Histamine H1 Antagonists; Hydrogen-Ion Concentration; Lactic Acid; Male; Meclizine; Mice; Mice, Inbred C57BL; Mitochondria; Neurons; Oxygen Consumption; Primary Cell Culture; Protective Agents; Stress, Physiological
PubMed: 27458119
DOI: 10.1016/j.freeradbiomed.2016.07.022 -
BMC Pregnancy and Childbirth Dec 2022Online information about safety of medications during pregnancy and breastfeeding is shown to be conflicting, resulting in anxiety and abstaining from use. The aim of...
Identifying target areas of medicines information efforts to pregnant and breastfeeding women by reviewing questions to SafeMotherMedicine: A Norwegian web-based public medicines information service.
BACKGROUND
Online information about safety of medications during pregnancy and breastfeeding is shown to be conflicting, resulting in anxiety and abstaining from use. The aim of this study was to characterize questions to SafeMotherMedicine, a web-based medicines information service for pregnant and breastfeeding women, to identify target areas that could guide subsequent development of medicines information directed at pregnant and breastfeeding women.
METHODS
The SafeMotherMedicine database contains all questions received through the web-based service and their corresponding answers. A retrospective database analysis of questions received from January 2016 to September 2018 was performed, using descriptive statistics.
RESULTS
A total of 11 618 questions were received including 5 985 questions (51.5%) concerning pregnancy, 4 878 questions (42.0%) concerning breastfeeding, and 755 questions (6.5%) concerning both conditions. The medications in question represented all therapeutic groups with paracetamol (7.0%), ibuprofen (4.1%), cetirizine (3.3%), desloratadine (3.2%) and meclizine (2.8%) being the top five. The 20 medications most frequently asked about for either pregnancy, breastfeeding or both pregnancy and breastfeeding, constituted half of all questions and were used to identify target areas. These included both symptomatic relief of common complaints, such as pain, nausea, and rhinitis, as well as treatment of chronic conditions such as allergy, psychiatric disorders, and asthma. Analysis of a subset of questions showed that most of these questions were asked before use of medications in a current pregnancy (49%) or during breastfeeding (72%). The questions concerned use of medications in all stages of pregnancy and breastfeeding. For 81.6% of the questions concerning pregnancy, and for 84.2% of the questions concerning breastfeeding, information of no or low risk for the foetus or the breastfed infant was provided by SafeMotherMedicine.
CONCLUSIONS
We found that target areas for medicines information directed at pregnant and breastfeeding women included both symptomatic relief of common complaints as well as treatment of chronic conditions. The questions concerned a wide range of medications and involved use in all stages of pregnancy and breastfeeding. Our findings indicate that developing medicines information addressing the identified target areas will meet the information need for a large proportion of this patient group.
Topics: Infant; Pregnancy; Humans; Female; Breast Feeding; Retrospective Studies; Information Services; Hypersensitivity; Internet
PubMed: 36461026
DOI: 10.1186/s12884-022-05252-3