Miyako Yoshida

Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain

BackgroundNeuropathic pain is characterized by hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to NSAIDs or even opioids. Gabapentin, a GABA analogue, was originally developed to treat epilepsy. Accumulating clinical evidence supports the effectiveness of this drug for diverse neuropathic pain. In this study, we showed that the anti-allodynic effect of gabapentin was changed by the circadian oscillation in the expression of its target molecule, the calcium channel α2δ-1 subunit.ResultsMice were underwent partial sciatic nerve ligation (PSL) to create a model of neuropathic pain. The paw withdrawal threshold (PWT) in PSL mice significantly decreased and fluctuated with a period length about 24 h. The PWT in PSL mice was dose-dependently increased by intraperitoneal injection of gabapentin, but the anti-allodynic effects varied according to its dosing time. The protein levels of α2δ-1 subunit were up-regulated in the DRG of PSL mice, but the protein levels oscillated in a circadian time-dependent manner. The time-dependent oscillation of α2δ-1 subunit protein correlated with fluctuations in the maximal binding capacity of gabapentin. The anti-allodynic effect of gabapentin was attenuated at the times of the day when α2δ-1 subunit protein was abundant.ConclusionsThese findings suggest that the dosing time-dependent difference in the anti-allodynic effects of gabapentin is attributable to the circadian oscillation of α2δ-1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.

Bitterness prediction of H1-antihistamines and prediction of masking effects of artificial sweeteners using an electronic tongue

The study objective was to quantitatively predict a drugs bitterness and estimate bitterness masking efficiency using an electronic tongue (e-Tongue). To verify the predicted bitterness by e-Tongue, actual bitterness scores were determined by human sensory testing. In the first study, bitterness intensities of eight H(1)-antihistamines were assessed by comparing the Euclidean distances between the drug and water. The distances seemed not to represent the drugs bitterness, but to be greatly affected by acidic taste. Two sensors were ultimately selected as best suited to bitterness evaluation, and the data obtained from the two sensors depicted the actual taste map of the eight drugs. A bitterness prediction model was established with actual bitterness scores from human sensory testing. Concerning basic bitter substances, such as H(1)-antihistamines, the predictability of bitterness intensity using e-Tongue was considered to be sufficiently promising. In another study, the bitterness masking efficiency when adding an artificial sweetener was estimated using e-Tongue. Epinastine hydrochloride aqueous solutions containing different levels of acesulfame potassium and aspartame were well discriminated by e-Tongue. The bitterness masking efficiency of epinastine hydrochloride with acesulfame potassium was successfully predicted using e-Tongue by several prediction models employed in the study.

Effect of Haloperidol on mPer1 Gene Expression in Mouse Suprachiasmatic Nuclei

The effect of a typical neuroleptic haloperidol (Hal) on mPer1 gene expression was investigated in mouse suprachiasmatic nuclei (SCN). Hal induced mPer1 mRNA levels both in vivo and in cultured SCN cells. For mechanisms underlying Hal-induced mPer1 expression, N-methyl-d-aspartate (NMDA) glutamate receptor subtype, the phosphorylation form of the transcription factor, and the Ser-133 phosphorylation form of cAMP-responsive element-binding protein (CREB) played an important role, because the induction of mPer1 mRNA significantly decreased after pretreatment with a non-competitive NMDA receptor antagonist, such as MK-801 or CREB antisense. These results suggest that Hal may increase CREB phosphorylation and mPer1 expression according to the activation of the NMDA receptor through the dopaminergic pathways. Although the injection of Hal during the light period increased the amplitude of mPer1 mRNA rhythmicity in a nondrug state, the injection of the drug during the dark period disturbed the rhythmic pattern of mPer1 mRNA. These results suggest that the rhythmicity of clock genes in SCN may be disturbed depending on the dosing time of Hal. On the other hand, because the induction of mPer1 mRNA by Hal seems to be at least partly caused by the NMDA receptor, showing a phase shift or resetting effect of the circadian clock, Hal may also cause such phase shift effects.

Evaluation of palatability of 10 commercial amlodipine orally disintegrating tablets by gustatory sensation testing, OD‐mate as a new disintegration apparatus and the artificial taste sensor

The purpose of this study was to evaluate and compare the palatability of 10 formulations (the original manufacturers formulation and nine generics) of amlodipine orally disintegrating tablets (ODTs) by means of human gustatory sensation testing, disintegration/dissolution testing and the evaluation of bitterness intensity using a taste sensor.

Preparation and In Vivo Evaluation of a Water-Soluble Prodrug for 2R-γ-Tocotrienol and as a Two-Step Prodrug for 2,7,8-Trimethyl-2S-(β-carboxyethyl)-6-hydroxychroman (S-γ-CEHC) in Rat

2R-γ-Tocotrienol (γ-T3) is currently receiving attention because it has beneficial effects not observed with α-tocopherol. To achieve the effective delivery of γ-T3, we synthesized three kinds of ester derivatives of γ-T3 and evaluated their use as hydrophilic prodrugs for γ-T3 in vitro and in vivo. 2R-γ-Tocotrienyl N,N-dimethylamino-acetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to γ-T3 by esterases in rat and human liver. Intravenous administration of 3 in rats led to a rapid increase in the plasma, liver, heart, and kidney levels of γ-T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4% and 100 ± 11.3% for 3 and γ-T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6% and 100 ± 4.8% for 3 and γ-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(β-carboxyethyl)-6-hydroxychroman (S-γ-CEHC), a metabolite of γ-T3, was 78.6% for compound 3, 47.1% for γ-T3 in surfactant, and 100% for racemic γ-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of γ-T3 and two-step prodrug of S-γ-CEHC.

Single injection of ONO-1301-loaded PLGA microspheres directly after ischaemia reduces ischaemic damage in rats subjected to middle cerebral artery occlusion

Objectives  ONO‐1301 was developed as a novel long‐acting prostacyclin agonist with thromboxane synthase inhibitory activity. In this study, we investigated the therapeutic time window of oral ONO‐1301 and the effect of a single subcutaneous injection of ONO‐1301‐loaded poly(lactide‐co‐glycolide) (PLGA) microspheres (ONO‐1301 PLGA MS) on infarction volume, functional deficits and plasma ONO‐1301 levels following a 1 h middle cerebral artery occlusion (MCAO) in rats.

Bitterness evaluation of intact and crushed Vesicare orally disintegrating tablets using taste sensors.

Vesicare tablets, whose main component is solifenacin succinate, are known to be extremely bitter. The purpose of this study was to evaluate the effect of crushing on the bitterness of the Vesicare orally disintegrating tablets (ODTs).

Preparation of ONO-1301-loaded poly(lactide-co-glycolide) microspheres and their effect on nerve conduction velocity

Objectives  The aim of this study was to prepare poly(lactide‐co‐glycolide) (PLGA) microspheres containing ONO‐1301, a novel long‐acting prostacyclin agonist with thromboxane synthase inhibitory activity, with 10% of drug released in the initial burst and a sustained‐release period of about 3 weeks after administration. The effect of PLGA type (molecular weight and the lactide/glycolide (L/G) ratio in PLGA), the preparative conditions and the particle size on the in‐vitro release profile were examined. The effect of optimized ONO‐1301‐loaded PLGA microspheres on delayed nerve condition velocity (NCV) was investigated in streptozotocin (STZ) induced diabetic rats.

Effect of antioxidants on the stability of ONO-1301, a novel long-acting prostacyclin agonist, loaded in PLGA microspheres.

The purpose of this study was to investigate the physicochemical stability of ONO-1301 in poly(lactide-co-glycolide) microspheres (PLGA MS) under storage for 28 days in the absence or presence of butylated hydroxytoluene (BHT) or α-tocopherol as antioxidant. First, we observed the hydrolysed product: (i) in acidic solution and oxidized product and (ii) in PLGA MS under storage in HPLC study, each structure was determined by liquid chromatography–nuclear magnetic resonance/mass spectrometry. Second, ONO-1301-loaded PLGA MS containing 10% BHT was shown to be superior to ONO-1301-loaded PLGA MS without BHT, in the standpoint of the stability under storage or in vitro drug-release test, and AUC0–28 following subcutaneous injection in rats. Finally, ONO-1301-loaded PLGA MS with 10% BHT were demonstrated to be significantly more effective than ONO-1301-loaded PLGA MS without BHT in a murine sponge model of angiogenesis. In conclusion, BHT is an effective antioxidant on the stability of ONO-1301 in PLGA MS under storage.

A new chalcone glycoside from Sapium sebiferum

A new chalcone glycoside, having an allenic ester moiety, was isolated together with chalcononaringenin 2′-O-β-D-glucopyranoside from the catkin of Sapium sebiferum. The structure elucidations of chalcone glycosides were based on the analyses of spectroscopic data.