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ChemSusChem Jan 2016Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We...
Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h(-1) .
Topics: Alcohols; Benzyl Compounds; Chemistry Techniques, Synthetic; Cinnarizine; Cyclizine; Histamine Antagonists; Molecular Structure; Piperazines
PubMed: 26663906
DOI: 10.1002/cssc.201501367 -
British Journal of Pharmacology Feb 2020Histamine H receptors are expressed in the peripheral vestibular system, and their selective inhibition improves vertigo symptoms in rats with unilateral vestibular...
BACKGROUND AND PURPOSE
Histamine H receptors are expressed in the peripheral vestibular system, and their selective inhibition improves vertigo symptoms in rats with unilateral vestibular lesions. The effects of SENS-111, a selective oral H receptor antagonist with high affinity to both animal and human receptors, on vertigo symptoms was evaluated in a translational in vivo model of unilateral vestibular loss.
EXPERIMENTAL APPROACH
Pharmacokinetics of SENS-111 in rats was determined to aid dose selection for efficacy testing. Vestibular lesions were induced in rats by unilateral transtympanic injection of kainic acid. The effect of SENS-111 (10 or 20 mg·kg ) on spontaneous nystagmus was evaluated compared with placebo vehicle using video-nystagmography, and the effective dose was compared with those of similar drugs used clinically, as single agents or combined with SENS-111.
KEY RESULTS
Doses were selected for plasma exposure were consistent with published phase 1 results from healthy volunteers. SENS-111 of 10 mg·kg gave a 21-22% reduction in nystagmus at 1 hr post-administration, whereas a loss of efficacy was seen with 20 mg·kg . Compared with SENS-111, meclizine and methylprednisolone had minimal effects on nystagmus as single agents, and meclizine abolished the effect of SENS-111 when combined with SENS-111. All evaluated drugs were well tolerated.
CONCLUSIONS AND IMPLICATIONS
The exposure-efficacy relationship for improved spontaneous nystagmus seen with SENS-111 in this in vivo model is consistent with phase 1 clinical results and provides preclinical support for pharmacokinetic/pharmacodynamic modelling and selection of effective clinical drug concentrations.
LINKED ARTICLES
This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.
Topics: Animals; Azetidines; Histamine; Histamine Antagonists; Pyrimidines; Rats
PubMed: 31347148
DOI: 10.1111/bph.14803 -
BMC Pregnancy and Childbirth Jun 2022Women suffering from severe nausea and vomiting during pregnancy, hyperemesis gravidarum, have poor quality of life and increased risk of potentially fatal maternal and...
BACKGROUND
Women suffering from severe nausea and vomiting during pregnancy, hyperemesis gravidarum, have poor quality of life and increased risk of potentially fatal maternal and fetal complications. There is increasing and reassuring knowledge about safety of antiemetics in pregnancy. In 2013, the European Medical Agency (EMA) issued a warning on metoclopramide limiting treatment to maximum five days. Metoclopramide was the most used antiemetic in pregnancy at the time the warning was implemented in the Norwegian hyperemesis guidelines (2014). We aimed at describing changes in the treatment of hyperemesis over time, including changes associated with the EMA warning.
METHODS
Retrospective chart review of all women hospitalized for hyperemesis gravidarum with metabolic disturbances between 01/Jan/2002 and 31/Dec/2019 at a university hospital serving nearly 10% of the pregnant population in Norway. Time-series analysis described changes over time and interrupted time series analysis quantified changes in treatment and clinical outcomes related to the EMA warning.
RESULTS
In total, 1,064 women (1.2% of the birthing population) were included. The use of meclizine, prochlorperazine, and ondansetron increased during 2002-2019. This led to a yearly increase in the percentage of women using any antiemetic of 1.5% (95%CI 0.6; 2.4) pre-hospital, 0.6% (95%CI 0.2; 1.1) during hospitalization, and 2.6% (95%CI 1.3; 3.8) at discharge. Overall, only 50% of the women received antiemetics pre-hospital. Following the EMA warning, prehospital use of metoclopramide dropped by 30% (95%CI 25; 36), while use of any antiemetic pre-hospital dropped by 20% (95%CI 5.7; 34). In timely association, we observed a decrease in gestational age (-3.8 days, 98.75%CI 0.6; 7.1) at first admission, as well as indication of increased rate of termination of pregnancy with an absolute increase of 4.8% (98.75%CI 0.9; 8.7) in 2014.
CONCLUSION
During 2002-2019, the overall use of antiemetics in treatment of hyperemesis increased. The EMA-warning on metoclopramide in 2013 temporarily limited pre-hospital antiemetic provision associated with hospitalization at lower gestational length and indication of an increase in termination of pregnancy.
Topics: Antiemetics; Female; Humans; Hyperemesis Gravidarum; Metoclopramide; Pregnancy; Quality of Life; Retrospective Studies
PubMed: 35655181
DOI: 10.1186/s12884-022-04777-x -
Frontiers in Pharmacology 2017[This corrects the article on p. 693 in vol. 8, PMID: 29046637.].
[This corrects the article on p. 693 in vol. 8, PMID: 29046637.].
PubMed: 29377038
DOI: 10.3389/fphar.2017.00991 -
Biomedicines Apr 2022Acne is a chronic inflammatory multifactorial disease involving the anaerobic bacterium Cutibacterium acnes (C. acnes). Current acne treatments are associated with...
Acne is a chronic inflammatory multifactorial disease involving the anaerobic bacterium Cutibacterium acnes (C. acnes). Current acne treatments are associated with adverse effects, limiting treatment compliance and use. We showed that meclozine, an anti-histaminic H1 compound, has anti-inflammatory properties. In Vitro, meclozine reduced the production of CXCL8/IL-8 and IL-1β mRNA and protein by C. acnes-stimulated human keratinocytes and monocytes. No cell toxicity was observed at the IC50. Meclozine prevented the phosphorylation of ERK and JNK. In Vivo, 1% meclozine gel significantly decreased C. acnes-mouse ear induced inflammation by 26.7% (p = 0.021). Ex vivo experiments on human skin explants showed that meclozine decreased the production of GM-CSF, IL-1β and TNF-α at transcriptional and translational levels. In a randomized, double-blind, placebo-controlled proof-of-concept clinical trial on 60 volunteers, 2% meclozine pharmaceutical gel decreased by 20.1% (p < 0.001) the ASI score in the treated group after 12 weeks of treatment. No adverse event was reported. Together, these results indicate that meclozine is a potent topical anti-inflammatory compound of potential value for acne treatment.
PubMed: 35625668
DOI: 10.3390/biomedicines10050931 -
Stroke Jul 2024The mitochondrial unfolded protein response (UPR) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic...
BACKGROUND
The mitochondrial unfolded protein response (UPR) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPR may be a potential therapeutic target for ischemic stroke.
METHODS
We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPR. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.
RESULTS
Inducing UPR with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPR could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPR with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPR in vivo, which reduced infarction and improved neurological outcomes.
CONCLUSIONS
These findings suggest that the UPR is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPR mechanism may provide a new therapeutic avenue for ischemic stroke.
Topics: Animals; Neurons; Mice; Glucose; Unfolded Protein Response; Mitochondria; Brain Ischemia; Male; Infarction, Middle Cerebral Artery; Oxygen; Mice, Inbred C57BL; Cells, Cultured; Neuroprotective Agents
PubMed: 38913800
DOI: 10.1161/STROKEAHA.123.045550 -
Free Radical Biology & Medicine Oct 2020Parkinson's disease (PD) is a neurodegenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. One of the...
Parkinson's disease (PD) is a neurodegenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. One of the genes involved in familial forms of the disease is DJ-1, whose mutations cause early-onset PD. Besides, it has been shown that an over-oxidized and inactive form of the DJ-1 protein is found in brains of sporadic PD patients. Interestingly, the DJ-1 protein plays an important role in cellular defense against oxidative stress and also participates in mitochondrial homeostasis. Valuable insights into potential PD pathogenic mechanisms involving DJ-1 have been obtained from studies in cell and animal PD models based on DJ-1 deficiency such as Drosophila. Flies mutant for the DJ-1β gene, the Drosophila ortholog of human DJ-1, exhibited disease-related phenotypes such as motor defects, increased reactive oxygen species production and high levels of protein carbonylation. In the present study, we demonstrate that DJ-1β mutants also show a significant increase in the activity of several regulatory glycolytic enzymes. Similar results were obtained in DJ-1-deficient SH-SY5Y neuroblastoma cells, thus suggesting that loss of DJ-1 function leads to an increase in the glycolytic rate. In such a scenario, an enhancement of the glycolytic pathway could be a protective mechanism to decrease ROS production by restoring ATP levels, which are decreased due to mitochondrial dysfunction. Our results also show that meclizine and dimethyl fumarate, two FDA-approved compounds with different clinical applications, are able to attenuate PD-related phenotypes in both models. Moreover, we found that they may exert their beneficial effect by increasing glycolysis through the activation of key glycolytic enzymes. Taken together, these results are consistent with the idea that increasing glycolysis could be a potential disease-modifying strategy for PD, as recently suggested. Besides, they also support further evaluation and potential repurposing of meclizine and dimethyl fumarate as modulators of energy metabolism for neuroprotection in PD.
Topics: Animals; Drosophila; Drosophila Proteins; Glycolysis; Humans; Nerve Tissue Proteins; Oxidative Stress; Parkinson Disease; Protein Deglycase DJ-1
PubMed: 32726690
DOI: 10.1016/j.freeradbiomed.2020.06.036 -
Experimental and Therapeutic Medicine Jan 2023X-linked hypophosphatemic rickets (XLH) is characterized by hypo-mineralization of the bone due to hypophosphatemia. XLH is caused by abnormally high levels of...
X-linked hypophosphatemic rickets (XLH) is characterized by hypo-mineralization of the bone due to hypophosphatemia. XLH is caused by abnormally high levels of fibroblast growth factor 23, which trigger renal phosphate wasting. Activated fibroblast growth factor receptor 3 (FGFR3) signaling is considered to be involved in XLH pathology. Our previous study revealed that meclozine attenuated FGFR3 signaling and promoted longitudinal bone growth in an achondroplasia mouse model. The present study aimed to examine whether meclozine affected the bone phenotype in a mouse model of XLH [X-linked hypophosphatemic (Hyp) mice]. Meclozine was administered orally to 7-day-old Hyp mice for 10 days, after which the mice were subjected to blood sampling and histological analyses of the first coccygeal vertebra, femur and tibia. Villanueva Goldner staining was used to assess bone mineralization, hematoxylin and eosin staining was used to determine the growth plate structure and tartrate-resistant acid phosphatase staining was used to measure osteoclast activity. The osteoid volume/bone volume of cortical bone was lower in meclozine-treated Hyp mice compared with untreated Hyp mice. Meclozine treatment improved the abnormally thick hypertrophic zone of the growth plate and ameliorated the downregulation of osteoclast surface/bone surface in Hyp mice. However, meclozine had only a marginal effect on mineralization in the trabecular bone and on calcium and phosphate plasma levels. A 10-day-tratment with meclozine partially ameliorated bone mineralization in Hyp mice; hence, meclozine could alleviate XLH symptoms.
PubMed: 36569439
DOI: 10.3892/etm.2022.11738 -
Journal of Virology Nov 2020Glycerophospholipids are major components of cell membranes. Phosphatidylethanolamine (PE) is a glycerophospholipid that is involved in multiple cellular processes, such...
Glycerophospholipids are major components of cell membranes. Phosphatidylethanolamine (PE) is a glycerophospholipid that is involved in multiple cellular processes, such as membrane fusion, the cell cycle, autophagy, and apoptosis. In this study, we investigated the role of PE biosynthesis in herpes simplex virus 1 (HSV-1) infection by knocking out the host cell gene encoding phosphate cytidylyltransferase 2, ethanolamine (Pcyt2), which is a key rate-limiting enzyme in one of the two major pathways for PE biosynthesis. Pcyt2 knockout reduced HSV-1 replication and caused an accumulation of unenveloped and partially enveloped nucleocapsids in the cytoplasm of an HSV-1-infected cell culture. A similar phenotype was observed when infected cells were treated with meclizine, which is an inhibitor of Pcyt2. In addition, treatment of HSV-1-infected mice with meclizine significantly reduced HSV-1 replication in the mouse brains and improved their survival rates. These results indicated that PE biosynthesis mediated by Pcyt2 was required for efficient HSV-1 envelopment in the cytoplasm of infected cells and for viral replication and pathogenicity The results also identified the PE biosynthetic pathway as a possible novel target for antiviral therapy of HSV-associated diseases and raised an interesting possibility for meclizine repositioning for treatment of these diseases, since it is an over-the-counter drug that has been used for decades against nausea and vertigo in motion sickness. Glycerophospholipids in cell membranes and virus envelopes often affect viral entry and budding. However, the role of glycerophospholipids in membrane-associated events in viral replication in herpesvirus-infected cells has not been reported to date. In this study, we have presented data showing that cellular PE biosynthesis mediated by Pcyt2 is important for HSV-1 envelopment in the cytoplasm, as well as for viral replication and pathogenicity This is the first report showing the importance of PE biosynthesis in herpesvirus infections. Our results showed that inhibition of Pcyt2, a key cell enzyme for PE synthesis, significantly inhibited HSV-1 replication and pathogenicity in mice. This suggested that the PE biosynthetic pathway, as well as the HSV-1 virion maturation pathway, can be a target for the development of novel anti-HSV drugs.
Topics: Animals; Chlorocebus aethiops; Cytoplasm; Female; HeLa Cells; Herpes Simplex; Herpesvirus 1, Human; Humans; Mice; Mice, Inbred ICR; Morphogenesis; Nucleocapsid; Phosphatidylethanolamines; RNA Nucleotidyltransferases; Vero Cells; Virion; Virulence; Virus Internalization; Virus Release; Virus Replication
PubMed: 32999028
DOI: 10.1128/JVI.01572-20 -
European Journal of Clinical... May 2016The purposes of this study were to investigate the treatments used for nausea and vomiting of pregnancy (NVP) according to NVP severity among Norwegian women and to...
PURPOSE
The purposes of this study were to investigate the treatments used for nausea and vomiting of pregnancy (NVP) according to NVP severity among Norwegian women and to assess whether maternal characteristics and attitudes were related to the use of pharmacological treatment of NVP.
METHODS
This is a cross-sectional Web-based study. Pregnant women and mothers with children ≤1 year of age were eligible to participate. Data were collected through an anonymous online questionnaire accessible from November 10th, 2014 to January 31st, 2015.
RESULTS
In total, 712 women were included in the study, of which 62 (8.7 %), 439 (61.7 %) and 210 (29.5 %) had mild, moderate and severe NVP, respectively, according to the Pregnancy-Unique Quantification of Emesis (PUQE) classification. A total of 277 (38.9 %) women had used one or more antiemetics, of which meclizine, closely followed by metoclopramide, was the most commonly used. Different drug utilisation patterns were found between the groups of women with mild, moderate and severe NVP. Many with moderate or severe symptoms did not use any pharmacological treatment (70.2 and 32.9 %, respectively). Sick leave was given without initiating medical treatment in 266 (62.1 %) women. The women's beliefs about medicines had an important impact on their use of medicines for NVP.
CONCLUSIONS
A large proportion of women suffered from moderate to severe symptoms of NVP, many of whom did not receive any pharmacological treatment. Many women, who had been on sick leave due to NVP, were not prescribed medicines.
Topics: Adult; Antiemetics; Cross-Sectional Studies; Drug Utilization; Female; Humans; Nausea; Norway; Pregnancy; Pregnancy Complications; Severity of Illness Index; Surveys and Questionnaires; Vomiting
PubMed: 26815908
DOI: 10.1007/s00228-016-2012-6