A Clinical Pharmacological Study to Evaluate the Sedative Effects of the Histamin H1 Antagonist, Diphenhydramine Hydrochloride (Drewell),in Healthy Male Elderly Subjects: Objective Evaluation of the Sedative Effects by Analysis of Saccadic Eye Movement

Kurosawa, Kenzou; Uchida, Naoki; Iwase, Masayasu; Yasuda, Kazuhiko; Li, Hua; Hirashima, Hayato; Ishigaki, Seiichirou; Matsuda, Kazuhiro; Yano, Rei; Sakuma, Dai; Yasuhara, Hajime

doi:10.3999/jscpt.37.5_283

Cited by 3 publications

(2 citation statements)

References 6 publications

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“…Additionally, the elderly have been reported to have delayed sedation and more common adverse events after diphenhydramine hypnotic therapy. 37,38 Finally, the residual effects of antihistamines are expected to amplify in those with liver dysfunction or in patients undergoing concomitant treatment with A-blockers, opioid analgesics, antidepressants, or antipsychotics because of drug interactions. It is therefore important that risk evaluation must be made individually, taking into consideration different factors.…”

Section: Discussionmentioning

confidence: 99%

Next-Day Residual Sedative Effect After Nighttime Administration of an Over-the-Counter Antihistamine Sleep Aid, Diphenhydramine, Measured by Positron Emission Tomography

Zhang¹,

Tashiro²,

Shibuya³

et al. 2010

Journal of Clinical Psychopharmacology

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Antihistamines often are self-administered at night as over-the-counter (OTC) sleep aids, but their next-day residual sedative effect has never been evaluated using a reliable quantitative method such as positron emission tomography (PET). We performed a double-blind, placebo-controlled, crossover study in which we evaluated the residual effect the next day after nighttime administration of diphenhydramine, a commonly used OTC sleep aid, in terms of brain H₁ receptor occupancy (H₁RO) measured using ¹¹C-doxepin-PET. We also compared the results of diphenhydramine with those of bepotastine, a second-generation antihistamine. Eight healthy adult male subjects underwent PET measurement the morning (11:00) after random oral administration of diphenhydramine (50 mg), bepotastine (10 mg), or placebo the night before (23:00). Binding potential ratios and H₁ROs were calculated in different brain regions of interest such as the cingulate gyrus, frontotemporal cortex, and cerebellum. Subjective sleepiness and plasma drug concentration also were measured. Calculation of binding potential ratios revealed significantly lower values for diphenhydramine than for bepotastine or placebo in all regions of interest (P < 0.01). Cortical mean H₁RO after diphenhydramine treatment was 44.7% compared with 16.6% for bepotastine treatment (P < 0.01). Subjective sleepiness was not significantly different among the subjects treated with each test drug or the placebo. In conclusion, the next-day residual sedative effect after nighttime administration of the OTC sleep aid diphenhydramine was verified for the first time by direct PET measurement of H₁RO. Taking into account the possible hangover effect of OTC antihistamine sleep aids, care needs to be taken during their administration.

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Section: Discussionmentioning

confidence: 99%

Next-Day Residual Sedative Effect After Nighttime Administration of an Over-the-Counter Antihistamine Sleep Aid, Diphenhydramine, Measured by Positron Emission Tomography

Zhang¹,

Tashiro²,

Shibuya³

et al. 2010

Journal of Clinical Psychopharmacology

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“…[22][23][24][25] We demonstrated in a recent article that a specific taste sensor output (AN0) correlated well with the response of the bitter drug or substance to hTAS2R10 or hTAS2R14. 26) In the present study, DPH, a widely used sedating antihistamine and known agonist of hTAS2R14, was used as a model bitter drug in the investigation of the bitterness-suppressing effects of the umami dipeptides Glu-Glu and Asp-Asp and their component amino acids, [27][28][29] using both the taste sensor and human gustatory sensation testing. The relative affinities of the umami dipeptides and their component amino acids for hTAS2R14 protein were examined using surface plasmon resonance (SPR).…”

Section: Introductionmentioning

confidence: 99%

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing

et al. 2020

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Diphenhydramine, a sedating antihistamine, is an agonist of human bitter taste receptor 14 (hTAS2R14). Diphenhydramine hydrochloride (DPH) was used as a model bitter medicine to evaluate whether the umami dipeptides (Glu-Glu and Asp-Asp) and their constituent amino acids (Glu, Asp) could suppress its bitterness intensity, as measured by human gustatory sensation testing and using the artificial taste sensor. Various concentrated (0.001-5.0 mM) Glu-Glu, Asp-Asp, Glu and Asp significantly suppressed the taste sensor output of 0.5 mM DPH solution in a dose-dependent manner. The effect of umami dipeptides and their constituent amino acids was tending to be ranked as follows, Asp-Asp > Glu-Glu >> Gly-Gly, and Asp > Glu >> Gly (control) respectively. Whereas human bitterness intensity of 0.5 mM DPH solution with various concentrated (0.5, 1.0, 1.5 mM) Glu-Glu, Asp-Asp, Glu and Asp all significantly reduced bitterness intensity of 0.5 mM DPH solution even though no statistical difference was observed among four substances. The taste sensor outputs and the human gustatory sensation test results showed a significant correlation. A surface plasmon resonance study using hTAS2R14 protein and these substances suggested that the affinity of Glu-Glu, Asp-Asp, Glu and Asp for hTAS2R14 protein was greater than that of Gly-Gly or Gly. The results of dockingsimulation studies involving DPH, Glu-Glu and Asp-Asp with hTAS2R14, suggested that DPH is able to bind to a space near the binding position of Glu-Glu and Asp-Asp. In conclusion, the umami dipeptides Glu-Glu and Asp-Asp, and their constituent amino acids, can all efficiently suppress the bitterness of DPH.

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大¹,

直樹²,

万里子³

et al. 2008

Jpn. J. Clin. Pharmacol. Ther.

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First-generation antihistamines have an adverse CNS effect such as sedation, whereas second-generation antihistamine drugs are generally non-sedating. The difference in the CNS sedation profile is mainly due to the CNS penetration of the drugs. We hypothesized that the non-sedating profile is caused by low CNS penetration due to regulation by the P-glycoprotein(P-gp)efflux transporter at the blood brain barrier(BBB). A three-way crossover study with more than a 6-day washout period was performed in 8 healthy volunteers. In order to evaluate the drug interaction on P-gp, we used ebastin(Eb)from the second-generation antihistamines and verapamil(Vr)as an inhibitor of P-gp. The three study medication groups were as follows：a single oral dose of Eb 10 mg(E10) ；a single oral dose of Eb 20 mg(E20) ；and a single oral dose of Eb 10 mg together with a single oral dose of Vr 80 mg at 3 hours after Eb dosing(EV). The sedative side effect of Eb was measured by both saccadic peak velocity(SPV)analysis, as an objective evaluation, and the visual analogue self-rating scale(VAS), as a subjective evaluation. No sedative effect was observed in any group. These results suggest that Eb has no clinically significant sedative effect even when the Eb dose is increased or with co-administration of P-gp inhibitor.

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A Clinical Pharmacological Study to Evaluate the Sedative Effects of the Histamin H1 Antagonist, Diphenhydramine Hydrochloride (Drewell),in Healthy Male Elderly Subjects: Objective Evaluation of the Sedative Effects by Analysis of Saccadic Eye Movement

Cited by 3 publications

References 6 publications

Next-Day Residual Sedative Effect After Nighttime Administration of an Over-the-Counter Antihistamine Sleep Aid, Diphenhydramine, Measured by Positron Emission Tomography

Next-Day Residual Sedative Effect After Nighttime Administration of an Over-the-Counter Antihistamine Sleep Aid, Diphenhydramine, Measured by Positron Emission Tomography

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing

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