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Drug interaction between rizatriptan benzoate, an anti-migraine agent, and sodium valproate (VPA-Na), an anticonvulsant, was studied in rats. When rizatriptan benzoate was administered orally immediately after VPA-Na oral administration, the pharmacokinetic parameters, such as plasma valproic acid (VPA) and area under the plasma concentration-time curve up to 3 h (AUC0–3), were significantly decreased compared with those in the control group. However, when rizatriptan benzoate was administered intraperitoneally immediately after VPA-Na orally, these parameters were not changed. In addition, when benzoic acid was administered orally immediately after VPA-Na orally, these were significantly lower compared with the control values. Therefore, it might be possible that VPA transport by monocarboxylate transporter was competitively inhibited by rizatriptan benzoate and thus absorption of VPA was decreased.

The drug interactions between tandospirone citrate,a non-benzodiazepine antianxiety drug,and oxazolam,a minor benzodiazepine tranquilizer and antianxiety agent,and valpronic acid (VPA),an anti-convulsant,were studied in rats.When tandospirone citrate or citric acid was administered orally immediately following oral administration (p.o.) of sodium valproate (VPA-Na),the plasma VPA levels were significantly lower than those in the control.In addition,pharmacokinetic parameters such as plasma VPA concentration and area under the plasma concentration-time curve up to 3 hr (AUC) were significantly decreased.However,when tandospirone citrate was administered intraperitonally,or both it and oxazolam were administered orally with VPA-Na,the VPA pharmacokinetic parameters were unchanged.These results suggest that decreases in plasma VPA concentrations (including those for AUC) may be due to a reduction in VPA-Na adsorption from the intestinal tract due to tandospirone citrate.

The effect of timing on the administration of spherical charcoal (Kremezin) on the pharmacokinetics of valproic acid (VPA) in the coadministration of sodium valproate and Kremezin was examined in rats.Kremezin, when administered either immediately or 30 min after the administration of sodium valproate, significantly decreased the area under the plasma concentration-time curve (AUC) 0-3 of VPA by about 30%. In addition, when Kremezin was administered 30 min or 1 hr before sodium valproate dosing it decreased the maximum plasma concentration (Cmax) of VPA by 39% and 27%, respectively, and significantly decreased the AUC0-3 of VPA by 54% and 45%, respectively. The plasma VPA concentrations in all Kremezin-treated groups were significantly lower than those in the controls. However, Kremezin administered 1 hr after sodium valproate dosing had no effect on the plasma VPA concentration, Cmax or AUC0-3 of VPA.These results suggest that Kremezin decreased the absorption of VPA due to adsorption after the coadministration of sodium valproate and Kremezin.

Drug interaction between meropenem (MEPM), a carbapenem of antibiotic agent, and sodium valproate (VPA), an anticonvulsant, was studied in rats and human volunteers. When sodium VPA and MEPM were administered simultaneously, the plasma VPA level was significantly lower and the blood cell/plasma VPA concentration ratio was significantly higher than after the administration of sodium VPA alone (control). Following the simultaneous administration of sodium VPA and MEPM, the pharmacokinetic parameters such as plasma VPA, volume of distribution (Vd) and clearance (CL) were significantly increased, while the maximum plasma concentration (Cmax) and area under the plasma concentration- time curve (AUC) till 3 h were significantly decreased. The ratio of free (unbound) VPA to protein-bound VPA was significantly increased after the administration of MEPM. The concentration of VPA in brain tissue was significantly decreased after the simultaneous administration of VPA and MEPM. Competition between VPA and MEPM for a protein binding site resulted in increased plasma levels of free (unbound) VPA, which then distributed to various tissues, in particular, the blood cells, liver and kidney. VPA which distributed to the liver was metabolized there and excreted. Subsequently, the levels of VPA in the plasma and brain would be significantly decreased.

Effects of salicylate on the pharmacokinetics of valproic acid (VPA) after oral administration (p.o.) of sodium valproate were investigated in rats. When salicylic acid was administered orally after sodium valproate p.o., the plasma VPA concentrations including maximum plasma concentration (C max ), area under the plasma concentration-time curve up to 3 h (AUC 0-3 ) and the elimination half-life ( t 1/2 ) of VPA were lower than control values. In addition, when salicylate was administered intraperitoneally or intravenously, the plasma VPA concentrations, AUC 0-3 and t 1/2 of VPA were lower than those in the control group. These results suggest that decreases in the plasma VPA concentrations including C max and AUC 0-3 with simultaneous oral administration of sodium valproate and salicylic acid may be related to both reduction of absorption and increase in clearance of VPA.

The effect of two kinds of 1,4-dihydropyridine calcium-channel blockers, nicardipine hydrochloride and nifedipine, on the disposition of carvedilol, was studied in rats. Blood samples were assayed for carvedilol levels using solid-phase extraction and high-performance liquid chromatography. The plasma carvedilol concentration was found to be significantly higher, and the area under the concentration-time curve up to 24 h (AUC0→24) was 6.7 and 3.0 times higher after simultaneous oral administration of 20 mg kg−1 carvedilol with 40 mg kg−1 nicardipine hydrochloride, or with 40 mg kg−1 nifedipine, respectively, than after administration of carvedilol alone. The pharmacokinetic interaction between carvedilol and dihydropyridine calcium-channel blockers is thought to be attributable to vasodilator-induced changes in hepatic first-pass metabolism, inhibition in the absorption barrier by P-glycoprotein and in the metabolism of carvedilol.

The drug interaction between sodium valproate (VPA), an anticonvulsant, and faropenem sodium (FRPM), a new penem antibiotic drug, was studied in rats. No significant change was observed in the plasma VPA concentration when compared with the control after the administration of VPA (TOO mg/kg per oral) simultaneously with FRPM (600 mg/kg per oral).

The purpose of the present study was to evaluate the pharmacokinetic interaction in rats between carvedilol and three kinds of dihydropyridine calcium-channel blockers, including nicaldipine hydrochloride, nifedipine and felodipine by high-performance inquid chromatography using a solid phase extraction column. The plasma crvedilol concentrations were found to be significantly higher than the control levels at 30 min-24 hr and 3-8 hr after the simultaneous administration of 20 mg/kg carvedilol and 40 mg/kg nicaldipine hydrochloride and 40 mg/kg nifedipine, respectively. In addition, the drug pharmacokinetic parameters, comprising the area under the concentration-time curve up to 24 hours (AUC0-24), were 6.7 and 3.0 times higher after the administration of both carvedilol and nicaldipine hydrochloride and nifedipine, respectively. In contrast, after the administration of carvedilol and 5 mg/kg felodipine, the AUC0-24 showed no change.These changes are though to be attributable to either the vasodilator-induced changes in the hepatic first-pass metabolism or the metabolic inhibition.

The pharmacokinetic interaction between carvedilol, a nonselective β-blocking agent and amlodipine besilate, a dihydropyridine calcium-channel blocker were investigated in rats. To determine the concentration-time profile of plasma carvedilol, blood samples were obtained from the tail vein after the oral administration of carvedilol either with or without amlodipine besilate. The plasma carvedilol concentrations and pharmacokinetic parameters, comprising the area under the concentration-time curve from 0 to 24 hours (AUC0-24) showed no changes after the simultaneous oral administration of 20 mg/kg carvedilol and 5 mg/kg amlodipine besilate. In contrast, the plasma carvedilol concentrations at 6 hr-12 hr and AUC0-24 after the oral administration of carvedilol with 40 mg/kg amlodipine besilate were significantly higher than those without amlodipine besilate.These results suggested the pharmacokinetic interaction between carvedilol and amlodipine to be dependent on the dose of amlodipine.

We investigated the effects of metoclopramide and propantheline bromide on the bioavailability of carvedilol in rats. To determine the concentration-time profile of plasma carvedilol, the blood samples were obtained from the tail vein after the simultaneous administration of 20mg/ kg carvedilol either with or without 5 mg/kg metoclopramide and 15 mg/kg propantheline bromide. The plasma carvedilol concentrations were significantly higher than the controls at 15 min.-1 hr and 3, 4 hr, and the drug pharmacokinetic parameters time to Cmax (Tmax) was 0.45 time shorter, while the absorption rate constant (Ka) and area under the concentration-time curve(AUC0-24) were 2.5 and 1.5 times higher after the oral administration of carvedilol with metoclopramide. The rate of bioavailability for carvedilol was accelerated by metoclopramide which stimulates gastric emptying. In contrast, the plasma carvedilol concentrations and Tmax., A UC0-24 did not change after the single intraperitoneal administration of carvedilol with the oral administration of metoclopramide. Conversely, propantheline bromide, which delays gastric emptying, slowed absorption, but not according the AUC0-24 of carvedilol.Other similar pharmacokinetic interaction probably occur since carvedilol are poorly absorbed from the stomach and numerous therapeutic agents influence gastrointestinal motility.

The current situation and practice of undergraduate and postgraduate education regarding clinical pharmacology at university and college hospital were investigated using questionnaires which were sent to 80 departments of pharmacy in university and college hospitals. The questionnaires were returned by 40 departments of pharmacy (50%). The major findings were as follows:1. Undergraduate clinical pharmacology education for medical students has been established at 27 out of 40 departments (67.5%), and the main persons responsible were the department of pharmacy staff members in 25 out of 27 university and college hospitals (93%).2. Postgraduate education for medical doctors and pharmacists has been established at 9 out of 40 departments (22.5%), and the main persons responsible were also the department of pharmacy staff members in 7 out of 9 university and college hospitals (78%).3. The course curriculum for clinical pharmacology tended to include: the prescription of drugs, pharmacokinetics, therapeutic drug monitoring, law and rules etc. in undergraduate programs, while it was seminars in postgraduate programs.4. Difficult issues in both undergraduate and postgraduate programs for clinical pharmacology were lacks of staff and time for sufficient education, etc.5. The most important factors for the future of clinical pharmacology education were sufficient equipment for the academic requirements and the establishment of a department of clinical pharmacology in the school of medicine etc.These results show that undergraduate education for clinical pharmacology has not yet been universally established at the departments of pharmacy in university and college hospitals, especially postgraduate education was poor, and therefore further efforts are called for to improve clinical pharmacology education.

The plasma sodium valproate (VPA) concentration was significantly lower than the control 0.5, 1, 2 hours after the simultaneous administration of VPA with imipenem/cilastatin (IPM/CS), but the blood cell VPA/plasma VPA concentration was significantly higher at 2 hours after VPA administration. When we injected IPM instead of IPM/CS into rats, the plasma VPA concentration demonstarated similar low levels. The pharmacokinetic parameters of plasma VPA, the volume of distribution (Vd) and clearance (CL) were significantly higher at 1.6 and 1.7 times basal levels white the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve up to 3 hours (AUC0→3) significantly decreased by 0.7 and 0.6 times the basal level after the simultaneous administration of VPA and IPM/CS. The rate of VPA unbound protein was 30.3% before injecting the IPM vein. Although, when IPM was injected inside the vein, it increased by 37.3% at 1 minute and significantly increased by 49.9% at 15 minutes after the administration of IPM. The liver and brain VPA tissue concentration significantly decreased after the simul taneous administration of VPA with IPM/CS.Based on these finding a large amount of unbound type VPA which was produced by competition with a protein binding part of VPA depending on IPM was distributed in the tissue. VPA was especially distributed to blood cells and the kidney. The VPA that had been distributed in the liver later metabolized and was excreted. Therefore, the VPA concentration in plasma, liver and brain was observed to significantly decrease.

Drug interaction of fleroxacin, new qunolone antibiotics, and talipexole, an antiparkinsonian drug, was studied in rats. When talipexole was administered orally before the oral administrations of fleroxacin, the plasma concentrations of fleroxacin and its metabolite, fleroxacin Noxide, decreased. The maximum plasma concentrations (Cmax) of fleroxacin and fleroxacin Noxide decreased and the time needed to reach Cmax.(Tmax) was also delayed significantly (p< 0.05) as compared to the control. This finding suggests that the pretreatment with talipexole thus decreases the rate of absorption of fleroxacin from the gastro-intestinal tract in rats. On the other hand, when fleroxacin and talipexole were administered simultaneously, the plasma concentrations of fleroxacin and fleroxacin N-oxide increased. Regarding the absorption rate constant, the Cmax and area under the plasma concentration-time curve from 0 to 24 hours (AUCo-24) of fleroxacin increased whereas Tm decreased significantly (p

We studied the use of high-performance liquid chromatography (HPLC) with a spectroflurometric detector, using a solid-phase extraction column (Bond Elut cartridge column), for the simple, rapid and sensitive determination of plasma fleroxacin (FLRX) levels in rats. Extracted aliquots were analyzed by HPLC, using a reverse phase octadecyl silica column. The analytical mean recovery of FLRX added to the blank plasma averaged 101.4%. The detection limit was 58 ng/ml in the plasma. The reproducibilities (C.V.) were 0.50-3.22% in the within-day assay and 2.87 C.V.% in the between-day assay, indicating that the analysis method was effective in the determination of FLRX plasma levels.

The povidone-iodine contents in liquid and ointment were determined using high-performance liquid chromatography (HPLC). The chromatograph equipped reversed phase ODS column and detector was set at 355 nm. The flow rate of the mobile phase of methanol: water (7: 3) containing 1% KI was 1.0ml/min.The retention time of povidone-iodine was 3.9 min. When this HPLC was applied to the povidone-iodine preparations (gurgle and solution) on the commercial market, the povidoneiodinecontents were found to comprise more than 95%. In the povidone-iodine sugar ointment, which was prepared in the hospital pharmacy, admixed with lysozyme chloride ointment, the iodine contents by this HPLC had a good correlation with the available iodine contents by titration (r=0.9999). Furthermore, this method could also be applied to povidoneiodine in the organic solution after extracting the povidone-iodine sugar ointment admixed with lysozyme chloride ointment.

19970825The plasma concentration of fleroxacin (FLRX) was significantly lower (P

The oral bioavailability of tacrolimus is low and varies considerably in humans due to first-pass metabolism by cytochrome P450 (CYP) 3A4 and the active efflux mediated by P-glycoprotein. This study was undertaken to elucidate the usefulness of rectal administration of tacrolimus as an alternative route to improve its bioavailability. Tacrolimus powder was suspended in a suppository base (witepsol H-15) and the tacrolimus suppository was inserted into the anus of the rats. For comparison, tacrolimus was suspended in 0.5% sodium methylcellulose solution and administered orally to rats. The dose of tacrolimus was fixed to 2 mg/kg. Blood samples were collected periodically up to 24 h after dosing, and tacrolimus concentrations were assayed by microparticle enzyme immunoassay. The whole blood concentrations of tacrolimus after rectal administration were much greater than those after oral administration. The C(max) and AUC(0-24 h) values after rectal administration were 3.9- and 6.9-fold greater than those after oral administration, respectively. These results clearly suggest a possibility that rectal administration of tacrolimus is capable of improving its bioavailability and cutting the costs of tacrolimus treatment.

The Endotoxin test was applied to detect endotoxin in the filtrates obtained using eight kinds of filter units employed for sterilization. The filtrate used in only one kind of filter unit was positive to this test. The concentrations of endotoxin in all of the filtrates were then determined by Limulus test using an ordinary reagent. In the filtrate that was positive to the endotoxin test, the endotoxin concentration was 0.873 EU/ml. On the other hand, in filtrates from the other filter units, the concentration was below the blank level. When endotoxin was determined in filtrates by Limulus test utilizing an endotoxin-specific reagent, in which a high concentration of endotoxin was detected, one of the five samples indicated a positive level, while the others demonstrated very low or blank level. These results suggest that even if the sample is positive to the endotoxin test, it is necessary to veify with the Limulus test utilizing endotoxin-specific reagent.

Eight kinds of the filter units were chosen to investigate the presence of UV absorbing substances in filtrate. In all of them, these substances were observed. Especially, in filter units which contain nitrocellulose membrane filter, nitrate was detected by qualitative reaction and determined by high-performance liquid chromatographic method.

The aim of this study is to determine whether pramipexole hydrochloride hydrate (PHH) and atropine sulfate affect valproic acid (VPA) pharmacokinetics and to evaluate how plasma VPA concentrations are altered by different PHH administration routes. The following studies were conducted on rats: 1) changes in plasma VPA concentration after simultaneous oral administration (PO) of PHH and VPA-Na; 2) effects of intraperitoneal administration (IP) of PHH on plasma VPA concentration after VPA-Na PO; 3) effects of PHH PO on plasma VPA concentration after intravenous administration (IV) of VPA-Na; and 4) changes in plasma VPA concentration after simultaneous PO of atropine sulfate and VPA-Na. Atropine sulfate PO significantly decreased the area under the concentration-time curve up to 3 h (AUC0-3, the total amount of drug plasma concentration) of VPA, suggesting that atropine sulfate decreases VPA-Na absorption probably due to reduced gastrointestinal motility by its anticholinergic action. Similarly, by PHH PO or IP, VPA AUC0-3 was significantly decreased. However, in cases of VPA-Na IV, all VPA parameters were unchanged by PHH PO. These results indicate that the PHH inhibitory effect may be caused in the absorption phase of VPA by pharmacological action of PHH, and thus PHH decreases VPA-Na bioavailability.

Fibronectin FN) eyedrops, which has been reported to facilitate healing trophic ulcer and recurrent corneal erosion, is usually prepared from 10ml volume of patient's own blood.Themethod for the preparation of this eyedrops was studied by determination of FN content.The results were as follows:1) From 20ml volume of blood, double concentration of FN in eyedrops could be made, or a couple of eyedrops could be done at a time.2) FN concentration in eyedrops and area under the curve (AUC) of FN fraction had a good correlation (Y=72.2X-8.7, r=0.979, p

The drug adsorption onto membrane filters (MF) from five kinds of eyedrops, atropine sulfate (AT), pilocarpine hydrochloride (PC), amphotericin B, dibekacin sulfate, and disodium edetate eyedrops during sterilization by filtration was investigated.The principal ingredients in eyedrops were scarcely adsorbed to MF.In the preservatives, methyl and propyl parahydroxybenzoates in AT eyedrops were almost adsorbed to acetylcellulose MF, while benzalkonium chloride in PC eyedrops was almost adsorbed to MF made from mixed esters of cellulose, nitrocellulose or polyvinyliden fluoride. However, the adsorption of the preservatives can be fairly prevented by discarding the first part of the filtrate from eyedrops. From these results, when eyedrops containing above preservatives are sterilized by filtration, the use of MF on which adsorption was observed should be avoided, or the first part of the filtrate should be discarded.

We studied the use of high-performance liquid chromatography (HPLC) with spectrofluorometric detection, using a solid-phase extraction for a simple, rapid and sensitive determination of plasma carvedilol levels in rats. Extracted aliquots were analyzed by HPLC, using a reversed-phase octadecyl silica column. The analytical mean recovery of carvedilol added to the blank plasma was 94.2%. The detection limit was 3.6 ng/ml in the plasma. The reproducibilities (C.V.) were 2.7-7.5% for the within-day assay, and 2.6-7.4% for the between-day assay, indicating that the method was effective for the determination of carvedilol plasma levels.

Compatibility of Bricef Dry Syrup (cefatrizine oral suspension) with oral liquids was investigated with regard to changes in appearance, pH value and residual potency. These changes were tested immediately, and 3, 7 and 14 days after admixing at room temperature, and in some admixtures, at 6°C.At room temperature, decrease in residual potency during incubation was observed in admixture with concentrated brocin-codeine, brocin, and transamin syrup; however, the decrease was prevented at 6°C. A large decrease in pH was observed in the admixture with decreased potency. Consequently, a correlation between decrease of pH and potency may be considered. Significant change in appearance was not observed in any of the combinations tested.

High performance liquid chromatography (HPLC) was used in determination of betamethasone-17-valerate (BM-V) incommercial ointment. The conditions of HPLC were as follows-model: Shimadzu LC-4A; detector: SPD-2SA; wavelength: 239nm; column: Zorbax ODS (4.6×250mm); short guard-column: Zorbax ODS (4.0×50mm); mobile phase: MeOH: H2O= 75: 25 (v/v); flow rate: 1ml/ min; pressure: 100kg/cm2 (at 40°C). BM-V in commercial ointment and other ointment or cream admixture was also measured by the present HPLC method. BM-V ointment or admixture was dissolved or suspended into cyclohexane, and then MeOH: H2O (9: 1 or 8: 2) was used to extract BM-V from cyclohexane. Naphthalene was used as an internal standard material. 10μl of extract solution was directly injected into HPLC column. The amount of BM-V was determined by comparing the peak height of BM-V to that of naphthalene on the chromatogram.The results showed the possibility that compatibility of BM-V ointment admixed with other ointment or cream can be studied with the present method.

Monoamine fluorescence was studied in the caudal neurosecretory system of eighty-four adult carp, Cyprinus carpio, of either sex. Some neurosecretory cells were surrounded with monoaminergic fluorescent varicosities, while others were not. The varicosities werc: also found adjacent to nerve terminals or capillaries in the urophysis. Noradrenaline, but not adrenaline or dopamine, was detected memically in the urophysis and the spinal cord. These results suggest that noradrenergic neurons seem to regulate both the synthesis and the release of neurosecretory material in the carp caudal neurosecretory system.

The introduction of a hydroxy group into N-methyl-8-aza-des-N-morphinan at the 3-position was achieved through nitration of the parent compound, followed by reduction and diazocization. The position of the substituent was determined by the spectral evidence from 3-methoxy-10-oxo-8-aza-des-N-morphinan which was derived from 3-hydroxy-8-aza-des-N-morphinan via the oxidation of 3-methoxy-derivative. A pharmacological study of the compound is also presented.

Axonal transport of norepinephrine (NE) and choline acetyltransferase (ChAc) in the distal portion to the transected and sutured region in the rat sciatic nerve was investigated together with correlations of the contractility of the reinnervated gastrocnemius-plantaris muscle. In the fluorescence histochemical study, the initial delay and the rate of regeneration of noradrenergic fibers were found to be approximately 2 days and 4 mm/day, respectively. In the regenerating nerves, the accumulation of ChAc was about one-half that of normal at 4 weeks and returned to normal at 12 weeks. The amplitude of muscle contraction induced by stimulation of the sciatic nerves was one-half that of normal at 4 weeks and recovered to normal at 12 weeks. The accumulation of NE was still one-fourth that of normal at 12 weeks, and catecholamine fluorescence in the sural artery was still weak, fine, and scattered, compared to that in the artery innervated by the normal sciatic nerve. These results indicate that the function of cholinergic motor fibers correlates with the accumulation of ChAc and that the recovery in amount of transportable NE in the sciatic nerve is much slower than that of the cholinergic component.