Hisakuni Hashimoto

Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors

1 The present study was undertaken to characterise the relationship between in vivo brain serotonin transporter (SERT) binding, plasma concentration and pharmacological effect of selective serotonin reuptake inhibitors (SSRIs) in mice. Oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at pharmacologically relevant doses exerted dose‐ and time‐dependent binding activity of brain SERT as revealed by significant increases in KD for specific [3H]paroxetine binding, and the in vivo SERT‐binding potency was in the order of paroxetine≫fluoxetine, sertraline>fluvoxamine. 2 The time courses of brain SERT binding by SSRIs in mice were mostly in parallel to those of their plasma concentrations. Also, norfluoxetine (active metabolite) has been suggested to contribute largely to the long‐lasting binding activity of brain SERT after the fluoxetine administration. 3 Oral administration of each SSRI suppressed significantly the marble‐burying behaviour with no change in locomotor activity in mice, and the extent and time course of suppression agreed well with those of brain SERT binding. Thus, the pharmacological potencies of SSRIs in the attenuation of marble‐burying behaviour correlated significantly with their brain SERT binding activities. 4 In conclusion, the present study has provided the first in vivo evidences to support that fluvoxamine, fluoxetine, paroxetine and sertraline orally administered bind to the pharmacologically relevant brain SERT in mice and that their SERT‐binding characteristics is closely associated with the pharmacokinetics and inhibition of marble‐burying behaviour.

Role of histamine H1 and H2 receptor antagonists in the prevention of intimal thickening

Vascular smooth muscle cell migration to the intima from the media and proliferation in the intima play key roles in atherosclerosis and restenosis after coronary angioplasty. Histamine released from adherent platelets at the injured artery and from mast cells in atheromas has stimulant actions on both smooth muscle cell migration and proliferation, and histamine receptor antagonists abolish the effect of histamine in vitro. The aim of this study was to examine the effect of histamine receptor antagonists on intimal thickening. Endothelial injury in the mouse femoral artery was induced by a photochemical reaction between localized irradiation by green light and intravenously administered rose bengal. The histamine H1 receptor antagonist, diphenhydramine, at a dose of 30 mg/kg or the histamine H2 receptor antagonist, cimetidine, at a dose of 200 mg/kg was intraperitoneally administered to mice for 21 days after endothelial injury. Twenty-one days after endothelial injury, morphometric analysis was performed to measure the cross-sectional areas of the intima and media. Diphenhydramine significantly reduced the intimal area to 1.1 +/- 0.3 (x 10(-3) mm2) compared with the value in the control group, which was 6.2 +/- 1.4 (x 10(-3) mm2), but cimetidine (5.5 +/- 1.9, x 10(-3) mm2) did not. Similarly, the ratio of intimal area to medial area in the diphenhydramine-treated group but not in the cimetidine-treated group was significantly reduced (83%). In the in vitro study, cimetidine inhibited neither proliferation nor migration of mouse vascular smooth muscle cells stimulated by platelet-derived growth factor (PDGF). In contrast, diphenhydramine significantly (P < 0.05) inhibited proliferation in a dose-dependent manner, but did not inhibit migration. These results suggest that diphenhydramine, a histamine H1 receptor antagonist, reduced the formation of intimal hyperplasia, at least in part due to inhibition of cell proliferation. However, cimetidine, a histamine H2 receptor antagonist, was ineffective. Histamine may play a key role in intimal thickening, in part via histamine H1 receptors in this model.

Influence of thyroid hormone on the positive inotropic effects mediated by α- and β-adrenoceptors in isolated guinea pig atria and rabbit papillary muscles

Abstract Effects of thyroxine treatment for 7–11 days on the positive inotropic effects mediated by α- and β-adrenoceptors were studied in isolated guinea pig atria and rabbit papillary muscles. In guinea pig atria, the thyroxine treatment inhibited the positive inotropic effect of lower concentrations of phenylephrine (PHE), and attenuated the inhibitory effect of phentolamine on the PHE response. The effect of isoproterenol (ISO) was potentiated by the thyroxine treatment. In rabbit papillary muscles, the thyroxine treatment shifted the dose—response curve for PHE to the right and attenuated the inhibitory effect of phentolamine on the PHE response. Propranolol, in both guinea pig atria and rabbit papillary muscles, inhibited the PHE response more effectively in preparations from thyroxine-treated animals than in controls. In guinea pig atria, the attenuation of the PHE response mediated by α-adrenoceptors was observed after the thyroxine treatment for only 2 days, whereas the potentiation of the ISO response required the thyroxine treatment for a longer period. It was concluded that the thyroxine treatment attenuated the positive inotropic effect mediated by α-adrenoceptors and potentiated that mediated by β-adrenoceptors in guinea pig atria and rabbit papillary muscles, and that the changes in the α- and β-adrenoceptor-mediated positive inotropic effects due to the thyroxine treatment may be independent of each other.

Changes in Vascular Reactivity in Experimental Diabetic Rats: Comparison with Hypothyroid Rats

The responsiveness to vasoactive agents in the perfused mesenteric vascular bed of streptozocin-induced diabetic rats was examined and compared with that of propylthiouracil-induced hypothyroid rats. Diabetic rats at 4 and 8 weeks after the induction of diabetes showed a significant decrease in isoproterenol-induced vasodilatation. In addition, the contractile responses to norepinephrine and 5-hydroxytryptamine and the vasodilative response to acetylcholine were significantly decreased in 12-week-diabetic rats. The contractile response to nerve stimulation was markedly decreased at 8 and 12 weeks. On the other hand, hypothyroid rats showed a decreased response to isoproterenol, but they did not show any change in the response to nerve stimulation. A decrease in plasma thyroid hormone levels in diabetic rats at any time period was similar in extent to that in hypothyroid rats. The data indicate that the progressive changes in vascular reactivity in diabetic rats may be divided into two stages. In the early stage, the altered reactivity of vasculature is likely to be mediated by hypothyroidism, whereas in the later stage, it is induced by other factors, e.g. hyperglycemia and hypoinsulinemia. Adrenergic neuropathy is not caused by hypothyroidism.

Effects of the ventricular premature beat on the alternation of the repolarization phase in ischemic myocardium during acute coronary occlusion in dogs

Effects of ventricular premature beats (VPB) on the alternans of the ST segment (ST alternans, STA) in the epicardial ECG and of the monophasic action potential (MAP) were examined during acute coronary occlusion in dogs. When STA was recorded simultaneously from four different points it was discordant in most cases. The discordant STA was accompanied by discordant alternation of the repolarization phase of MAP. A VPB transformed the discordant alternans into a concordant one and potentiated the degree of alternans. Transient prolongation or shortening of the cycle length showed effects similar to those of the VPB. The concordant alternans which was transformed from a discordant one by a VPB was not remarkably potentiated by a VPB, or by prolongation or shortening of the cycle length. It is possible that the transformation of the discordant alternans into a concordant one may contribute to the potentiation of STA by a VPB, and that the effects of VPB are due to the effects of the compensatory pause as well as the short cycle length associated with the VPB.

Effects of MS-551, a new class III antiarrhythmic drug, on programmed stimulation-induced ventricular arrhythmias, electrophysiology, and hemodynamics in a canine myocardial infarction model.

Summary: We examined the effects of MS-551 (1,3-dimethyl-6-{(2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino} 2,4(1H,3H)-pyrimidinedione hydrochloride), a new class III antiarrhythmic drug, on programmed electrical stimulation (PES)-induced ventricular arrhythmias, the effective refractory period (ERP), intraventricular conduction, and hemodynamics in a canine myocardial infarction (MI) model. MS-551 was administered intravenously (i.v.) in two consecutive doses; the first dose (low dose) was 0.05 mg/kg/min after a bolus injection of 0.3 mg/kg, and the second dose (high dose) was 0.1 mg/kg/min after a bolus injection of 0.3 mg/kg. PES induced ventricular tachycardia (VT) or ventricular fibrillation (VF) in 10 of 12 animals. MS-551 abolished or lessened the ventricular arrhythmias in 7 of 10 animals at both doses. ERP was significantly prolonged by MS-551 in both the normal and infarcted zones in a dose-dependent fashion. Ventricular conduction of a premature excitation induced by a premature stimulation with various coupling intervals was decreased only at a coupling interval approximating that of ERP. MS-551 at either low or high dose did not significantly change the heart rate (HR), mean blood pressure (MBP), cardiac output (CO), or maximum rate of increase in left ventricular pressure (LVP) significantly. MS-551 produced a suppression of the PES-induced ventricular arrhythmias through prolongation of ERP without having any significant effect on hemodynamics in a canine MI model.

Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C9*1/*3 genotype

An 89‐year‐old man with severe hypertension (190/82 mm Hg) and chronic heart failure (New York Heart Association class II) despite treatment with benidipine, doxazosin mesylate (INN, doxazosin), and furosemide was given oral candesartan cilexetil (4 mg/d), an angiotensin II type 1 receptor blocker metabolized via cytochrome P450 (CYP) 2C9. Two days later, he started to have severe dizziness and returned to the hospital on the fourth day without taking any of his medications. The blood pressure 30 hours after the last dose of candesartan was 126/64 mm Hg. Polymorphism analysis revealed the heterozygous poor metabolizer genotype CYP2C9*1/*3. The area under the concentration‐time curve and the mean residence time of candesartan were both increased 2.5‐fold, and the oral clearance of candesartan was 48% lower than that of the average elderly Japanese patient with hypertension. These results suggest that the CYP2C9*1/*3 genotype could be associated with decreased clearance and increased plasma concentration of candesartan, potentially enhancing its hypotensive effect.

Reversal Effect of Thyroxine on Altered Vascular Reactivity in Diabetic Rats

The influence of thyroxine treatment on the altered reactivity of the isolated perfused mesenteric vasculature from streptozocin-induced diabetic rats was examined and compared with that of insulin. After 8 weeks of diabetes, the time when the decreased response to isoproterenol appeared, treatment with thyroxine reversed this decreased response to control levels. However, thyroxine replacement did not reverse the decreased responsiveness to norepinephrine, 5-hydroxytryptamine, acetylcholine, and isoproterenol after 12 weeks of diabetes. On the other hand, insulin replacement improved the vascular responsiveness to these agonists at 8 and 12 weeks. Insulin treatment also reversed the attenuated response to nerve stimulation found in diabetic rats, whereas thyroxine treatment did not improve it. Insulin treatment reversed the decreased plasma thyroid hormone levels similarly as thyroxine treatment. These results suggest that thyroid hormone deficiency is likely to be involved partly in the altered reactivity of the rat mesenteric vasculature at the early period of diabetes. On the other hand, adrenergic neuropathy is not induced by hypothyroidism.

PHARMACOKINETIC ADVANTAGES OF A NEWLY DEVELOPED TACROLIMUS OIL-IN-WATER-TYPE EMULSION VIA THE ENTERAL ROUTE

We developed an oleic acid oil-in-water (o/w)-type emulsion of a new tacrolimus formulation that presented an improvement in the delivery of the drug for oral absorption. This investigation was undertaken to assess a sustained release drug delivery system and selective drug transfer into the lymphatic system. The whole blood concentration profiles after oral administration at a dose of 2mg/kg and bone marrow, spleen, liver, lung, small intestine, kidney, brain, and whole blood distribution after oral administration at a dose of 1 mg/kg of o/w emulsion formulation of tacrolimus (O/W group) were compared with those of commercially available formulation (T group) in the rat. The mean diameter of the o/w emulsion droplets was 0.47 μm immediately after preparation. The tacrolimus entrapping efficiency of o/w emulsion was 71.3+5.0% in 12 h and did not change for 2 d. The area under the whole blood concentration-time curve (AUC) in the O/W group was significantly higher (P<0.01) than that in the I group. In contrast, the values of constant elimination rate and total clearance in the O/W group were significantly lower (P<0.01) than those in the T group, with a comparative bioavailability of 115.9%. The tissue concentration of tacrolimus in the O/W group was significantly higher levels in the bone marrow, spleen, liver, lung, and small intestine, and significantly lower in the brain and kidney, relative to the T group. The o/w emulsion of tacrolimus may be an improved dosage form via the enteral route.

Potentiating effects of a ventricular premature beat on the alternation of the ST-T complex of epicardial electrograms and the incidence of ventricular arrhythmias during acute coronary occlusion in dogs*

A relation between ST-T alternans (STTA) and incidence of ventricular arrhythmias (VA) was examined, and the effects of a premature beat on these were tested during acute coronary occlusion in dogs. Epicardial unipolar electrograms, epicardial and endocardial bipolar electrograms and monophasic action potentials were recorded during coronary occlusion. During the period of STTA, a remarkably late conduction and its alternation were also observed in ischemic areas. The more serious delay appeared during the negative deflection of the ST-T complex. VA followed mainly the negative deflection of the ST-T complex. The first premature activation appeared in either ischemic areas or the border areas. A ventricular premature beat (VPB) which occurred spontaneously or was produced by an electrical stimulation potentiated STTA, and additional VA frequently followed the negative deflection of the ST-T complex of the second sinus beat after the VPB. A VPB pronounced the conduction delay during the second sinus beat. The discordant STTA became concordant after the VPB. The duration of a monophasic action potential of the second sinus beat after the VPB in mildly ischemic areas decreased. These changes and enhanced STTA may contribute to the occurrence of the additional VA.