The phosphatidylethanolamine biosynthesis pathway provides a new target for cancer chemotherapy.

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.

Lipids bearing extruded-spheronized pellets for extended release of poorly soluble antiemetic agent-Meclizine HCl.

BACKGROUND: Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. METHODS: Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol®), Glyceryl palmitostearate (Precirol®), Glyceryl behenate (Compritol®) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5-1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. RESULTS: Sphericity indicated by shape factor (eR) varied with type and concentration of lipids: Geleol® (eR = 0.891-0.997), Precirol® (eR = 0.611-0.743), Compritol® (eR = 0.665-0.729) and Carnauba wax (eR = 0.499-0.551). Highly spherical pellets were obtained with Geleol® (Aspect ratio = 1.005-1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153-1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol® and Compritol®, (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax. Scanning electron microscopy of Compritol® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol® and Compritol® pellets, explained by Korsmeyer-Peppas (R2 = 0.978-0.993) indicated non-Fickian diffusion (n = 0.519-0.597). Combinations of (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax pellets followed Zero-order (R2 = 0.991-0.995). Similarity test was performed using combination of Geleol® and Compritol® (i) as a reference. CONCLUSIONS: Matrices for the extended release of Meclizine HCl from extruded-spheronized pellets were successfully formed by using three lipids (Geleol®, Compritol® and Carnauba wax) in different combinations. The encapsulated pellets of Meclizine HCl can be effectively used for treatment of motion sickness, nausea and vertigo for extended period of time.

Prenatal and developmental toxicity study of meclizine and caffeine combination in female albino Wistar rats.

Meclizine and caffeine combination is used for the treatment of morning sickness. Both compounds are teratogenic and caffeine is known to possess anti-fertility activity also. The present study was undertaken to evaluate the reproductive toxic effect of meclizine and caffeine combination. Three doses were taken for the study; low dose (LD; meclizine 3.7 mg/kg and caffeine 3 mg/kg) was selected from commercially available formulation, middle dose (MD; meclizine 37 mg/kg and caffeine 30 mg/kg) and high dose (HD; meclizine 370 mg/kg and caffeine 300 mg/kg). The mixture was administered 1-7 days and 8-14 days for fertility and embryotoxic studies respectively. Laparotomy was done on 10t day of gestation period. Number of implants and corpora lutea were counted, pre and post-implantation losses were determined. In embryo toxicity study fetuses were evaluated for external, skeletal and visceral examination. High dose was removed from both fertility and embryotoxicity studies due to its severe toxicity to the dam. Significant anti-fertility activity was observed at middle dose. Embryotoxicity study showed significant reduction in fetal body weight, body length and body mass index, dam body weight gain on gestation day 14. Absolute kidney weight in MD and absolute and relative spleen weight in both LD and MD were significantly reduced. There was no increase in external or internal congenital anomalies at both LD and MD. The, results suggest that prescription of meclizine and caffeine for morning sickness in early pregnancy should be reviewed carefully.

Evaluation of teratogenic effects of risperidone following simultaneous administration with antihypertensive and antiemetic drugs.

Multiple drug administration is an important aspect of clinical practice particularly in specific physiological situation such as in neonates, elderly or pregnancy, since in all such situations, possibility of unwanted effects increases due to altered body physiology. In present study, the teratogenic effects of multiple drug administration risperidone, meclizine/pyridoxine and hydralazine have been compared with the teratogenic effects of individual drugs in pregnant mice. Moreover the role of folic acid and α-tocopherol if any had also been investigated in reducing the teratogenic effects of these drugs in combinations.

Biphasic dosing regimen of meclizine for prevention of postoperative nausea and vomiting in a high-risk population.

The purpose of this study was to determine if giving 50 mg of meclizine the night before and on the day of surgery would effectively reduce postoperative nausea and vomiting (PONV) for the entire 24 hours after surgery in patients identified as being at high risk for PONV Subjects were randomly assigned to receive either 50 mg of oral meclizine (experimental group) or a placebo (control group) the night before and the day of surgery. All subjects were intravenously administered 4 mg of ondansetron before the conclusion of surgery. Seventy subjects (35 control; 35 experimental) were included in analysis. postoperaIn the placebo group we noted higher verbal numeric rating scale scores for nausea, a higher incidence oftive nausea and vomiting (PONV) continues to be a common complication after general anesthesia, with the incidence ranging from 17% to 87%.15 It has been reported that PONV increased antiemetic requirements, and lower overall anesthesia satisfaction scores at all time intervals measured, compared with the experimental group, but the differences were not statistically significant until analyzed by postoperative setting. No difference in sedation or side effects was noted between groups. Based on these results, we recommend that the administration of 50 mg of oral meclizine the night before and on the day of surgery be considered effective antiemetic prophylaxis in patients identified as having a high risk for PONV.

Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia.

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean Cmax, Tmax, AUC0-24h, t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng·h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC0-10h of the fasting and fed condition were 504 ng·h/mL and 813 ng·h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.

Nanotechnology based blended chitosan-pectin hybrid for safe and efficient consolidative antiemetic and neuro-protective effect of meclizine hydrochloride in chemotherapy induced emesis.

The aim of this study was to formulate an easily-administered, safe and effective dosage form loaded with meclizine for treatment of chemotherapy-induced nausea and vomiting (CINV) through the buccal route. CINV comprises bothersome side effects accompanying cytotoxic drugs administration in cancer patients. Meclizine was loaded in chitosan-pectin nanoparticles which were further incorporated within a buccal film. Different formulations were prepared based on a 21.31 full factorial study using Design Expert®8. The optimum formulation possessed favorable characters regarding its particle size (129 nm), entrapment efficiency (90%) and release profile. Moreover, its permeation efficiency through sheep buccal mucosa was assessed via Franz cell diffusion and confocal laser microscopy methods. Enhanced permeation was achieved compared with the free drug form. In-vivo performance was assessed using cyclophosphamide induced emesis. The proposed formulation exerted significant relief of the measured responses (reduced body weight and motor coordination, elevated emesis, anorexia, proinflammatory mediators and neurotransmitters that were also associated with scattered degenerated neurons and glial cells). The developed formulation ameliorated all behavioral, biochemical and histopathological changes induced by cyclophosphamide. The obtained data were promising suggesting that our bioadhesive formulation can offer an auspicious medication for treating distressing symptoms associated with chemotherapy for cancer patients.

Vertigo - part 2 - management in general practice.

BACKGROUND: Vertigo is a common clinical problem managed by general practitioners. OBJECTIVE: This article focuses on the acute management of a vertigo attack, specific management of conditions causing vertigo, and the long term management issues associated with chronic vertigo. DISCUSSION: Supportive treatment, antiemetic and vestibular blocking agents help relieve an acute vertigo attack, however the prolonged use of such medications is not recommended. Specific treatments for various conditions causing vertigo are available, however, the majority of patients are managed symptomatically. The patient's ability to drive safely should be carefully assessed according to Austroads guidelines and advice from an ear, nose and throat surgeon should be sought when in doubt. There is evidence to support the efficacy of vestibular rehabilitation programs for unilateral peripheral vestibular disorder and these programs should be considered. A simple program including patient education and home based exercises can be sufficient.

Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia.

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3). No effective FGFR3-targeted therapies for ACH are currently available. By drug repositioning strategies, we identified that meclozine, which has been used as an anti-motion-sickness, suppressed FGFR3 signaling in chondrocytes and rescued short-limbed phenotype in ACH mouse model. Here, we conducted various pharmacological tests for future clinical application in ACH. Pharmacokinetic analyses demonstrated that peak drug concentration (Cmax) and area under the concentration-time curve (AUC) of 2 mg/kg of meclozine to mice was lower than that of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. Pharmacokinetic simulation studies showed that repeated dose of 2 mg/kg of meclozine showed no accumulation effects. Short stature phenotype in the transgenic mice was significantly rescued by twice-daily oral administration of 2 mg/kg/day of meclozine. In addition to stimulation of longitudinal bone growth, bone volume and metaphyseal trabecular bone quality were improved by meclozine treatment. We confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined.

Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.

OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3ach mice than in wild-type mice (p < 0.005). There were no bony bridges in the spheno-occipital and anterior intraoccipital synchondroses in wild-type mice, while some of the synchondroses prematurely closed in untreated Fgfr3ach mice at PD 4.5. The average bony bridge score in the cranial base was 7.053 ± 1.393 in untreated Fgfr3ach mice and 6.125 ± 2.029 in meclozine-treated Fgfr3ach mice. The scores were not statistically significant between mice with and those without meclozine treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 ± 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 ± 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature closure of synchondroses in some Fgfr3ach mice, but the effect on preventing bony bridge formation was not significant, probably due to low placental transmission of the drug. Meclozine is likely to exhibit a marginal effect on premature closure of synchondroses at the cranial base in ACH.

Preparation of an oral thin film containing meclizine hydrochloride: In vitro and in vivo evaluation.

Oral thin film (OTF) is a preparation of postage stamp size, with advantages of flexible, tasty and without water for oral administration. A commercial product (Zentrip®) was developed for people who suffered from motion sickness. In order to improve the mechanical strength of Zentrip®, OTF containing meclizine hydrochloride (MH) was designed and prepared using the solvent casting method. The characteristics of the prepared OTF were evaluated using micrometer, auto stripping tester, DSC, X-ray diffraction. ATR-FTIR was employed to investigate the interaction between drug and polymer. The thickness of MH OTF obtained was 0.116±0.004mm, the tensile strength was 17.37±1.54Nmm(-2) and the drug dissolution at 5min was more than 80% both in distilled water and 0.1mol/L HCL. DSC and XRD showed MH was amorphous in the polymer. ATR-FTIR indicated the MH molecules inserted into the network structure of polymer, which resulted in an inhibition of drug recrystallization. The Cmax of Zentrip® and MH OTF were 1.46±0.44µg/mL and 1.91±0.51µg/mL, and the AUC were 10.38±2.93µgh/mL and 13.74±3.23µgh/mL, respectively. Compared with Zentrip®, MH OTF successfully overcome the weakness of mechanical strength, possessed faster dissolution profile and showed bioequivalence in pharmacokinetics, deserving to a further development.

Comparison of meclizine levels in the plasma of rats and dogs after intranasal, intravenous, and oral administration.

Meclizine, used prophylactically for the prevention of motion sickness and vertigo, is presently available only in oral form. We report herein that, when given intranasally, meclizine dihydrochloride is absorbed in rats about half as effectively as when given intravenously, but about six times more effectively than after oral administration, as estimated by the area under the plasma concentration-time curve. The mean times to peak levels in plasma are about 8.5 min after an intranasal dose and 49.0 min after oral delivery. We extended these studies to a second species, the beagle dog, and achieved qualitatively similar results with a new formulation (Mecnazone; Nastech Pharmaceutical Co., Inc.). The fraction absorbed intranasally was about 0.89 that of an equivalent intravenous dose but about four times that of an equivalent oral administration. In these studies, the mean times to peak levels in plasma was 11.9 min after an intranasal dose and 70.0 min after an oral dose. Terminal elimination kinetics were the same for all routes within each species. Intranasal delivery of meclizine therefore appears to be superior to the oral route for the more rapid achievement of substantial levels in plasma at a reduced dose.

Apparatus for studying in vitro drug release from medicated chewing gums.

An apparatus for in vitro drug release testing of medicated chewing gums has been developed and is described in detail. The effects on the drug release when varying critical instrumental settings such as the chewing stroke frequency, the distance between the chewing surfaces, the twisting movements of these surfaces and the temperature of the test medium have been thoroughly investigated. It has been shown that the drug release can be tuned to obtain suitable drug release profiles for a number of products: Nicorette((R)) and Nicotinell((R)) (active substance nicotine), Travvell((R)) (dimenhydrinate), V6((R)) (xylitol) and an experimental formulation containing meclizine. The main usage of the present apparatus should be within quality control but the present study has also shown that it may be employed within development pharmaceutics since useful in vivo/in vitro relationships may be obtained due to the versatile settings of the critical instrumental parameters.

Equipment for drug release testing of medicated chewing gums.

An apparatus was specially designed and constructed for release testing of medicated chewing gums. The adjustable instrumental settings such as temperature, chewing frequency, chewing time, volume of test medium, distance between the jaws and twisting angle increased the versatility of the apparatus. Selection of the test medium was also an important parameter. Each sample was kneaded mechanically in separate test chambers and the drug release was followed by sampling and HPLC analysis. Different gum formulations were tested and the obtained results demonstrated satisfactory release curves for a variety of formulations and active ingredients. The tested gum formulations comprised nicotine, meclizine, dimenhydrinate and xylitol. The apparatus proved to be suitable in product control of commercial batches but also a useful tool in the research and development of medicated gum formulations.

Transdermal scopolamine in the treatment of acute vertigo.

A double-blind, parallel investigation was undertaken to evaluate the efficacy of transdermally delivered scopolamine hydrobromide in acute vertigo as compared to meclizine hydrochloride and placebo. Statistical analysis of subjective patient responses and clinical observations suggested that both scopolamine and meclizine are more effective than placebo. Both have significant, but different, side effects.

Prevention and treatment of space sickness in shuttle-orbiter missions.

Today it is impossible accurately to predict susceptibility to space sickness of crew members making their first transition into orbit, for want of a ground-based validated model of free fall. Even assuming that space sickness is simply a specific designation for motion sickness that may be experienced in orbital flight (and here agreement is not general), preventive therapy poses difficult problems because, for a priori reasons, either all crew members or none should receive treatment. If all receive preventive therapy, everyone should execute head movements in a programmed manner to ensure rapid adaptation to the environment; at least a large minority will not benefit but rather will experience whatever sideeffects inevitably accompany administration of a drug. If none receive preventive therapy prelaunch, at least a large minority will pose two problems--treatment for acute motion sickness and rapid acquisition of adaptation. Trade-offs will involve the identification of long-acting antimotion sickness drugs for use prelaunch that will be efficacious for at least 90% of those going aloft for the first time and the effectiveness of combining rapid adaptation with treatment of motion sickness. The following report describes recent experiments dealing with these problems.

In vitro release of meclozine hydrochloride from lipophilic suppository bases with or without tensides.

Meclozine hydrochloride suppositories were prepared with lipophilic bases, and the release rate of the drug from molten suppositories was investigated in vitro. Among various suppository bases, the highest rate was obtained when Witepsol H 15 was used. The release rates were affected if nonionic tensides (Tween 20 and 80) were incorporated. In comparison to the tensides-free suppositories, the rates obtained with suppositories containing 5, 20 and 30% of tensides were higher, approximately the same, and lower (respectively). The results were interpreted in terms of the micellar solubilization of the drug with nonionic tensides.

[Dissolution and absorption behavior of meclizine dihydrochloride from soft gelatin capsules].

Two kinds of soft gelatin capsules containing meclizine dihydrochloride (MZ) were prepared by using a medium-chain length triglyceride as a base. One is a self-emulsifying type, and the other is an oil dispersing type. The release of MZ from soft capsules and its in vivo absorption behavior were examined and compared with those of a commercial tablet. The release of MZ from the self-emulsifying soft capsule which was only slightly affected by pH was greater than those from the oil dispersing soft capsule and commercial tablet. The serum levels of MZ after the administration of preparations orally to beagle dogs increased in the order of self-emulsifying soft capsule, commercial tablet, oil dispersing soft capsule. This result suggests that the self-emulsifying soft capsule is useful for the increase of the bioavailability of the drug.

Meclizine metabolism and pharmacokinetics: formulation on its absorption.

Meclizine, an antihistamine, has been widely used for prophylactic treatment and management of motion sickness. However, the onset of action of meclizine was about 1 hour for the treatment of motion sickness and vertigo. A new suspension formulation of meclizine (MOS) was developed with the intention to achieve a rapid effect. To investigate the pharmacokinetics of the new MOS formulation versus the marketed meclizine oral tablet (MOT), a phase 1 pharmacokinetic study was performed in 20 healthy volunteers. In addition, an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme was also performed to determine the metabolic pathway in the human body. The plasma concentration of MOS appeared more rapidly in comparison to the MOT. The geometric mean ratios (90% confidence interval) of AUC(0-24) and AUC(0-∞) indicated no significant difference in bioavailability between the 2 formulations. CYP2D6 was found to be the dominant enzyme for metabolism of meclizine, and its genetic polymorphism could contribute to the large interindividual variability. In view of the similar bioavailability with a much shorter peak time of the plasma meclizine concentration from the MOS formulation, this new formulation is expected to produce a much quicker onset of action when used for the management of motion sickness.