Acute Inhibition of the Human Kv1.5 Channel by H1 Receptor Antagonist Dimenhydrinate: Mode of Action.

Dimenhydrinate, an H1 receptor antagonist, is generally used for the prevention and treatment of nausea and vomiting. However, cardiac arrhythmias have been reported to be associated with the overdose of histamine H1 receptor antagonists, indicating the probable effect of antihistamines on ion channels. By using a two-microelectrode voltage clamp, we have herein studied the electrophysiological effects of dimenhydrinate on the human Kv1.5 channel in the Xenopus oocyte expression system. Dimenhydrinate acutely and reversibly suppressed the amplitudes of the peak and the steady-state current, within 6 min. The inhibitory effect of dimenhydrinate on the peak and the steady-state Kv1.5 currents increased progressively from -10 to +50 mV. At each test voltage, the drug suppressed both the peak and the steady-state currents to a similar extent. When the oocytes were stimulated at the rates of 5- and 30-s intervals, dimenhydrinate-induced a use-dependent blockade of the human Kv1.5 channel. Dimenhydrinate expedited the timecourse of the Kv1.5 channel activation more effectively than the timecourse of its inactivation. However, the activation and inactivation curves of the channel were not altered by the H1 receptor antagonist. In conclusion, we found that dimenhydrinate inhibits the human Kv1.5 channel by changing the channel's activation mode, thereby possibly increasing the possibility of triggering cardiac arrhythmias and affecting atrial fibrillation.

Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer.

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.

Effect of common antivertiginous agents on the high velocity vestibulo-ocular reflex.

OBJECTIVE: It has long been suggested that antivertiginous medications exert their symptomatic effect through inhibition of the vestibulo-ocular reflex (VOR). We tested this hypothesis by directly measuring the VOR after administration of three agents from different substance classes: an antihistamine, a benzodiazepine and a calcium channel antagonist. METHODS: The gain and the variability of the high velocity VOR was assessed using video head impulses (vHIT) under the following conditions: baseline, after dimenhydrinate, after diazepam and after cinnarizine. RESULTS: We found that all three medications did not change any VOR gain or variability parameter: At 60ms, the gain was 0.95 at baseline, 0.99 under dimenhydrinate, 0.99 under diazepam and 0.96 under cinnarizine. The gain variability across repetitive head impulses remained also uninfluenced. CONCLUSIONS: The human high frequency VOR remains robust to pharmacological perturbations at common clinical doses and the assumption that symptomatic vertigo relief is achieved merely through impairment of the VOR requires re-examination. SIGNIFICANCE: Alternative mechanisms of pharmacological action might be operant, such as the modulation of vestibulo-cortical pathways, a differential effect on the low frequency VOR and an altered sensitivity to drugs in acute unilateral vestibulopathy.

Meniere's disease.

Meniere's disease (MD) is a disorder of the inner ear that causes vertigo attacks, fluctuating hearing loss, tinnitus and aural fullness. The aetiology of MD is multifactorial. A characteristic sign of MD is endolymphatic hydrops (EH), a disorder in which excessive endolymph accumulates in the inner ear and causes damage to the ganglion cells. In most patients, the clinical symptoms of MD present after considerable accumulation of endolymph has occurred. However, some patients develop symptoms in the early stages of EH. The reason for the variability in the symptomatology is unknown and the relationship between EH and the clinical symptoms of MD requires further study. The diagnosis of MD is based on clinical symptoms but can be complemented with functional inner ear tests, including audiometry, vestibular-evoked myogenic potential testing, caloric testing, electrocochleography or head impulse tests. MRI has been optimized to directly visualize EH in the cochlea, vestibule and semicircular canals, and its use is shifting from the research setting to the clinic. The management of MD is mainly aimed at the relief of acute attacks of vertigo and the prevention of recurrent attacks. Therapeutic options are based on empirical evidence and include the management of risk factors and a conservative approach as the first line of treatment. When medical treatment is unable to suppress vertigo attacks, intratympanic gentamicin therapy or endolymphatic sac decompression surgery is usually considered. This Primer covers the pathophysiology, symptomatology, diagnosis, management, quality of life and prevention of MD.

Evaluation of the effects of anti-motion sickness drugs on subjective sleepiness and cognitive performance of healthy males.

This study aimed to investigate the clinical and cognitive side effects of baclofen (10 mg), meclizine (25 mg), dimenhydrinate (40 mg) plus cinnarizine (25 mg) and promethazine (25 mg) plus d-amphetamine (10 mg). The study had a double-blind, placebo controlled, repeated measures design and was conducted on healthy male volunteers. The psychomotor vigilance test, the Sternberg working memory task, the implicit memory test and the automated Operation Span (Ospan) task were performed. The Stanford, the Karolinska and the Epworth Sleepiness scale determined the degree of sleepiness. The Profile of Mood States (POMS) evaluated mood states and adverse effects were reported on a 22-item questionnaire. Letter recalls and time for solving mathematical problems, recorded during the Ospan task, were impaired by baclofen and dimenhydrinate-cinnarizine respectively, suggesting an influence of these drugs on the working memory. Significant side effects for baclofen were: sleepiness, tiredness, blurred vision, concentration problems and dizziness whereas for dimenhydrinate-cinnarizine only sleepiness and blurred vision were reported. Meclizine decreased the accuracy on the Sternberg working memory task and thus seemed to affect short-term memory. A reported side effect was increased sleepiness. Promethazine plus d-amphetamine did not affect any of the tested cognitive functions. However, many side effects such as sleepiness, dry mouth, dizziness, vertigo, confusion, insomnia and tremors were reported. The results show that meclizine and dimenhydrinate combined with cinnarizine were the two drugs with the most acceptable combination of side effects.

Prophylaxis of intra- and postoperative nausea and vomiting in patients during cesarean section in spinal anesthesia.

BACKGROUND: This paper describes a randomized prospective study conducted in 308 patients undergoing caesarean section in spinal anaesthesia at a single hospital between 2010 and 2012 to find a suitable anti-emetic strategy for these patients. MATERIAL AND METHODS: Spinal anesthesia was performed in left prone position, at L3/L4 with hyperbaric 0.5% Bupivacaine according to a cc/cm body height ratio. There were no opioids given peri-operatively. The patients received either no prophylaxis (Group I) or tropisetron and metoclopramide (Group II) or dimenhydrinate and dexamethasone (Group III), or tropisetron as a single medication (Group IV). The primary outcome was nausea and/or vomiting (NV) in the intraoperative, early (0-2 h) or late (2-24 h) postoperative period. Multivariate statistical analysis was conducted with a regression analysis and a backward elimination of factors without significant correlation. RESULTS: All prophylactic agents significantly reduced NV incidence intraoperatively. Relative risk reduction for NV by prophylaxis was most effective (59.5%) in Group II (tropisetron and metoclopramide). In Group III (dimenhydrinate and dexamethasone), NV risk was reduced by 29.9% and by 28.7% in Group IV (tropisetron mono-therapy). The incidence of NV in the early (0?2 h) and the late (2?24 h) postoperative period was low all over (7.8%), but the relative risk reduction of NV in the early postoperative period was 54.1% (Group IV), 45.1% (Group III), and 34.8% (Group II), respectively. In the late postoperative period, there was no significant difference between the 4 groups. CONCLUSIONS: We recommend a prophylactic medication with tropisetron 2 mg and metoclopramide 20 mg for patients during caesarean section. These agents are safe, reasonably priced, and highly efficient in preventing nausea and vomiting.

No effects of anti-motion sickness drugs on vestibular evoked myogenic potentials outcome parameters.

OBJECTIVE: To investigate the effects of meclizine (50 mg), baclofen (10 mg), cinnarizine (20 mg) + dimenhydrinate (40 mg), and promethazine (25 mg) + dextro-amphetamine (5 mg) on the parameters of the vestibular evoked myogenic potential (VEMP) test. STUDY DESIGN: Double-blind placebo-controlled prospective randomized trial. SETTING: University hospital. SUBJECTS: Twenty-four (first block: baclofen versus placebo) and 20 healthy male subjects (second block: meclizine, cinnarizine + dimenhydrinate and promethazine + dextro-amphetamine versus placebo). INTERVENTIONS: VEMP test. MAIN OUTCOME MEASURES: Threshold, p13 and n23 latencies, p13-n23 latency difference, p13-n23 peak-to-peak amplitude, mean rectified voltage of the sternocleidomastoid muscle contraction and the corrected amplitude. RESULTS: There were no clinically significant pharmacologic effects on the VEMP outcome parameters. However, there was a statistically significant left-right asymmetry after intake of the combination promethazine + d-amphetamine for the parameters p13 and latency difference. CONCLUSION: The absence of clinically significant effects can be explained by the predominant presence of the target receptors for the applied drugs in the medial vestibular nucleus, which receives the lowest grade of saccular projections. It also can be hypothesized that the VEMP methodology and techniques in general do not allow determining pharmacologic effects in a healthy group of subjects because of a too small discriminative power. The left-right asymmetry can be explained by a depressive action of the drugs on the central compensation mechanisms. Because there were no significant differences between the VEMP parameters obtained after intake of the placebos of both blocks, we concluded that there were no training effects.

Histaminergic and cholinergic neuron systems in the impairment of human thermoregulation during motion sickness.

Motion sickness (MS) exaggerates body cooling during cold-water immersion. The aim of the present study was to investigate whether such MS-induced predisposition to hypothermia is influenced by two anti-MS drugs: the histamine-receptor blocker dimenhydrinate (DMH) and the muscarine-receptor blocker scopolamine (Scop). Nine healthy male subjects were immersed in 15 degrees C water for a maximum of 90min in five conditions: (1) control (CN): no medication, no MS provocation; (2) MS-control (MS-CN): no medication, MS provocation; (3) MS-placebo (MS-P): placebo DMH and placebo Scop, MS provocation; (4) MS-DMH: DMH and placebo Scop, MS provocation; (5) MS-Scop: Scop and placebo DMH, MS provocation. MS was induced by use of a rotating chair. Throughout the experiments rectal temperature (T(re)), the difference in temperature between the non-immersed right forearm and third finger (T(ff)) as an index of peripheral vasoconstriction, and oxygen uptake (VO(2)) as a measure of shivering thermogenesis, were recorded. DMH and Scop were similarly efficacious in ameliorating nausea. The fall in T(re) was greater in the MS-CN and MS-P conditions than in the CN condition. DMH, but not Scop, prevented the MS-induced increase in body-core cooling. MS attenuated the cold-induced vasoconstriction, an effect which was fully prevented by DMH but only partially by Scop. MS provocation did not affect VO(2) in any condition. The results suggest that the MS-induced predisposition to hypothermia is predominantly mediated by histaminergic mechanisms and that DMH might be useful in conjunction with maritime accidents or other scenarios where exposure to cold and MS are imminent features.

Effects of anti-histaminic and anti-cholinergic substances on human thermoregulation during cold provocation.

The roles of histaminergic and cholinergic neuron systems in the regulation of body temperature have been studied almost exclusively in animals. Recently, we have found that motion sickness, i.e. a condition where hippocampal cholinergic mismatch signals induce a release of histamine in the vomiting centre, accelerates the decline in body temperature in men during exposure to cold. In the present study we measured the thermoregulatory effects of two substances commonly used against motion sickness, i.e. the histamine (H1) receptor blocker dimenhydrinate (DMH) and the muscarine receptor blocker scopolamine (SCOP). In three trials, control (CN), DMH and SCOP, 10 male subjects were immersed in 15 degrees C water for a maximum of 90 min. The trials were separated by a minimum of three days and their order was alternated between subjects. In all trials the subject received, in a double blind fashion, a transdermal patch (SCOP or placebo) 12-14 h before immersion and a tablet (DMH or placebo) 1h before immersion. Mean skin temperature, rectal temperature (T(rec)), the difference in temperature between the non-immersed right forearm and 3rd finger of the right hand (T(ff)), and oxygen uptake (VO(2)) were recorded. The fall in T(rec) was smaller in the DMH than in the CN and SCOP conditions. The recordings of T(ff) and VO(2) suggest that SCOP attenuates peripheral vasoconstriction while DMH increases shivering thermogenesis. Notably, thermal discomfort was reduced in the SCOP condition. Findings are thoroughly discussed in the context of animal studies on the neuropharmacology and neurophysiology of thermoregulation and motion sickness.

Formulation and evaluation of in situ gelling system of dimenhydrinate for nasal administration.

Nasal drug delivery has a variety of advantages. Drugs can be rapidly absorbed through the nasal mucosa, giving rapid onset of action, and avoiding presystemic metabolism. In present study; the nasal mucoadhesive in situ gels of anti-emetic drug Dimenhydrinate were formulated using Gellan gum and Carbopol 934P. The in situ gels so prepared were characterized for gelation, viscosity, gel strength, mucoadhesion, drug content, drug diffusion, ex vivo permeation and histopathological studies. The optimized formulation passing from above tests was further subjected to accelerated stability study. It retained the good stability over the period of 90 days. From the overall performance this in situ gel seems to be an effective delivery system for the nasal route.

Effects of endolymphatic sac drainage with steroids for intractable Meniere's disease: a long-term follow-up and randomized controlled study.

OBJECTIVE: Meniere's disease is a common inner ear disease with an incidence of 15 to 50 per 100,000 population. Since Meniere's disease is thought to be triggered by an immune insult to the inner ear, we examined intraendolymphatic sac application of steroids as a new therapeutic strategy for intractable Meniere's disease. STUDY DESIGN: Prospective randomized controlled study. METHODS: Between 1996 and 2005, we enrolled and assigned 197 intractable Meniere's patients to three groups in a randomized controlled trial: Group I (G-I)- patients who underwent endolymphatic sac drainage and steroid-instillation; Group II (G-II)-those who underwent endolymphatic sac drainage without steroid-instillation; and Group III (G-III)-those who declined endolymphatic sac drainage. Definitive spells and hearing in all three groups were determined for 2 to 7 years after treatment. RESULTS: According to the 1995 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) criteria, 2-year results demonstrated that vertigo was completely controlled in 88.0% of patients in G-I (n = 100), 85.1% of patients in G-II (n = 47), and 8.0% in G-III (n = 50). Statistically, G-I = G-II>G-III. Hearing was improved in 49.0% of patients in G-I, 31.9% in G-II, and 6.0% in G-III (G-I>G-II>G-III). Results after 7 years showed that vertigo was completely controlled in 78.8% of patients in G-I, 79.2% in G-II, and 25.0% in G-III (G-I = G-II>G-III). Hearing improved in 36.5% of patients in G-I, 8.3% in G-II, and 0.0% in G-III (G-I>G-II = G-III). CONCLUSIONS: From non-surgical observation in G-III for at least 7 years after treatment, steroids instilled into endolymphatic sac in G-I patients significantly improved hearing in intractable Meniere's patients, more so than endolymphatic sac drainage without steroids in G-II patients.

Dimenhydrinate effect on cerebral oxygen status and salivary chromogranin-A during cognitive tasks.

To investigate the effects of dimenhydrinate on cerebral oxygen status (COS; cerebral oxygenated hemoglobin concentration changes) and salivary chromogranin-A (CgA) during a cognitive test battery, a double-blind, placebo-controlled, randomized, crossover protocol was used to examine the effect of 50 mg of dimenhydrinate or placebo in 12 subjects. This test battery includes tests of both reaction time and fundamental cognitive ability and was used in the assessment of pilots. Poor cognitive performance was observed in the subjects taking dimenhydrinate. We used two-channel near-infrared spectroscopy to investigate the effects of dimenhydrinate on the COS. With the one exception of shifting attention task in the left forehead, no significant difference was found between dimenhydrinate and placebo during the tasks of the test battery. Under placebo treatment, on the other hand, CgA levels were significantly elevated during cognitive testing when compared with baseline. However, CgA levels were not significantly elevated above baseline following dimenhydrinate. The present study is one of the first to demonstrate that the first-generation antihistamine drugs altered the responses of salivary CgA during cognitive tasks. The changes in salivary CgA secretion, as a result of dimenhydrinate administration, may serve as a sensitive biomarker of a psychological status such as a drug-induced sedation during the performance of a cognitive test battery. Further studies, however, are required to examine the usefulness of this sensitive biomarker in investigation of psychological agents during cognitive tasks.

A randomized comparison of ginger and dimenhydrinate in the treatment of nausea and vomiting in pregnancy.

OBJECTIVE: To study the efficacy of ginger and dimenhydrinate in the treatment of nausea and vomiting in pregnancy. STUDY DESIGN: Double blind randomized controlled trial. SETTING: Department of Obstetrics and Gynecology, Thammasat Hospital, Faculty of Medicine, Thammasat University. MATERIAL AND METHOD: Between January 2005 and December 2005, 170 pregnant women who attended at antenatal clinic Thammasat University Hospital with the symptoms of nausea and vomiting in pregnancy were randomly allocated into group A (n = 85) and group B (n = 85). The patients in group A received one capsule of ginger twice daily (one capsule contained 0.5 gm of ginger powder) while the patients in group B received the identical capsule of 50 mg dimenhydrinate twice daily. The visual analogue nausea scores (VANS) and vomiting times were evaluated at day 0-7 of the treatment. RESULTS: There was no significant difference in the visual analogue nausea scores (VANS) between group A and group B in day 1-7 of the treatment. The vomiting episodes of group A were greater than group B during the first and second day of the treatment with statistically significant difference. No difference in vomiting episodes during the day 3-7 of treatment was found in both groups. There was a statistically significant difference in the side effect of drowsiness after treatment in group B greater (77.64%) than group A (5.88%) (p < 0.01). CONCLUSION: From the presented data, ginger is as effective as dimenhydrinate in the treatment of nausea and vomiting during pregnancy and has fewer side effects.

Effect of dimenhydrinate on autonomic activity in humans.

The purpose of this study was to examine the effect of dimenhydrinate on resting muscle sympathetic nerve activity (MSNA), the vestibulosympathetic reflex, and the baroreflexes. Sixteen subjects participated in two double-blinded studies that measured mean arterial pressure (MAP), heart rate (HR), and MSNA responses before and after oral administration of dimenhydrinate (100 mg) or a placebo. In study one, 3 min of head-down rotation (HDR) was performed to engage the otolith organs. Dimenhydrinate (n = 10) did not alter resting MSNA, MAP, or HR. HDR increased MSNA before (Delta5 +/- 1 bursts/min; P < 0.01) and after (Delta4 +/- 1 bursts/min; P < 0.01) drug administration, but these responses were not different from the placebo (n = 6). In study two, 4 min of lower body negative pressure (LBNP) at -30 mmHg was performed. During the third min of LBNP, HDR was performed. MSNA increased during the first 2 min of LBNP before (Delta13 +/- 2 bursts/min; P < 0.01) and after (Delta14 +/- 2 bursts/min; P < 0.01) dimenhydrinate. HDR combined with LBNP increased MSNA further during the third min of LBNP (Delta18 +/- 2 bursts/min before and Delta17 +/- 2 bursts/min after dimenhydrinate; P < 0.01). These responses were not significantly different from the placebo. In contrast, HR responses to LBNP during the dimenhydrinate trial were increased when compared to all other trials (Delta5 +/- 1 beats/min; P < 0.01). These results indicate that dimenhydrinate augments heart rate responses to baroreceptor unloading, but does not alter resting MSNA, the sympathetic baroreflexes, or the vestibulosympathetic reflex.

[Evaluation of anti-seasick properties of pyrroxan and dimenhydrinate under conditions of maximal and submaximal statokinetic load in humans].

Pyrroxan and dimenhydrinate exhibit comparable anti-seasick effects in the test involving maximal and submaximal statokinetic load. Pyrroxan somewhat more significantly increases the vestibular stability, predominantly in humans with inherently high and medium stability, whereas dimenhydrinate is also effective in humans with low resistance to seasick. Pyrroxan primarily decreases the statokinetic (somatic) manifestations (dizziness, defensive movements, nystagmus), while dimenhydrinate mostly abolishes vegetative manifestations (hyperhydrosis, nausea, vomiting, fever sensation). Thus, the two drugs produce approximately equal anti-seasick action, while differing in the point of application (somatic versus vegetative).

Motion-sickness medications for aircrew: impact on psychomotor performance.

INTRODUCTION: Motion sickness remains a significant problem for aircrew both in the flying environment (airsickness) and for aircrew deployed at sea (seasickness). While some anti-motion-sickness medications provide reasonable efficacy, adverse neurocognitive effects limit their use in military personnel engaged in safety-sensitive operational roles such as flying. The purpose of this study was to assess the impact on psychomotor performance of promethazine, meclizine, and dimenhydrinate and to determine if the addition of pseudoephedrine or damphetamine to promethazine would ameliorate its adverse effects. METHODS: There were 21 subjects (11 men, 10 women), aged 22-59, who were assessed for psychomotor performance on 4 tasks as well as with sleepiness and drug side-effects questionnaires. Psychomotor testing was conducted prior to, and for 7 h after, ingestion of a single dose of each of placebo, promethazine 25 mg, meclizine 50 mg, dimenhydrinate 50 mg, promethazine 25 mg plus pseudoephedrine 60 mg, and promethazine 25 mg plus d-amphetamine 10 mg. RESULTS: Relative to placebo, promethazine, meclizine, and promethazine plus pseudoephedrine impaired performance on all four tasks [serial reaction time (SRT), logical reasoning (LRT), serial subraction (SST), and multitask (MT)]. Dimenhydrinate impaired performance on the SRT only. Promethazine plus d-amphetamine did not impair performance on any task nor did it result in increased sleepiness. The times to recovery of normal performance for SRT with promethazine, meclizine, dimenhydrinate, and promethazine plus pseudoephedrine were > 7.25, 7.25, 4.25, and 7.25 h, respectively; for LRT were > 7.25, > 7.25, ns, and 7.25 h; for SST were > 7.25, > 7.25, ns, and 7.25 h; for MT were 7.25, 7.25, ns, and 7.25 h. Recovery times to baseline sleepiness levels for promethazine, meclizine, dimenhydrinate, and promethazine plus pseudoephedrine were 7.25, > 7.25, 6.25, and > 7.25 h. CONCLUSION: Only promethazine plus d-amphetamine was free from impact on psychomotor performance and did not increase sleepiness.

Influence of an antivertiginous combination preparation of cinnarizine and dimenhydrinate on event-related potentials, reaction time and psychomotor performance--a randomized, double-blind, 3-way crossover study in healthy volunteers.

In the present comparative, double-blind, 3-way crossover study, possible effects of an antivertiginous combination preparation on event-related potentials (ERPs) and performance were investigated. Twenty-one healthy volunteers received 4 doses (within 24 h) of a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg (Arlevert, ARL), dimenhydrinate 50 mg, or a placebo, in randomized order at 1-week intervals. Auditory event-related potentials (ERPs), reaction time (RT) and psychometric tests were assessed before as well as 60 and 150 minutes after the intake of the 1st (Day 1) and the 4th (Day 2) dose of study medication. The evaluation was primarily based on the difference in the outcomes measured 150 min after the 4th dose (t5) and those before the start of medication intake (t0). None of the medications affected the latency and amplitude of the sensory ERP component N100, neither under passive listening nor under discrimination task conditions. The latency of P300 in response to the rare target tones (oddball paradigm and binary series), showed significant (p < 0.05) delays after 4 doses of dimenhydrinate (18-24 ms), and no significant differences between ARL (3-17 ms) and either dimenhydrinate or placebo (4-13 ms). Responses to nontarget tones remained almost unaffected after medication intake. The secondary analysis of the P300 amplitude showed the greatest decreases under DH in both active series, with no significant differences between ARL and either DH or placebo. The 3 medications did not significantly prolong RT nor did they impair the performance of psychometric tests, or cause significant shifts of current mood. The combination preparation ARL showed the lowest rate of adverse events (n = 1), followed by dimenhydrinate (n = 3) and placebo (n = 6). Two subjects withdrew because of adverse events, both after the intake of placebo. In conclusion, the results gave no evidence for an impairment of central information processing and psychomotor performance after multiple dosing with the fixed combination ARL in healthy volunteers, which might, when present, represent an adverse reaction limiting its use in antivertiginous therapy. No significant differences were found between ARL and placebo.

Dimenhydrinate produces a conditioned place preference in rats.

Dimenhydrinate (DMH; trade names Gravol and Dramamine) is a compound of diphenhydramine (DP) and 8-chlorotheophylline in equimolar ratios. DMH has been reported to be abused by humans for its euphoric and hallucinogenic properties but few studies have evaluated its reinforcing effects in animals. To evaluate the hypothesis that DMH and its constituents DP and 8-chlorotheophylline are rewarding in animals, rats were tested for conditioned place preference (CPP). The paradigm consisted of pre-exposure (three 15-min sessions of access to both sides of the chamber), conditioning [eight 30-min pairings of one side with drug (four sessions) and, on alternate days, the other side with vehicle (four sessions)] and test phases (three 15-min sessions of access to both sides of the chamber). Significant preferences for the drug-paired location were found on test session one after conditioning with 60.0, but not 25.0, 40.0 or 50.0 mg/kg of DMH, and after conditioning with 37.8 but not 27.0 or 32.4 mg/kg of DP. No preference was found after conditioning with 23.0, 27.6 or 32.2 mg/kg of 8-chlorotheophylline. All three drugs stimulated locomotor activity during conditioning sessions and DMH and DP showed sensitization over conditioning sessions. DMH doses that showed sensitization (25.0 and 40.0 mg/kg) were lower than the dose (60.0 mg/kg) that produced a CPP revealing a dissociation of locomotor stimulating versus rewarding effects. Results reveal that DMH and DP have rewarding properties, although the molar equivalent dose-response curve for DP appeared to be further to the right than that for DMH. Future investigations into the neurotransmitter systems modulating this effect are awaited.

Cocaine-induced anxiety: alleviation by diazepam, but not buspirone, dimenhydrinate or diphenhydramine.

Clinical reports and animal experiments indicate that both cocaine administration and cocaine withdrawal increase anxiety. We investigated the ability of a number of putative anxiolytic agents to alleviate these anxiety states using the elevated plus-maze. Rats in the cocaine condition received either saline or cocaine (20 mg/kg) 40 min prior to testing; those in the withdrawal condition were tested 48 h following a chronic treatment regime (saline or cocaine 20 mg/kg per day for 14 days). Prior to testing, animals received a benzodiazepine (1.0 or 2.0 mg/kg diazepam), a serotonergic agonist (0.5 or 1.0 mg/kg buspirone), an antihistamine (50 mg/kg dimenhydrinate or 27 mg/kg diphenhydramine) or a saline injection. All drugs were administered intraperitoneally. Cocaine administration and cocaine withdrawal reduced the percentage time spent on and the number of entries into the open arms. Diazepam dose-dependently alleviated cocaine withdrawal-induced anxiety and non-significantly attenuated cocaine-induced anxiety. Buspirone, dimenhydrinate and diphenhydramine did not consistently alleviate the anxiety caused by either cocaine pre-treatment regime; in the saline conditions, however, each of these treatments was anxiogenic. In summary, benzodiazepines alleviated cocaine-induced anxiety, while future research on the ability of serotonergic and antihistaminergic drugs to alleviate these anxiety states is warranted.

Mechanisms and abuse liability of the anti-histamine dimenhydrinate.

The over-the-counter anti-emetic dimenhydrinate (DMH) (Gravol or Dramamine) has been reported to be abused for non-medicinal purposes. Street drug users abuse DMH for the acute effects of euphoric sensations and hallucinations, while psychiatric patients abuse DMH for its anxiolytic or anti-cholinergic effects. DMH is an H(1) histamine receptor antagonist, but it interacts either directly or indirectly with other neurotransimitter systems, including those using acetylcholine, serotonin, norepinephrine, dopamine, opioids or adenosine. Animal behavioural studies, such as self-administration, conditioned place preference, drug discrimination, and modulation of operant responding, show that anti-histamines have abuse potential. Further support comes from reports of acute and chronic abuse of DMH by humans. Collectively, results confirm the abuse liability of DMH.