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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 -
The Medical Letter on Drugs and... Oct 2019
Review
Topics: Acetazolamide; Altitude Sickness; Antiemetics; Carbonic Anhydrase Inhibitors; Central Nervous System Stimulants; Dexamethasone; Humans; Jet Lag Syndrome; Modafinil; Motion Sickness
PubMed: 31599874
DOI: No ID Found -
The Medical Letter on Drugs and... Oct 2019
Review
Topics: Animals; Antimalarials; Diarrhea; Humans; Insect Bites and Stings; Malaria; Travel; Travel-Related Illness
PubMed: 31599872
DOI: No ID Found -
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 -
Anticancer Research Jul 2019Previously, we showed that KBV20C cancer cells highly resistant to antimitotic drugs were sensitized by co-treatment with a repositioned drug fluphenazine.
BACKGROUND/AIM
Previously, we showed that KBV20C cancer cells highly resistant to antimitotic drugs were sensitized by co-treatment with a repositioned drug fluphenazine.
MATERIALS AND METHODS
Considering that fluphenazine plays a role as a histamine receptor antagonist, we investigated low doses of 21 other histamine receptor antagonists (lidocaine, cimetidine, chlorpromazine, diphenhydramine, promethazine, ranitidine, famotidine, clemastine, chlorpheniramine, desloratadine, loratadine, cyproheptadine, azelastine, brompheniramine, carbinoxamine, fexofenadine, hydroxyzine, levocetirizine, meclizine, nizatidine, and pemirolast) to identify repositioned drugs for their sensitizing effects on antimitotic drug-resistant KBV20C cells at relatively low doses.
RESULTS
Co-treatment with loratadine, and with azelastine highly sensitized KBV20C cells to vincristine treatment. Loratadine and azelastine reduced cell viability, increased G arrest, and up-regulated apoptosis when co-administered with vincristine. In detailed quantitative analysis, combination of vincristine with loratadine had a higher sensitization effect than that with azelastine. Azelastine had a higher P-glycoprotein (P-gp)-inhibitory activity, similar to that of verapamil, indicating that sensitization by vincristine-azelastine involved the P-gp-inhibitory effects of azelastine. However, loratadine had a very low P-gp-inhibitory activity, suggesting that loratadine sensitization to vincristine is independent of the P-gp-inhibition. Co-treatment with eribulin and loratadine increased the sensitization of KBV20C cells, suggesting that loratadine can be combined with other antimitotic drugs to sensitize resistant cancer cells.
CONCLUSION
These findings provide important information regarding the sensitization of drug-resistant cells and indicate that loratadine may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antimitotic Agents; Apoptosis; Cell Line, Tumor; Drug Repositioning; Drug Resistance, Neoplasm; Drug Synergism; Histamine Antagonists; Humans; Loratadine; Phthalazines; Vincristine
PubMed: 31262903
DOI: 10.21873/anticanres.13525 -
Reproductive Toxicology (Elmsford, N.Y.) Aug 2019Nausea and vomiting of pregnancy (NVP) is the most common medical complaint during pregnancy affecting up to 70% of pregnant women worldwide. Some antiemetic medications...
Nausea and vomiting of pregnancy (NVP) is the most common medical complaint during pregnancy affecting up to 70% of pregnant women worldwide. Some antiemetic medications (AEM) (droperidol, domperidone, granisetron, metoclopramide and trifluoperazine) used to treat NVP have the unwanted side effect of hERG blockade. The hERG potassium channel is essential for normal heart rhythm in both the adult human and the human and rat embryo. Animal studies show hERG blockade in the embryo causes bradycardia and arrhythmia leading to cardiovascular malformations and other birth defects. Whole rat embryo in vitro culture was used to determine the effect of the above listed AEM and meclizine on the heart rate of Gestational day 13 rat embryos. These embryos are similar in size and heart development to 5-6-week human embryo. The results showed that all of the AEMs caused a concentration-dependent bradycardia. Droperidol had the lowest margin of safety.
Topics: Animals; Antiemetics; Bradycardia; Domperidone; Droperidol; Embryo, Mammalian; Granisetron; Heart; Heart Rate; Meclizine; Metoclopramide; Rats, Sprague-Dawley; Trifluoperazine
PubMed: 31199962
DOI: 10.1016/j.reprotox.2019.06.002 -
Tidsskrift For Den Norske Laegeforening... May 2019A woman in her fifties was admitted to hospital with decreased awareness and circulatory failure. She had been treated with left atrial cryoablation a few weeks before...
BACKGROUND
A woman in her fifties was admitted to hospital with decreased awareness and circulatory failure. She had been treated with left atrial cryoablation a few weeks before admission and had been cardioverted a few days after the procedure because of relapse of atrial fibrillation.
CASE PRESENTATION
On admission, the patient had systolic blood pressure of 80 mm Hg and an ECG with broad QRS-complexes at 380 ms. We suspected intoxication and she was intubated to administer activated charcoal after gastric lavage. She was cardiovascularly unstable and in need of intravenous infusion of noradrenaline and adrenaline. Further investigations at her home suggested that she had poisoned herself with 4-5 g flecainide, 0.3 g oxazepam and 0.5 g meclizine. After administration of 500 mmol sodium bicarbonate and 5 mmol calcium chloride, the QRS complexes narrowed temporarily. On day 2, due to sustained bradycardia and hypotension despite receiving adrenergic medications, a temporary pacemaker was implanted, leading to improved heart rate and blood pressure. She experienced several complications including hypertensive pulmonary oedema, atrial fibrillation, extensively prolonged QT interval because of polypharmacy and Takotsubo cardiomyopathy. She was discharged from the hospital in good health on day 17. At a follow-up visit at the outpatient clinic 12 weeks later, cardiac function had normalised. The QT interval was now normal; however, there were persistent T-wave inversions in leads I, aVL and V4-6.
INTERPRETATION
Flecainide blocks sodium channels in cardiomyocytes. Intoxication with flecainide is rare, with mortality rates of about 10 %. Sodium bicarbonate in larger doses has been reported to stabilise patients with flecainide intoxication due to modification of the binding of flecainide to sodium receptors in cardiomyocytes, and due to alkalisation which makes flecainide detach from sodium receptors. Our patient had a temporary effect with narrowing of QRS complexes after receiving sodium bicarbonate. She also showed a beneficial effect from implantation of a temporary pacemaker, although earlier case reports have described problems with high thresholds and capture failure.
Topics: Anti-Arrhythmia Agents; Charcoal; Drug Overdose; Electrocardiography; Female; Flecainide; Humans; Middle Aged; Pacemaker, Artificial; Shock; Sleepiness; Sodium Bicarbonate
PubMed: 31140247
DOI: 10.4045/tidsskr.18.0683 -
Acta Tropica Jul 2019Leishmaniases are infectious diseases caused by protozoan parasites Leishmania and transmitted by sand flies. Drug repurposing is a therapeutic approach that has shown...
Leishmaniases are infectious diseases caused by protozoan parasites Leishmania and transmitted by sand flies. Drug repurposing is a therapeutic approach that has shown satisfactory results in their treatment. Analyses of antihistaminic drugs have revealed their in vitro and in vivo activity against trypanosomatids. In this way, this study evaluated the antileishmanial activity of H1-antihistamines and identified the cellular alterations in Leishmania (L.) infantum. Cinnarizine, cyproheptadine, and meclizine showed activity against promastigotes with 50% inhibitory concentration (IC) values between 10-29 μM. These drugs also demonstrated activity and selectivity against intracellular amastigotes, with IC values between 20-35 μM. Fexofenadine and cetirizine lacked antileishmanial activity against both forms. Mammalian cytotoxicity studies revealed 50% cytotoxic concentration values between 52 - >200 μM. These drugs depolarized the mitochondria membrane of parasites and caused morphological alterations, including mitochondrial damage, disorganization of the intracellular content, and nuclear membrane detachment. In conclusion, the L. infantum death may be ascribed by the subcellular alterations followed by a pronounced decrease in the mitochondrial membrane potential, indicating dysfunction in the respiratory chain upon H1-antihistamine treatment. These H1-antihistamines could be used to explore new routes of cellular death in the parasite and the determination of the targets at a molecular level, would contribute to understanding the potential of these drugs as antileishmanial.
Topics: Animals; Antiprotozoal Agents; Female; Histamine H1 Antagonists; Leishmania infantum; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C
PubMed: 31002807
DOI: 10.1016/j.actatropica.2019.04.017 -
Scandinavian Journal of Primary Health... Mar 2019Hyperemesis gravidarum (HG) affects 0.3-3% of pregnant women and is a leading cause of hospitalization in early pregnancy. The aim of the study was to investigate...
OBJECTIVE
Hyperemesis gravidarum (HG) affects 0.3-3% of pregnant women and is a leading cause of hospitalization in early pregnancy. The aim of the study was to investigate women's treatment and management of HG, as well as the consequences of HG on women's daily life.
DESIGN AND SETTING
A cross-sectional study based on a structured telephone interview and an online questionnaire. Participants were recruited by social media and by the Norwegian patient's organization for HG.
SUBJECTS
Norwegian women that experienced HG.
MAIN OUTCOME MEASURE
Women's perspectives on management and consequences of HG.
RESULTS
The study included 107 women. Maternal morbidity was profound; about 3/4 of participants were hospitalized due to HG, and the majority showed clinical signs of dehydration (79%), ketonuria (75%), and >5% weight loss (84%). Antiemetics were used by >90% and frequently prescribed "as needed". Metoclopramide (71%) and meclozine (51%) were most commonly used. Participants described HG as having severe psychosocial consequences and profound impact on daily activities. Almost two out of five reported thoughts of elective abortion, and 8 women had at least one elective pregnancy termination due to HG. Overall, 20 women (19%) changed GPs due to dissatisfaction with HG management.
CONCLUSION
Despite the high psychosocial burden and major impact on daily activities, many women with HG reported a lack of support from healthcare professionals and suboptimal management. Greater awareness and knowledge among healthcare professionals is needed to improve care for women with HG. Key Points There is a paucity of studies on management and the consequences of HG on women's daily lives and psychosocial burden. We found that: • Many women described HG as one of their worst life experiences with profound morbidity. • Many women reported suboptimal management of HG and lack of support from healthcare professionals. • Greater understanding of patient perspectives among healthcare professionals is important to improve care and management for HG patients.
Topics: Abortion, Induced; Activities of Daily Living; Adult; Antiemetics; Attitude; Cross-Sectional Studies; Dehydration; Emotions; Female; Hospitalization; Humans; Hyperemesis Gravidarum; Ketosis; Meclizine; Metoclopramide; Nausea; Norway; Patient Satisfaction; Pregnancy; Pregnant Women; Quality of Life; Severity of Illness Index; Surveys and Questionnaires; Weight Loss
PubMed: 30822254
DOI: 10.1080/02813432.2019.1569424 -
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