Appropriateness of surgical antimicrobial prophylaxis in Japanese university hospitals.

BACKGROUND: Surgical antimicrobial prophylaxis (SAP) is one of the major purposes of antimicrobial use. AIM: To determine the adherence to the Japanese SAP guidelines in Japanese university hospitals. METHODS: This was a retrospective cohort study including 15 general hospitals and one dental university hospital. Up to three cases of 18 designated surgeries were evaluated regarding adherence to Japanese SAP guidelines: selection of antibiotics, timing of administration, re-dosing intervals, and duration of SAP. When all items were appropriate, surgery was defined as 'appropriate'. FINDINGS: In total, 688 cases (22-45 cases per surgery) were included. The overall appropriateness was 46.8% (322/688), and the appropriateness of each surgery ranged from 8.0% (2/25, cardiac implantable electronic device implantation) to 92.1% (35/38, distal gastrectomy). The appropriateness of each item was as follows: pre/intraoperative selections, 78.5% (540/688); timing of administrations, 96.0% (630/656); re-dosing intervals, 91.6% (601/656); postoperative selection, 78.9% (543/688); and duration of SAP, 61.4% (423/688). The overall appropriateness of hospitals ranged from 17.6% (9/51) to 73.3% (33/45). The common reasons for inappropriateness were the longer duration (38.5%, 265/688) and choice of antibiotics with a non-optimal antimicrobial spectrum before/during, and after surgery (19.0%, 131/688 and 16.9%, 116/688, respectively), compared to the guideline. CONCLUSIONS: Adherence to the guidelines differed greatly between the surgeries and hospitals. Large-scale multi-centre surveillance of SAP in Japanese hospitals is necessary to identify inappropriate surgeries, factors related to the appropriateness, and incidences of surgical site infections.

Decreased monocarboxylate transporter 1 in rat soleus and EDL muscles exposed to clenbuterol.

We hypothesized that a shift in muscle fiber type induced by clenbuterol would change monocarboxylate transporter 1 (MCT1) content and activity of lactate dehydrogenase (LDH) and isoform pattern and shift myosin heavy chain (MHC) pattern in soleus (Sol) and extensor digitorum longus (EDL) of male rats. In the clenbuterol-administered rats (2.0 mg x kg(-1) x day(-1) subcutaneously for 4 wk), the ratio of muscle weight to body weight increased in the Sol (P < 0.05) and the EDL (P < 0.01). Clenbuterol induced the appearance of fast MHC(2D) and decreased slow MHC(1) in Sol (13%) but had no effect on EDL. The MHC pattern of Sol changed from slow to fast type. Clenbuterol increased LDH-specific activity (P < 0.01) and the ratio of the muscle-type isozyme of LDH to the heart type (P < 0.05) in Sol. The LDH total activity of the EDL muscle was also increased (P < 0.05). Furthermore, MCT1 content significantly (P < 0.05) decreased in both Sol and EDL (27 and 52%, respectively). This study suggests that clenbuterol might mediate the shift of MHC from slow to fast type and the changes in the regulation of lactate metabolism. Novel to this study is the observation that clenbuterol decreases MCT1 content in the hindlimb muscles and that the decrease in MCT1 is not muscle-type specific. It may suggest that the genetic expressions of individual factors involving slow-type MHC, heart-type isozyme of LDH, and MCT1 are associated with one another but are regulated independently.

Daily cost of ophthalmic solutions for treating glaucoma in Japan.

PURPOSE: We conducted a study of the daily cost of various ophthalmic solutions used in Japan for treating glaucoma: beta-adrenergic blockers (11 products), epinephrine (3), cholinergics (3), prostaglandins (2), and carbonic anhydrase inhibitors (2). METHODS: The total number of drops in one bottle of each solution was counted drop by drop. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle. The daily cost of therapy was calculated by multiplying the cost per drop by the number of drops typically used per day. RESULTS: The average cost of each preparation was calculated based on the prices and the daily usage. The daily cost of the beta-adrenergic blockers studied ranged widely, from $0.43 to $1.04. CONCLUSIONS: These data may be useful in selecting ophthalmic products for glaucoma therapy in Japan.

Amnesic effects of the anticholinergic drugs, trihexyphenidyl and biperiden: differences in binding properties to the brain muscarinic receptor.

An amnesic effect of anticholinergic drugs was previously described from several behavioral studies. We examined this effect induced by trihexyphenidyl and biperiden, clinically used in the parkinsonism and schizophrenic patients, by using passive avoidance tasks. Both of these drugs (0.1-10 mg/kg, s.c.) showed dose-dependent amnesic effects in the acquisition and retrieval phases. However, the effect induced by trihexyphenidyl was transient, whereas that of biperiden was long-lasting. To clarify the reason for the different duration of the amnesic activity, binding to the muscarinic receptor was examined. In the Scatchard analysis, trihexyphenidyl competed with [(3)H]quinuclidinyl benzilate ([(3)H]QNB) on the muscarinic receptor (showed increased K(d) and unchanged B(max) value), while biperiden decreased [(3)H]QNB binding (B(max) value) significantly. Furthermore, in an exchange assay for receptor inactivation, trihexyphenidyl binding to muscarinic receptors was exchanged by [(3)H]QNB completely, but biperiden decreased the exchangeable binding of [(3)H]QNB in a dose dependent manner (0.1-100 nM). These results suggested that the binding of trihexyphenidyl and biperiden to muscarinic receptor might be completely reversible and partially irreversible, respectively, whereas the K(i) values of these two drugs were similar. In conclusion, this difference in binding property may explain the difference in the time-course of the amnesic effect induced by trihexyphenidyl and biperiden.

Early recognition of patients with decreased methotrexate clearance following high-dose methotrexate infusion therapy.

The purpose of this study was to identify the patients with decreased methotrexate (MTX) clearance as early as possible after the start of high-dose methotrexate (HD-MTX) infusion. Fifty-six patients (age: 18 approximately 83 years) received a HD-MTX infusion (dosage: 1.9 approximately 3.8 g/m2) for 6 h. These patients were retrospectively divided into a low-clearance group and a high-clearance group based on the serum MTX concentration at 48 h (1 microM). Six out of the 56 patients showed decreased MTX clearance. The MTX concentrations in the low-clearance group were significantly higher than those in the high-clearance group even in earlier sampling times than at 48 h. The average MTX concentrations were 330 microM at 6 h, 72 microM at 12 h, and 16 microM at 24 h in the low-clearance group, and those in the high-clearance group were 210 microM, 18 microM, and 1.0 microM, respectively. The estimated elimination half-lives (t1/2) at 6 approximately 12 h and 12 approximately 24 h after the start of the infusion were also significantly longer in the low-clearance group (2.8 vs. 1.7 h and 5.0 vs. 2.8 h, respectively). Therefore, we proposed convenient criteria based on the mean + 1 S.D. of the high-clearance group: the concentration > 270 microM at 6 h and > 32 microM at 12 h; the t1/2 value > 2.1 h at 6-12 h. All 6 patients were recognized as belonging to the low-clearance group at an early stage after HD-MTX infusion by using our proposed criteria. These results indicate that patients with decreased MTX clearance could be identified within the first 12 h after the start of HD-MTX infusion. The factors influencing the prolonged elimination of MTX were also investigated. A significant decrease in renal function on day 2 was observed in the low-clearance group. The MTX level at 12 h and the estimated t1/2 values were significantly correlated with BUN, Scr and Clcr on the 2nd day after HD-MTX therapy, suggesting that an alteration in renal function occurs within 12 h of the HD-MTX infusion. The prolonged elimination of MTX could be attributable to this decrease in renal function.

Regional characteristics of [125I]cholecystokinin octapeptide specific binding to rat brain membranes following 6-hydroxydopamine treatment.

The relative changes in the amount of specific [125I]cholecystokinin octapeptide (CCK8) bound to regional brain membrane preparations after 6-hydroxydopamine (6-OHDA) treatment were examined. The specific binding in the frontal cortex and striatum decreased and reached a minimum on the 3rd day after 6-OHDA treatment. Thereafter, the specific binding recovered to 60% and 65% of control values in the frontal cortex and striatum respectively on the 28th day. On the other hand, in the nucleus accumbens, where CCK8 co-exists in the dopamine neuron, the specific binding decreased gradually, and its recovery was delayed compared with that of the frontal cortex and striatum. In the hippocampus, 6-OHDA treatment had no effect on the specific binding throughout the experimental period. The decrease of [125I]CCK8-specific binding could be caused by enhanced release of CCK8 in the frontal cortex, striatum, and nucleus accumbens, and the recovery of specific binding could be induced by depletion of CCK8 in nerve terminals. Particularly in the nucleus accumbens, the delayed recovery of specific binding suggests the loss of the pre-synaptic binding site, which exists in the CCK8/DA co-existing neuron, together with a change in CCK8 release.

Effects of L-dopa on cholecystokinin octapeptide tissue levels in normal and 6-hydroxydopamine-treated rat brain.

We investigated the changes in cholecystokinin octapeptide (CCK8) tissue levels after the intraperitoneal administration of L-3,4-dihydroxyphenylalanine (L-dopa) in normal and 6-hydroxydopamine (6-OHDA) treated rat brains to clarify the interaction between CCK8 and dopamine (DA). The administration of L-DOPA to the normal rats elevated the regional CCK8-like immunoreactivity (CCK8LI) tissue levels in a dose dependent manner in the frontal cortex, striatum, and nucleus accumbens where CCK neurons were closely associated with DA neurons but not in the hippocampus where CCK neurons were identified as local circuit neurons. Moreover, coadministration of D2-selective antagonist, L-sulpiride, with L-dopa inhibited the elevation of CCK8LI levels in several brain regions. This evidence indicates that CCK8 release was inhibited by exogenous DA converted from L-dopa via D2 receptor stimulation. In the 6-OHDA treated rats on the 3rd day after the treatment, the L-dopa administration elevated the CCK8 levels in several regions. However, the elevation of CCK8LI levels was not observed on the 7th day after the 6-OHDA treatment. These results suggest that there would be a great difference in the effect of L-DOPA on CCK8LI levels between the 3rd day and 7th day after 6-OHDA treatment. It was concluded that the changes in CCK8LI levels would be due to changes in CCK8 release, and that the CCK8 release would be regulated by extracellular DA via D2 receptor.

Pharmacokinetic behavior of cyclosporine A in liver dysfunction.

The pharmacokinetic behavior of cyclosporine A (CyA), known as a potential immunosuppressive agent to prevent graft rejection in transplantation, was studied in patients with acute hepatitis and primary biliary cirrhosis (PBC). The ratios of blood concentration of total CyA (CyA and its metabolites), CyA, and CyA metabolites to dose/kg body weight, (t-CyA/dose, CyA/dose, and CyA-Met/dose, respectively) were significantly higher in patients with hepatitis than those in renal transplantation. In PBC patients these ratios showed a tendency to be smaller than those in renal transplantation, but were not significant. The ratio of CyA-Met/CyA was higher in the patients with hepatitis and PBC than that in renal transplantation. It was highest in the patients with PBC. The ratio of CyA-Met/CyA was significantly increased with a decrease of liver functions evaluated by serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and total serum bilirubin (t-Bil). These results indicate that hepatic function affects the pharmacokinetic behavior of CyA and the increased ratio of CyA-Met/dose could be caused by a possible increased efflux of metabolites into the blood circulation due to impaired bile excretion. These results also indicate the importance of therapeutic drug monitoring (TDM) in the use of CyA with patients with hepatic dysfunction.

Changes of cholecystokinin octapeptide tissue levels in rat brain following dopamine neuron lesions induced by 6-hydroxydopamine.

Cholecystokinin octapeptide sulfated (CCK8) tissue levels in several regions of the rat brain were measured by amino terminal specific radioimmunoassay following the intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) to investigate the interaction between CCK8 and dopamine (DA). Pargyline and desmethylimipramine were administered 2 h before 6-OHDA injection. The levels of CCK8-like immunoreactivity in the frontal cortex, striatum, hippocampus, substantia nigra, and nucleus accumbens increased transiently on day 1 after 6-OHDA treatment. The levels in the frontal cortex, striatum and substantia nigra fell gradually to reach a subnormal level on day 7. In the nucleus accumbens, where the coexisting CCK8 and DA neurons lie, the tissue levels fell to a subnormal level on day 3. These decreased levels were unchanged until day 28. The irreversible destruction of DA neurons induced by 6-OHDA might cause drastic changes in regional CCK8-like immunoreactivity. The changes would depend on the neuromorphological differences in each structure. These results suggest that the CCK8 systems are closely related to the DA systems in several brain regions and that DA plays an important role in CCK8 release.

Pharmacokinetic interaction of zonisamide in rats. Effect of zonisamide on other antiepileptics.

The effects of zonisamide (ZNS) on the pharmacokinetics of phenobarbital (PB), valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) were investigated in rats. Additionally, the influence of ZNS on the serum protein binding, erythrocyte distribution and metabolism of these antiepileptics was studied in vitro. The t 1/2 and AUC values of PB were significantly increased by ZNS coadministration, and a significant decrease in the Vd/F value of PHT was observed after multiple dosing of ZNS. By contrast, ZNS showed no significant effect on VPA and CBZ kinetics. No significant effect of ZNS was observed in the serum protein binding, erythrocyte distribution or metabolism of other antiepileptics. These results suggest that ZNS has little effect on the pharmacokinetic behaviors of other antiepileptic drugs.

Pharmacokinetic interaction of zonisamide in rats. Effect of other antiepileptics on zonisamide.

The pharmacokinetics of zonisamide (ZNS) and the effects of phenobarbital (PB), valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) on ZNS kinetics were investigated in rats. The effects of other antiepileptics on the serum protein binding, erythrocyte distribution and metabolism of ZNS were also studied in vitro to elucidate the mechanism of pharmacokinetic interaction of ZNS. ZNS showed a linear disposition kinetics after oral administration of ZNS within the dose examined. Moreover, the pharmacokinetic behaviors of ZNS were not altered after multiple dosing. The decreased t1/2 value of ZNS by PB or CBZ pretreatment and the increased Vd/F value of ZNS by VPA pretreatment were observed, although it showed no marked effect of PHT on ZNS kinetics. The enhanced metabolism of ZNS was observed by PB or CBZ pretreatment from an in vitro metabolism study. The serum protein binding and erythrocyte distribution of ZNS showed no significant change in the presence of other antiepileptics in vitro. These results indicate that the decreased t1/2 value of ZNS is attributable to the enzyme inducing effect of PB or CBZ, and that neither protein binding nor erythrocyte distribution of ZNS could be the reason for the increased Vd/F value of ZNS by VPA coadministration.

Pharmacokinetic analysis of maprotiline and its demethylated metabolite in serum and brain of rats after acute and chronic oral administration of maprotiline.

Compartmental model analysis by simultaneous curve fitting was used to ascertain the pharmacokinetic relationship between maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and brain of rats after single or multiple oral administrations of MAP. The extent of bioavailability and the fraction metabolized to DMAP after acute oral administration were 0.202 and 0.065, respectively, indicating first-pass metabolism of MAP. Although the estimated transfer rate constants to and from the brain (k(in) and k(out)) of MAP were higher than those of DMAP, the k(in):k(out) ratio for MAP was similar to that for DMAP. These findings indicate the equivalent ability of MAP and DMAP to penetrate into the brain after acute oral administration. The estimated values of bioavailability and fraction metabolized to DMAP increased 2.6 and 1.7 times, respectively, after chronic administration of MAP. These findings are attributable to inhibited distribution in tissue. The k(in) and k(out) values of MAP decreased, whereas those of DMAP showed no marked change. Therefore, the k(in):k(out) ratio for MAP decreased, whereas that for DMAP did not change. These results suggest that the permeability of MAP into the brain might be affected and that of DMAP is not modified by chronic administration of MAP.

Pharmacokinetic analysis of amitriptyline and its demethylated metabolite in serum and brain of rats after acute and chronic oral administration of amitriptyline.

The compartmental model analysis by use of simultaneous curve fitting was carried out to ascertain the pharmacokinetic relationship between amitriptyline (AMT) and nortriptyline (NRT) in the serum and brain after acute or chronic oral administration of AMT. The estimated F value, a fraction of dose reached at systemic circulation, and the MD value, a fraction metabolized to NRT, were 0.044 and 0.020, respectively, after acute administration, indicating first-pass metabolism of AMT. The estimated parameters kin and kout, the transfer rate constants to and from the brain, showed no marked difference between AMT and NRT. These findings indicate equivalent ability of AMT and NRT to penetrate into the brain. The area under the concentration curve (AUC) values of AMT and NRT in the serum increased 1.4 and 8.2 times, respectively, with the increase of NRT being greater after chronic administration. The MD value was increased from 0.020 to 0.096, whereas the estimated F value showed no marked change. These results indicate the enhanced first-pass metabolism. The estimated transfer rate constants kin and kout of AMT were close to those of NRT. In addition, the transfer rate constants after chronic administration were similar to those after acute administration, indicating no marked change in penetration into the brain by multiple dosing.

Factors influencing serum concentration of zonisamide in epileptic patients.

The relationship between daily dose and serum concentration of zonisamide (ZNS) and the effects of patient age on the serum level/dose (L/D) ratio for ZNS were studied in epileptic patients (mean age +/- S.D. = 10.6 +/- 6.2 years) who chronically received ZNS. The influence of phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ) and valproic acid (VPA) on the serum protein binding of ZNS in vitro and the correlation between total and unbound serum levels of ZNS in patients were also examined. Significant correlations were obtained between daily dose per body weight or per body surface area and serum level of ZNS. The correlation coefficient of the latter was higher than that of the former. There was no effect of age on the L/D ratio on the basis of body surface area, whereas that on the basis of body weight increased significantly with age. No significant increase in the free fraction of ZNS was observed in the presence of PHT, PB and CBZ except VPA in vitro. There were significant correlations between total and unbound serum levels of ZNS in the two patient groups coadministered with and without VPA. Although the free fraction of ZNS in the former was significantly higher than that of the latter, the increase was small. These results suggest that dosage regimens on the basis of body surface area would be more accurate than those on a body weight basis and that there is little effect of other antiepileptics on the serum protein binding of ZNS.

Pharmacokinetics of maprotiline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of maprotiline.

The concentrations of maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of MAP in rats. MAP was eliminated in a biexponential manner from the serum and monoexponentially from the brain. The DMAP declined monoexponentially from the serum and brain regions. No significant difference was observed in elimination among the eight brain regions examined. In the brain, MAP distributed unevenly after chronic administration, whereas DMAP showed an even distribution. In the acute administration, the AUCbrain: AUCserum ratio of MAP was similar to that of DMAP, and the AUCDMAP: AUCMAP ratio in the serum was almost equal to that in the brain, indicating equivalent ability of MAP and DMAP to penetrate into the brain. After chronic administration, the AUCDMAP value in the serum increased 4.1 times, whereas no marked change was observed for MAP. There was no evidence of enhanced N-demethylation activity from in vitro metabolism study, suggesting that the enhanced AUCDMAP value was not attributable to the enhancement of drug metabolizing activity. Although the AUCMAP value in the brain, as well as in the serum, increased slightly, the AUCDMAP in the brain increased 2.3 times, showing less increase than that in the serum. These findings suggest inhibited distribution of DMAP into tissue, including brain regions, after chronic administration. The pharmacokinetics of the demethylated metabolite DMAP is affected more than that of MAP by chronic administration of MAP.

Pharmacokinetics of amitriptyline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of amitriptyline.

The concentrations of amitriptyline (AMT) and its demethylated metabolite nortriptyline (NRT) in the serum and in specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of AMT in rats. Both AMT and NRT declined from the serum in a biexponential manner and were eliminated monoexponentially from the brain regions, with no significant difference in elimination among the eight brain regions examined. In the brain, both AMT and NRT were unevenly distributed after chronic administration, whereas an even distribution was observed after acute administration. The AUCbrain:AUCserum ratio of AMT was higher than that of NRT, indicating greater transport of AMT into the brain regions. The AUCAMT value in the serum increased 1.6 times after chronic administration, whereas no significant changes were observed in the brain regions. The AUCNRT values increased 9.0 times in the serum and 6.8 times in the brain, with the increase in the serum being greater. These results suggest inhibited distribution of the drugs into the tissues, including the brain regions, and enhanced metabolism of AMT.

Ocular pharmacokinetics of latamoxef and cefaclor in humans. Penetration into aqueous humor.

Penetrations of latamoxef (LMOX) and cefaclor (CCL) into the aqueous humor after intravenous or oral administration were investigated in patients admitted with cataract. Concentrations of antibiotics in plasma and aqueous humor were determined periodically by microbiological assay. LMOX disappeared from plasma in a monoexponential manner with a half-life of 2.7 h after intravenous administration at a dose of 1000 mg. The maximum concentration of LMOX in aqueous humor (4.7 micrograms/ml) was observed 2 h after administration. When CCL was administered orally at a dose of 500 mg, the maximum concentration of CCL in aqueous humor was 0.53 microgram/ml 2 h after administration, whereas the maximum plasma concentration of 8.4 micrograms/ml was observed at 1 h. Pharmacokinetic analysis (simultaneous simulation) of plasma and aqueous humor concentration-time courses was done by using the best-fitting compartment model examined (modified two-compartment model). Prediction of the concentration of antibiotics in aqueous humor from the plasma concentration profile was also examined using the same compartment model in a separate experiment. The predicted concentration in aqueous humor was proved to fit reasonably with the measured concentration.