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Clinical Drug Investigation Nov 2019Vertigo derived from peripheral vestibular disorders is quite frequently encountered in daily clinical practice and can be a severely disabling symptom associated with... (Comparative Study)
Comparative Study Randomized Controlled Trial
Efficacy and Safety of a Fixed Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg vs Betahistine Dihydrochloride 16 mg in Patients with Peripheral Vestibular Vertigo: A Prospective, Multinational, Multicenter, Double-Blind, Randomized, Non-inferiority Clinical Trial.
BACKGROUND AND OBJECTIVE
Vertigo derived from peripheral vestibular disorders is quite frequently encountered in daily clinical practice and can be a severely disabling symptom associated with substantial impairment of health-related quality of life for the affected patients. Betahistine, a structural analogue of histamine and presumably the most widely prescribed anti-vertigo drug worldwide, has previously been shown to be an effective and safe treatment for these patients. The objective of the present study was to evaluate whether the fixed combination of cinnarizine and dimenhydrinate (Arlevert) is non-inferior and thus a potentially useful alternative to betahistine dihydrochloride in the treatment of patients suffering from peripheral vestibular vertigo.
METHODS
In this prospective, multicenter, double-blind, randomized, non-inferiority clinical trial, outpatients from 8 ENT clinics in Austria, Bulgaria, the Czech Republic and Russia were randomly assigned to receive three times daily one tablet of either the fixed combination cinnarizine 20 mg/dimenhydrinate 40 mg or betahistine dihydrochloride 16 mg for 4 weeks. Primary endpoint was the reduction of the mean vertigo score (MVS), a validated 12-item composite score defined as the mean of 6 vertigo symptoms (dystasia and walking unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation, blackout) and 6 trigger factors for vertigo (change of position, bowing, getting up, driving by car/train, head movements, eye movement), after 4 weeks of therapy, as judged by the patient on a 5-point visual analogue scale (VAS). The non-inferiority margin was set to 0.3. Secondary outcomes included the patient's and investigator's judgment of global efficacy, the patient's rating of impairment of daily activities, and safety/tolerability of the treatments.
RESULTS
Three hundred and six patients (mean age 53.5 years, approximately 60% female) were enrolled and randomized to the fixed combination cinnarizine/dimenhydrinate (n = 152) or betahistine (n = 154) groups; 297 patients completed the study and 294 (146 and 148, respectively) were valid for the per-protocol analysis, which was used for the non-inferiority analysis. Treatment with cinnarizine/dimenhydrinate led to a stronger reduction of the MVS [least squares mean (LSM)] after 4-week therapy (primary endpoint) in comparison to betahistine (0.395 vs 0.488; difference: - 0.093, 95% CI - 0.180; - 0.007, p = 0.035); since the upper limit of the two-sided 95% confidence interval was not only below the non-inferiority margin of 0.3, but also entirely below 0, superiority of the fixed combination could be demonstrated. The combination preparation was also more effective after 1 week of therapy and received more favorable patient's ratings on overall efficacy and impairment of daily activities. Both treatments were very well tolerated. Only 12 patients (3.92%) reported 13 non-serious adverse events; 2 cinnarizine/dimenhydrinate-treated patients discontinued the study prematurely due to adverse events as compared to 5 betahistine-treated patients.
CONCLUSION
The fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg was found to be not only non-inferior, but superior to betahistine 16 mg in the improvement of peripheral vestibular vertigo. Furthermore, taking into account a good and slightly favorable safety profile, the present study provides evidence that the fixed-combination preparation is a potent and even superior alternative to betahistine in the treatment of vertigo related to peripheral vestibular disorders.
STUDY REGISTRATION
EudraCT No. 2011-004025-27.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Betahistine; Cinnarizine; Dimenhydrinate; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Prospective Studies; Vertigo; Young Adult
PubMed: 31571128
DOI: 10.1007/s40261-019-00858-6 -
BMJ Quality & Safety Dec 2019Benzodiazepines and sedative hypnotics (BSH) have numerous adverse effects that can lead to negative outcomes, particularly in vulnerable hospitalised older adults. At... (Comparative Study)
Comparative Study
BACKGROUND
Benzodiazepines and sedative hypnotics (BSH) have numerous adverse effects that can lead to negative outcomes, particularly in vulnerable hospitalised older adults. At our institution, over 15% of hospitalised older adults are prescribed sedative-hypnotics inappropriately. Of these prescriptions, 87% occurred at night to treat insomnia and almost 20% came from standard admission order sets.
METHODS
We conducted a time-series study from January 2015 to August 2016 among medical and cardiology inpatients following the implementation in August 2015 of a sedative reduction bundle (education, removal of BSH from available admission order sets and non-pharmacological strategies to improve sleep). Preintervention period was January-July 2015 and postintervention period was August 2015-August 2016. A surgical ward served as control. Primary outcome was the proportion of BSH-naive (not on BSH prior to admission) patients 65 years or older discharged from medical and cardiology wards who were prescribed any new BSH for sleep in hospital. Data were analysed on statistical process control (SPC) p-charts with upper and lower limits set at 3δ using standard rules. Secondary measures included Patient-reported Median Sleep Quality scores and rates of fall and sedating drug prescriptions that may be used for sleep (dimenhydrinate).
RESULTS
During the study period, there were 5805 and 1115 discharges from the intervention and control units, respectively. From the mean baseline BSH prescription rate of 15.8%, the postintervention period saw an absolute reduction of 8.0% (95% CI 5.6% to 10.3%; p<0.001). Adjusted for temporal trends, the intervention produced a 5.3% absolute reduction in the proportion of patients newly prescribed BSH (95% CI 5.6% to 10.3%; p=0.002). BSH prescription rates remained stable on the control ward. Patient-reported measure of sleep quality, falls and use of other sedating medications remained unchanged throughout the study duration.
CONCLUSION
A comprehensive intervention bundle was associated with a reduction in inappropriate BSH prescriptions among older inpatients.
Topics: Aged; Aged, 80 and over; Drug Utilization; Female; Health Education; Health Personnel; Hospitalization; Hospitals, University; Humans; Hypnotics and Sedatives; Inpatients; Male; Ontario; Prescription Drug Misuse; Sleep Initiation and Maintenance Disorders
PubMed: 31270252
DOI: 10.1136/bmjqs-2018-009241 -
Drug Delivery and Translational Research Oct 2019The objective of the study was the development and in vitro characterization of a self-emulsifying drug delivery system (SEDDS) for the nasal application of...
The objective of the study was the development and in vitro characterization of a self-emulsifying drug delivery system (SEDDS) for the nasal application of dimenhydrinate. Final composition of SEDDS was established based on drug solubility and stability studies. Dimenhydrinate was loaded into the SEDDS pre-concentrates to 7.5% (m/v). The droplet size of the final SEDDS formulations was in a range between 60 and 220 nm. Permeability, as well as tissue toxicity, of the formulations was investigated using bovine nasal mucosa. Enhancement in permeation up to 2.8-fold compared to pure dimenhydrinate was confirmed. Furthermore, toxicity studies did not reveal any serious tissue damages related to the SEDDS. Additionally, irritation potential of SEDDS was evaluated in ciliary beat frequency measurements. Incorporation of dimenhydrinate into SEDDS might therefore be considered as a promising approach within the field of nasal delivery of antiemetics by utilizing permeation enhancement strategy.
Topics: Administration, Intranasal; Animals; Antiemetics; Cattle; Cilia; Dimenhydrinate; Drug Delivery Systems; Drug Liberation; Emulsions; In Vitro Techniques; Nasal Mucosa; Permeability; Solubility
PubMed: 30877627
DOI: 10.1007/s13346-019-00634-1 -
Journal of Addiction Medicine 2019: Reporting of intoxication and withdrawal from aberrant use of over-the-counter medication has been sparse and inconsistent in literature. Attributed to their...
: Reporting of intoxication and withdrawal from aberrant use of over-the-counter medication has been sparse and inconsistent in literature. Attributed to their anticholinergic properties, medications such as dimenhydrinate (Gravol) taken in supratherapeutic doses have been associated with euphoria, anxiolysis, and hallucinations. We present a case of a woman in her forties, with a psychiatric history of bipolar disorder, and complex concurrent medical history including familial Mediterranean fever (FMF), and fibromyalgia, admitted for withdrawal management of her intravenous dimenhydrinate use. As a result of her FMF, there were numerous hospital admissions and treatment which required intravenous access. Hence, a physician-inserted intravenous access port was placed on her chest. The port was maintained monthly with the help of a community agency. In this port, she was injecting 100 to 200 mg of dimenhydrinate hourly for its euphoric and calming effects, consuming upwards of 2400 mg/d. Comprehensive laboratory work-up and urine drug screening were unremarkable. Vital signs were stable. Her mental status at time of admission was lethargic, unfocused, but calm. Her withdrawal symptoms included severe nausea, vomiting, sedation, headaches, dizziness, anxiety, and muscle stiffness. Her detoxification was managed with benztropine and lorazepam, and was well tolerated. The patient was discharged to a community inpatient rehabilitation center. Urine drug testing before discharge was negative. This case draws attention to the addictive potential of dimenhydrinate and offers a regime for its medical withdrawal management. Additionally, this case highlights that screening and management of over-the-counter medications warrants further clinical consideration and investigation.
Topics: Benztropine; Bipolar Disorder; Dimenhydrinate; Female; Humans; Infusions, Intravenous; Lorazepam; Middle Aged; Poisoning; Psychotropic Drugs
PubMed: 30844875
DOI: 10.1097/ADM.0000000000000511 -
Veterinary Dermatology Apr 2019Histamine type-1 (H1) receptor antagonists such as diphenhydramine are frequently used for treatment of pruritus in dogs, yet therapeutic efficacy for allergic disorders... (Comparative Study)
Comparative Study
Diphenhydramine pharmacokinetics after oral and intravenous administration of diphenhydramine and oral administration of dimenhydrinate to healthy dogs, and pharmacodynamic effect on histamine-induced wheal formation: a pilot study.
BACKGROUND
Histamine type-1 (H1) receptor antagonists such as diphenhydramine are frequently used for treatment of pruritus in dogs, yet therapeutic efficacy for allergic disorders is reported to be highly variable. Dimenhydrinate is a salt of diphenhydramine and 8-chlorotheophylline, and has been reported to produce superior oral absorption of diphenhydramine.
HYPOTHESIS/OBJECTIVE
To determine the pharmacokinetic and pharmacodynamic properties of diphenhydramine in dogs after intravenous (1 mg/kg) and oral (5 mg/kg) administration, and when given orally as dimenhydrinate at a dose of 10 mg/kg (≈5 mg/kg diphenhydramine).
ANIMALS
Each drug was administered to six healthy, fasted mixed-breed dogs in a research facility, using a cross-over design.
METHODS AND MATERIALS
Blood samples were collected for pharmacokinetic analysis of diphenhydramine and chlorotheophylline at defined intervals. Pharmacodynamic response was measured by histamine-mediated cutaneous wheal formation.
RESULTS
There was great variability in the data and one dog was an extreme outlier. The mean systemic availabilities of diphenhydramine were 7.8% and 22.0% after oral administration of diphenhydramine and dimenhydrinate, respectively, whereas the mean maximum concentrations were 36 (± 20) and 124 (± 46) ng/mL. The terminal elimination half-lives of diphenhydramine and dimenhydrinate were 5.0 (± 7.1) and 11.6 (± 17.7) h, respectively. Plasma diphenhydramine concentrations did not correlate with the percentage reduction in histamine-induced wheal formation. Theophylline reached plasma concentrations considered to be therapeutic for dogs.
CONCLUSION
Oral absorption of diphenhydramine was approximately three times greater with a longer half-life when it was administered as the combination product dimenhydrinate.
Topics: Administration, Intravenous; Administration, Oral; Animals; Cross-Over Studies; Dimenhydrinate; Diphenhydramine; Dogs; Female; Half-Life; Histamine; Histamine Antagonists; Male; Pilot Projects; Theophylline; Urticaria
PubMed: 30779257
DOI: 10.1111/vde.12727 -
Advanced Pharmaceutical Bulletin Nov 2018To develop fast dissolving oral film to address vomiting and nausea in pediatric population. Oral films of Dimenhydrinate were prepared by solvent casting method by...
To develop fast dissolving oral film to address vomiting and nausea in pediatric population. Oral films of Dimenhydrinate were prepared by solvent casting method by using hydroxypropylmethyl cellulose E5 (HPMC E5), polyethylene glycol 400 (PEG 400) and croscarmellose sodium. Solubility of dimenhydrinate was enhanced by ethanol as a co-solvent. To make dimenhydrinate palatable sodium saccharin and peppermint oil were used. All films were evaluated for mechanical parameters, surface pH, morphology, disintegration time and percent dissolution. Films were smooth, acceptable and white in colour. For optimized batch, drug content (99.106%), disintegration time (25 sec), dissolution (99.10% in 210 sec), surface pH (6.81) were acceptable. Optimized batch, due to its potential to deliver through fast dissolving film, can be developed for clinical use.
PubMed: 30607345
DOI: 10.15171/apb.2018.081 -
Biomedicine & Pharmacotherapy =... Jan 2019Colorectal cancer (CRC) is the most common carcinoma of the digestive tract. The slow growing nature of CRC offers a great opportunity for prevention strategies. The...
Colorectal cancer (CRC) is the most common carcinoma of the digestive tract. The slow growing nature of CRC offers a great opportunity for prevention strategies. The concept of chemoprevention of colorectal cancer using plant derived natural products is gaining substantial attention because it is an inherently safe and cost-effective alternative to conventional cancer therapies. Piperlongumine (PL), a natural alkaloid present in Piper longum Linn has been reported to exhibit notable anticancer effects in various in vitro studies. Nonetheless, the chemopreventive potential of PL has not been studied in experimentally induced colon cancer yet. Ras/PI3K/Akt/mTOR signaling axis plays a central role in promoting tumor cell growth, proliferation and survival by inhibiting apoptosis. In the present study, we demonstrated, for the first time, the chemopreventive effects of PL in DMH + DSS induced colon carcinogenesis animal model. We showed that PL displayed potent antineoplastic activity against colon cancer cell growth by targeting Ras proteins and PI3K/Akt signaling cascade. PL mediated inhibition of tumor cell growth was associated with inhibition of Ras protein levels and its preferred companion protein PI3K levels that led to suppressed activity of Akt/NF-κB, c-Myc and cyclin D1. It was also found that PL arrested the cell cycle progression at G2/M phase and induced mitochondrial apoptotic pathway by downregulating Bcl-2 levels. Furthermore, the results of liver and kidney toxicity suggested that PL exhibit no toxicity in animals. Our results suggest that PL may be an effective chemopreventive agent for colon cancer.
Topics: Alkaloids; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Dextran Sulfate; Dimenhydrinate; Dioxolanes; G2 Phase Cell Cycle Checkpoints; Male; Mice; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinases; Piper; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 30551398
DOI: 10.1016/j.biopha.2018.10.182 -
Materials Science & Engineering. C,... Jan 2019In the present study, electrochemical studies and potentiometric determination of captopril (CAP) drug were presented using a glassy carbon electrode (GCE) and carbon...
Application of a nano-structured molecularly imprinted polymer as an efficient modifier for the design of captopril drug selective sensor: Mechanism study and quantitative determination.
In the present study, electrochemical studies and potentiometric determination of captopril (CAP) drug were presented using a glassy carbon electrode (GCE) and carbon paste electrode (CPE), respectively; which is modified with a synthetic nano-structured molecularly imprinted polymer (MIP). CAP-MIP sample with an average particle size of 95 nm was synthesized using a precipitation polymerization method. The electrochemical behavior of CAP was studied on a MIP modified GCE, in an aqueous solution at pH 3.0. The electron transfer coefficient (α) was determined for the CAP drug, using electrochemical approaches. The prepared CAP-MIP was also used as a modifier in a CPE to design a selective CAP sensor, before its potentiometric determination. The modified CPE exhibits a good electrochemical response with a Nernstian slope of 59.15 ± 1.5 mV per decade over a wide linearity in the concentration range of 3.0 × 10-1.0 × 10 mol L. The cyclic voltammetry results were in good agreement with the electrochemical studies for the 1H/1e process. The designed electrode indicates a reasonable selectivity for CAP over other studied drugs such as ibuprofen, paracetamol, acyclovir, pyrazinamide, dimenhydrinate, and naproxen as well as with an excellent applicability in some pharmaceutical products.
Topics: Captopril; Carbon; Electrochemical Techniques; Electrodes; Glass; Hydrogen-Ion Concentration; Molecular Imprinting; Nanostructures; Polymers; Reproducibility of Results; Spectroscopy, Fourier Transform Infrared; Tablets; Time Factors
PubMed: 30423775
DOI: 10.1016/j.msec.2018.10.042 -
Deutsches Arzteblatt International Oct 2018Seasickness and travel sickness are classic types of motion illness. Modern simulation systems and virtual reality representations can also induce comparable symptoms.... (Review)
Review
BACKGROUND
Seasickness and travel sickness are classic types of motion illness. Modern simulation systems and virtual reality representations can also induce comparable symptoms. Such manifestations can be alleviated or prevented by various measures.
METHODS
This review is based on pertinent publications retrieved by a PubMed search, with special attention to clinical trials and review articles.
RESULTS
Individuals vary in their susceptibility to autonomic symptoms, ranging from fatigue to massive vomiting, induced by passive movement at relatively low frequencies (0.2 to 0.4 Hz) in situations without any visual reference to the horizontal plane. Younger persons and women are considered more susceptible, and twin studies have revealed a genetic component as well. The various types of motion sickness are adequately explained by the intersensory conflict model, incorporating the vestibular, visual, and proprioceptive systems and extended to include consideration of postural instability and asymmetry of the otolith organs. Scopolamine and H1-antihistamines, such as dimenhydrinate and cinnarizine, can be used as pharmacotherapy. The symptoms can also be alleviated by habituation through long exposure or by the diminution of vestibular stimuli.
CONCLUSION
The various types of motion sickness can be treated with general measures to lessen the intersensory conflict, behavioral changes, and drugs.
Topics: Fatigue; Histamine Antagonists; Humans; Motion Sickness; Neurophysiology; Vomiting
PubMed: 30406755
DOI: 10.3238/arztebl.2018.0687 -
Chemosphere Jan 2019Exposure to high levels of metals/metalloids may impair semen quality. Computer-aided sperm analysis (CASA) can be used for kinematic analysis of spermatozoa, which...
BACKGROUND
Exposure to high levels of metals/metalloids may impair semen quality. Computer-aided sperm analysis (CASA) can be used for kinematic analysis of spermatozoa, which provides additional insights into sperm motion characteristics.
OBJECTIVE
To explore the associations of urinary and seminal plasma metal/metalloid concentrations with CASA motion parameters and assess the degree of correspondence between the two sample types.
METHODS
Eighteen metals/metalloids in seminal plasma and repeated urine samples were determined among 746 men recruited from a reproductive center. We assessed their associations with 6 CASA motion parameters [i.e., straight-line velocity (VSL), curvilinear velocity (VCL), average path velocity (VAP), linearity (LIN), straightness (STR) and amplitude head displacement (ALH)] using multivariable linear regression models.
RESULTS
We found significantly inverse dose-dependent relationships between seminal plasma arsenic (As) and VSL, VCL and VAP, between seminal plasma selenium (Se) and VSL and VAP, between seminal plasma zinc (Zn) and STR and LIN, and between seminal plasma manganese (Mn) and LIN in single-metal models [all false discovery rate (FDR) adjusted P for trend < 0.05]. These dose-response relationships remained statistically significant based on multiple-metal models and restricted cubic spline functions. Metal/metalloid concentrations in urine poorly predicted the same-day seminal plasma concentrations [coefficient of determination (R) < 0.15]. We didn't find any significant associations between urinary metal/metalloid concentrations and the CASA motion parameters.
CONCLUSION
Exposure to high levels of As, Se, Mn and Zn may impair sperm motion capacity. Concentrations of metals/metalloids in spot urine samples cannot accurately predict same-day seminal plasma exposure levels.
Topics: Dimenhydrinate; Humans; Male; Metalloids; Semen; Semen Analysis; Spermatozoa
PubMed: 30296767
DOI: 10.1016/j.chemosphere.2018.10.001