Evaluating the activity of N-89 as an oral antimalarial drug.

Despite the recent progress in public health measures, malaria remains a troublesome disease that needs to be eradicated. It is essential to develop new antimalarial medications that are reliable and secure. This report evaluated the pharmacokinetics and antimalarial activity of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the rodent malaria parasite Plasmodium berghei in vivo. After a single oral dose (75 mg /kg) of N-89, its pharmacokinetic parameters were measured, and t1/2 was 0.97 h, Tmax was 0.75 h, and bioavailability was 7.01%. A plasma concentration of 8.1 ng/ml of N-89 was maintained for 8 h but could not be detected at 10 h. The dose inhibiting 50% of parasite growth (ED50) and ED90 values of oral N-89 obtained following a 4-day suppressive test were 20 and 40 mg/kg, respectively. Based on the plasma concentration of N-89, we evaluated the antimalarial activity and cure effects of oral N-89 at a dose of 75 mg/kg 3 times daily for 3 consecutive days in mice harboring more than 0.5% parasitemia. In all the N-89- treated groups, the parasites were eliminated on day 5 post-treatment, and all mice recovered without a parasite recurrence for 30 days. Additionally, administering oral N-89 at a low dose of 50 mg/kg was sufficient to cure mice from day 6 without parasite recurrence. This work was the first to investigate the pharmacokinetic characteristics and antimalarial activity of N-89 as an oral drug. In the future, the following steps should be focused on developing N-89 for malaria treatments; its administration schedule and metabolic pathways should be investigated.

A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice.

Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

Genomic and biological features of Plasmodium falciparum resistance against antimalarial endoperoxide N-89.

Drug resistance of malaria parasites remains a problem affecting antimalarial treatment and control of the disease. We previously synthesized an antimalarial endoperoxide, N-89, having high antimalarial effects in vitro and in vivo. In this study we seek to understand the resistant mechanism against N-89 by establishing a highly N-89-resistant clone, named NRC10H, of the Plasmodium falciparum FCR-3 strain. We describe gene mutations in the parent FCR-3 strain and the NRC10H clone using whole-genome sequencing and subsequently by expression profiling using quantitative real-time PCR. Seven genes related to drug resistance, proteolysis, glycophosphatidylinositol anchor biosynthesis, and phosphatidylethanolamine biosynthesis exhibited a single amino acid substitution in the NRC10H clone. Among these seven genes, the multidrug resistance protein 2 (mdr2) variant A532S was found only in NRC10H. The genetic status of the P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC), a potential target of N-89, was similar between the NRC10H clone and the parent FCR-3 strain. These findings suggest that the genetic alterations of the identified seven genes, in particular mdr2, in NRC10H could give rise to resistance of the antimalarial endoperoxide N-89.

Pharmacokinetic analysis of new synthetic antimalarial N-251.

BACKGROUND: With the emergence and growing number of drug-resistant Plasmodium falciparum, a new drug for malaria control must be urgently developed. The new antimalarial synthetic compound N-251 was recently discovered. As an endoperoxide structure in the body, the compound shows high antimalarial activity and curative effects. We performed a pharmacokinetic (PK) analysis of N-251 under various conditions using mice to understand the inhibitory effect of N-251 in parasite-infected mice. RESULTS: PK study of N-251 after intravenous and oral administration in mice showed plasma concentration of N-251 was decreased drastically by intravenous route. C max was reached in 2 h after oral administration of N-251, and the level decreased to a level similar to that obtained after intravenous administration. The area under the curves (AUCs) of the plasma concentration of N-251 increased dose-proportionally in both administrations, and bioavailability (F) was approximately 23%. Additionally, T max, C max, AUC, and F increased in fasted mice compared to normal-fed mice after the administration of N-251, indicating the influence of diet on the absorption kinetics of N-251. Furthermore, in parasite-infected fasted mice, the plasma concentration-time profile of N-251 was similar to that in normal-fasted mice. Based on the PK parameters of single oral administration of N-251, we investigated the effect of multiple oral doses of N-251 (68 mg/kg three times per day for 2 days) in normal-fed mice. The plasma concentration of N-251 was between 10 and 1000 ng/mL. The simulation curve calculated based on the PK parameters obtained from the single-dose study well described the plasma concentrations after multiple oral dosing, indicating that N-251 did not accumulate in the mice. Multiple oral administrations of N-251 in mice were required to completely eliminate parasites without accumulation of N-251. CONCLUSIONS: N-251 has been selected as a potent antimalarial candidate. We found that N-251 showed short half-life in plasma, and AUCs increased proportionally to dose. With multiple doses of N-251, the plasma level of N-251 was greater than 10 ng/mL in normal-fed mice, and accumulation of N-251 was not observed; however, multiple treatments with N-251 are required for the complete cure of parasite-infected mice. Determining the appropriate dosage was an important step in the clinical applications of N-251.

Potential of synthetic endoperoxides against Trichomonas vaginalis in vitro.

Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC50 value, 50% of killing concentration for T. vaginalis, was very low for metronidazole-sensitive isolates (11.7 to 22.8µM), but was high for metronidazole-resistant ones (182.9 to 730.4µM). The IC50 values of N-89 and N-251 were 41.0 to 60.0µM, and 82.0 to 300.0µM for metronidazole-sensitive and -resistant isolates, respectively. In conclusion, we found the endoperoxides, N-89 and N-251, have anti-trichomonal effect against metronidazole-resistant T. vaginalis as well as metronidazole-sensitive ones. These results indicate that the anti-trichomonal effects for our endoperoxides are equivalent or better in metronidazole-resistant T. vaginalis in comparison to metronidazole.

Pharmaceutical properties of a low-substituted hydroxypropyl cellulose (L-HPC) hydrogel as a novel external dressing.

Controlling the moisture balance between exudates and their transpiration from the surface of wounded skin is important for healing. Low-substituted hydroxypropyl cellulose (L-HPC) hydrogel sheets (HGSs) possessing high water retention and water vapor transmission properties were prepared by neutralizing the highly viscous alkaline liquid of 7-10% L-HPC. Glycerol-impregnated L-HPC hydrogel sheets (L-HPC G-HGSs) were obtained by exchanging aqueous liquid in L-HPC HGSs. The physical characteristics required for wound dressings, i.e., mechanical strength, adhesive strength, and water retention properties, as well as the water vapor transmission (WVT) properties of L-HPC HGSs and L-HPC G-HGSs were evaluated. The mechanical strengths of L-HPC HGSs were enhanced with increases in the L-HPC content. The impregnation of glycerol in L-HPC HGSs yielded a significantly elasticated sheet. The adhesive strengths of L-HPC HGSs were significantly lower than those of commercial medical dressings. Water retention in L-HPC HGSs after being stored for 2h at 37°C was approximately 50%. The WVT rate of 7% L-HPC HGS was approximately 40g/m(2)/h, which was markedly higher than that of silicone gel type medical dressings. In conclusion, L-HPC HGSs are promising dressings that maintain an adequate moisture balance by transpiring excessive wound exudates with less damage to the healing wound.

Effects of peritoneal dialysis on pharmacotherapy: a deductive pharmacokinetic-model approach to predict drug concentration profiles in plasma and peritoneal fluid.

The aim of this study was to present a deductive compartment pharmacokinetic (PK) model to predict the concentration profiles of drugs in plasma and peritoneal fluid in peritoneal dialysis (PD) rats. PK parameters of model drugs in normal and experimentally induced acute renal failure (ARF) rats not undergoing PD were obtained inductively in a common regression manner with a two-compartment model. In PD normal and ARF rats, PK parameters relating to the transfer of drugs to the peritoneal dialysate and the progress of renal failure were deductively modified to simulate the drug concentration-time profiles in plasma and in the peritoneal fluid in PD rats. The deductively introduced modifiers were the volume of distribution in the peripheral compartment, plasma protein binding, and solvent movement factor to the peritoneal fluid. Predicted profiles of tolbutamide, propranolol and cefazolin in PD normal and ARF rats were compared with the corresponding observed data. This minimal deductive approach yielded satisfactory accuracy in the prediction of both the plasma and peritoneal fluid concentrations of tolbutamide and propranolol.

In vivo application of chitosan to facilitate intestinal acyclovir absorption in rats.

The effect of chitosan on the intestinal absorption of acyclovir (ACV) was evaluated in rats, and factors influencing its facilitative effect on the ACV absorption were examined. When ACV solution containing 1% chitosan with an average molecular weight of 150 kDa was administered into the upper jejunum, a significant increase in the plasma ACV concentration was observed, with the peak ACV concentration being eight times greater than that observed with the chitosan-free solution. The chitosan-free ACV solution, whose viscosity was adjusted to remain unchanged with polyethylene glycol, did not cause an increase in the plasma concentration, and neither did the chitosan-free solutions substitutionally containing low molecular cationic compounds, triethanolamine and kanamycin. When chitosan was digested with chitosanase to shorten its polycationic polysaccharide structure, chitosan subjected to 150-min digestion retained its facilitative effect on ACV absorption, but that subjected to 420-min digestion no longer caused facilitation, in which its average molecular weight was reduced to around 10 kDa. It is therefore indicated that intestinal ACV absorption can be facilitated with chitosan, and that it is necessary for chitosan to have a certain length of polycationic polysaccharide structure to exert such facilitation.

[Development of advanced educational programs, including research programs, for undergraduate students in National Universities: the facts in 2010].

This article summarizes detailed facts obtained from the questionnaire conducted in 2010 at about 14 National Universities on the topic of "Research programs and advanced educational programs for undergraduate students". The contents of the questionnaire included: (1) Research programs based on the coalition of university and hospital and/or community pharmacy, other Graduate Schools, such as School of Medicine etc., and the University Hospital, (2) Educational systems for the achievement of research programs and their research outcomes, (3) Research programs based on pharmacist practices, (4) Ongoing advanced educational programs for undergraduate students, taking advantage of the coalition with Graduate School, School of Medicine (and Dentistry), and University Hospital. Some of the advanced educational programs outlined in this questionnaire will be carried out by our group in the coming years and the educational benefits together with associated problems shall as well be clarified. This approach will be informative for the development of the leader-oriented pharmacist programs for the college of Pharmacy.

Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure.

To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, K(m) and V(max) , were examined in the incubation study, the K(m) values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The V(max) values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased K(m) values accompanied the decreased V(max) values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the K(m) value was observed in ARF rats, but it did not accompany the decrease in the V(max) value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats.

Pharmacodynamic characterization of nitric oxide-mediated vasodilatory activity in isolated perfused rat mesenteric artery bed.

Vasodilation profiles following a short-term infusion of nitric oxide (NO), acetylcholine (ACh), and sodium nitroprusside (SNP) into an isolated perfused mesenteric artery bed were analyzed in rats to examine their vasodilatory efficacy under physiological conditions. These compounds commonly increase the intracellular NO concentration to exert vasodilatory activity. In an experiment with exogenous NO infusion where 100 µl of 1 : 300 diluted NO-saturated solution (approx. 53 pmol of NO) was applied, the infusion caused transient vasodilation in a dose-dependent manner, with the peak vasodilation value being 74.7% of the maximum relaxation value. In experiments with ACh, the peak vasodilation value was 81.5% of the maximum at a dose of 60 pmol. The vasodilation profile of ACh was similar to that of NO infusion, but the ACh-induced vasodilation reduced at a slower rate than that induced by NO infusion. The vasodilatory activity of SNP was less potent than that of ACh, and its peak value was 62.8% of the maximum at a dose of 2000 pmol. However, SNP activity was augmented by removing the vascular endothelia of the mesenteric artery bed, and the peak value reached 67.3% of the maximum at a dose of 60 pmol. Pharmacodynamic analysis indicated that NO and ACh are equivalent regarding their vasodilatory efficacy, while the efficacy of SNP was less than 1% of theirs, as the arterial vascular endothelium impeded intracellular SNP-related NO generation, by which 95% of SNP's vasodilatory efficacy was negated. These findings will be helpful to understand factors influencing the therapeutic efficacy of vasodilators.

Pharmacokinetic properties of newly synthesized retinoid X receptor agonists possessing a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton in rats.

OBJECTIVE: The pharmacokinetic properties of three newly synthesized retinoid X receptor (RXR) agonists were evaluated in rats to elucidate the structural factor influencing their pharmacokinetic properties. MATERIAL AND METHODS: Three RXR agonists possessing a common 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton and side chain structures that are slightly different from each other were prepared as we previously reported (Takamatsu et al., ChemMedChem, 2008; 3:780-787). The plasma concentration profiles of these compounds were evaluated following the intravenous and intra-intestinal administrations. Their hepatic metabolism was characterized using rat liver microsomes. RESULTS: Based on the plasma concentration profile, NEt-3IP (3-isopropoxy) was shown to have a distribution volume of 4.53 L/kg, and to be cleared from the body with an elimination half-time of 0.95 h. The bioavailability of NEt-3IP is 16.4%, whereas those of the isobutoxy analog NEt-3IB and the cyclopropylmethoxy analog NEt-3cPM are 46.5% and 22.6%, respectively. Subsequently, in the experiments using rat liver microsomes, the K(m) and V(max) values of NEt-3IP were determined as 7.85 µM and 0.48 nmol/min/mg protein, respectively. This K(m) value is nearly the same as those of NEt-3IB and NEt-3cPM, but the V(max) value is noticeably smaller. Additionally, it was revealed that the CYP family mainly metabolizing NEt-3IP is different from those metabolizing the other analogs. CONCLUSION: Based on these findings, the pharmacokinetic properties of the compounds possessing this type of the skeleton seem to be largely influenced by a slight modification of the side chain structure.

Empirical approach for improved estimation of unbound serum concentrations of valproic acid in epileptic infants by considering their physical development.

The unbound serum concentration of valproic acid (VPA) is closely related to its therapeutic efficacy. In epileptic infants, the unbound VPA concentration varies largely from patient to patient, being difficult to predict using the reported equations for older children. To establish an equation to estimate the unbound concentration in infants, we empirically characterized the relationship between total and unbound VPA concentrations, taking their growth and development into consideration. Data were retrospectively collected from archived clinical records of 30 epileptic infants aged 0-11 months old. The relationship between total and unbound VPA concentrations was analyzed according to the Langmuir equation, in which the patient's body weight, height, and body surface area were considered as physical development indices. Inter- and intra-individual variabilities in the VPA concentrations were also considered. It was shown that the unbound VPA concentration in infants is properly estimated when their body weights are taken into account, in which the parameter for the maximum binding site concentration (Bm) increases as the body weight increases, while that for the dissociation constant (Kd) is unaltered. Additionally, the relationship was shown to slightly change when the infants are concomitantly treated with VPA and the other antiepileptics. These findings provide useful information to adjust the VPA dosage to achieve optimal therapeutic efficacy in epileptic infants.

Altered electrolyte handling of the choroid plexus in rats with glycerol-induced acute renal failure.

The altered electrolyte handling of the choroid plexus was investigated in rats with acute renal failure (ARF) using lithium and rubidium as surrogate markers for sodium and potassium, respectively. Firstly, the transport of these two markers from the plasma to cerebrospinal fluid (CSF) was evaluated after they were concurrently injected into the femoral vein. As a result, their disposition from the plasma to CSF was shown to decrease in ARF rats, but the relationship profile between those two markers was not different from that observed in normal rats, indicating that the decreased disposition of lithium and rubidium occurs without affecting the stoichiometric balance. To clarify the mechanisms accounting for the decreased disposition, an inhibition study was then performed. When bumetanide, an inhibitor of the Na(+) /K(+) /2Cl(-) co-transporter, was directly introduced into the cerebroventricle prior to lithium and rubidium being intravenously administered, a marked increase in the markers' disposition was observed. However, such an increased disposition did not occur when bumetanide was injected into the femoral vein. Other inhibitors, such as amiloride for the Na(+) /H(+) exchanger and ouabain for Na(+) /K(+) -ATPase, did not show any effects on marker disposition regardless of the inhibitor being administered into either the cerebroventricle or femoral vein. These findings suggest that the decreased marker disposition in ARF rats is due to an increased efflux process of the choroid plexus mediated by the Na(+) /K(+) /2Cl(-) co-transporter. That is, electrolyte efflux from the CSF to plasma increases, and thereby the electrolyte influx from the plasma to CSF is counteracted.

Factorial invariance of a questionnaire assessing medication beliefs in Japanese non-adherent groups.

OBJECTIVE: The aim of our study was to verify invariance of latent factors derived from the BMQ (Belief about Medicines Questionnaire) among Japanese adherent and non-adherent groups (adherent to medication and intentionally, unintentionally, and overlapping non-adherent groups) and to estimate mean differences of the latent factors among the groups. SETTING: A Japanese university hospital. METHODS: After administration of a cross-sectional survey, covariance structure analyses of the two-factor model were conducted. Groups that exhibited factorial invariance were identified, and structured mean analyses estimated the differences of the latent means of the factors between groups using the bootstrap method without relying on theoretical assumptions for sampling distributions. Effect size was employed as an indicator of these differences. MAIN OUTCOME MEASURE: The differences in the latent means of the two factors (the necessity and concerns factors for prescribed medications) across the groups exhibiting factorial invariance, which reflect true differences between them. RESULTS: Factorial invariance was demonstrated only across adherent and unintentionally non-adherent groups. Unintentionally non-adherent patients had significantly lower latent means for the necessity factor than adherent patients, with a very close to medium effect size (-0.49; 95% CI -0.84, -0.14; bootstrap method). CONCLUSION: A meaningful comparison of BMQ scale scores can be made between adherent and unintentionally non-adherent groups of Japanese patients.

Population pharmacokinetic analysis of vancomycin using serum cystatin C as a marker of renal function.

We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoek's formula correlated linearly with VAN clearance (VAN clearance [ml/min]=0.825xGFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (-3.45 to -1.38) of the difference in each value of the mean absolute error (-2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.

Comparative study of increased plasma quinidine concentration in rats with glycerol- and cisplatin-induced acute renal failure.

A comparative study of altered plasma concentration of quinidine in rats with glycerol- and cisplatin-induced acute renal failure (ARF) was conducted with quinidine used as a positively charged and liver-metabolized therapeutic compound. Although apparent total body clearance of quinidine decreased to 68 and 48% of the normal value in glycerol- and cisplatin-induced ARF rats, respectively, its distribution decreased only in glycerol-induced ARF rats. The plasma unbound fraction of quinidine decreased in glycerol-induced ARF rats, which was not observed in cisplatin-induced ARF rats. The plasma level of alpha(1)-acid glycoprotein (AGP) increased in glycerol-induced ARF, but not in cisplatin-induced ARF rats. It is therefore conceivable that the plasma concentration of positively charged and liver-metabolized compounds generally increases due to hepatic elimination suppressed as renal function decreases, but the pharmacokinetic impact of suppressed hepatic elimination is occasionally difficult to observe in some ARF model rats since it may be blurred by the influence of increased plasma AGP level.

Efficacy of peritoneal dialysis of tolbutamide in rats under conditions of the plasma unbound fraction being increased.

Peritoneal dialysis of a highly protein-bound compound, tolbutamide, was examined in rats to clarify whether the efficacy of the peritoneal dialysis of such compounds increases proportionally as their unbound fractions increase. As expected, it was shown that the tolbutamide concentration of the peritoneal dialysate rose as the unbound fraction of tolbutamide increased. However, the efficacy of peritoneal dialysis of tolbutamide was proportionally elevated only when the unbound fraction was slightly increased by sulfamethoxazole treatment. When the unbound fraction of tolbutamide was increased 7.8 times by sulfadimethoxine treatment, the dialysis efficacy was increased to only 58% of that expected. This discrepancy between the observed and expected values regarding dialysis efficacy was more marked when experiments were performed in rats with experimentally induced acute renal failure. Pharmacokinetic analysis indicated that the intrinsic dialysis clearance of tolbutamide decreased when its unbound fraction was greatly increased. These findings suggest that peritoneal dialysis may be mediated not only by passive diffusion, but also by concentration-dependent processes. The efficacy of the peritoneal dialysis of therapeutic compounds may be overestimated if the estimation is based only on their unbound fraction measured under control conditions.

[Frequency of decreased renal function between patients treated with brand and generic products of vancomycin hydrochloride injection].

The frequency of decreased renal function was compared between patients treated with brand and generic products of vancomycin injection (VCM) in a retrospective manner based on the clinical examination records archived in Okayama University Hospital. A total of 122 patients were found to have been solely treated with vancomycin injection for MRSA infection, and their examination records were analyzed. The renal function of those patients was evaluated based on the serum creatinine concentration (SCr), and patients whose SCr was maximally elevated above the defined upper limit of the normal range (1.20 mg/dl for males and 0.96 mg/dl for females) were considered to show decreased renal function. Although the amount of VCM administered to patients was larger in the case of generic rather than brand products, the percentage of patients whose renal function was decreased during VCM treatment was not significantly different between the VCM products, in which 2 among 62 patients receiving the brand product and 4 among 60 receiving the generic product were reported to show decreased renal function. It was additionally revealed that 3 of those 4 patients with a decreased renal function related to the generic product were not treated as instructed by the package insert, and their trough VCM concentration exceeded the recommended level of 10 microg/ml. With these findings, the brand and generic VCM products are considered to be similar regarding the adverse effect of decreasing renal function.

Decreased lithium disposition to cerebrospinal fluid in rats with glycerol-induced acute renal failure.

PURPOSE: The lithium disposition to cerebrospinal fluid (CSF) was evaluated in rats with acute renal failure (ARF) to examine whether electrolyte homeostasis of the CSF is perturbed by kidney dysfunction. In addition, the effects of renal failure on choroid plexial expressions of the Na+-K+-2Cl- co-transporter (NKCC1) and Na+/H+ exchanger (NHE1) were also studied. METHODS: After lithium was intravenously administered at a dose of 4 mmol/kg, its concentration profile in plasma was evaluated by collecting plasma specimens, while that in CSF was monitored with a microdialysis probe in the lateral ventricles. NKCC1 and NHE1 expressions were measured via the Western immunoblot method using membrane specimens prepared from the choroid plexus in normal and ARF rats. RESULTS: The lithium concentration in CSF of ARF rats was 30% lower than that of normal rats, while their plasma lithium profiles were almost the same, indicating that the lithium disposition to CSF was decreased in ARF rats. It was revealed that the choroid plexial expression of NKCC1 was increased by 40% in ARF rats, but that of NHE1 was unchanged. CONCLUSION: ARF decreases the lithium disposition to CSF, possibly by promoting lithium efflux from CSF due to increased NKCC1 expression in the choroid plexus.