Retrospective analysis of risk factors for liposomal amphotericin B-associated nephrotoxicity.

In this study, we examined patients who received liposomal amphotericin B (L-AMB) to determine the risk factors associated with nephrotoxicity before and during L-AMB treatment. In this retrospective, single-center, observational cohort study, we examined 37 patients who received L-AMB treatment between April 2018 and December 2019. Nephrotoxicity was observed in 11 (29.7%) patients. We focused on the baseline albumin level and body surface area (BSA) before L-AMB treatment. Univariate analysis showed that the BSA and baseline albumin levels in patients with nephrotoxicity were significantly higher than those in patients without nephrotoxicity. Moreover, univariate analysis showed that albumin supplementation was significantly associated with the frequency of nephrotoxicity during L-AMB treatment. Multiple logistic regression analysis revealed the following independent risk factors for nephrotoxicity before or during L-AMB treatment: baseline albumin level (odds ratio [OR] = 16.000; 95% CI 1.480-172.000; P = 0.022) and albumin supplementation (OR = 40.800; 95% CI 2.210-753.000; P = 0.013). In conclusion, we identified baseline albumin level and albumin supplementation as novel risk factors for L-AMB-induced nephrotoxicity.

The human plasma glutathione peroxidase-encoding gene: organization, sequence and localization to chromosome 5q32.

A genomic clone encoding the human plasma glutathione peroxidase (PGPx), a major enzyme in reducing lipid hydroperoxide and hydrogen peroxide in plasma, was isolated and 5618 nucleotides (nt) were determined. The nt sequence data revealed that the PGPx gene is composed of five exons spanning approx. 10 kb. Primer extension experiments mapped the transcription start point at 298 nt upstream from the predicted start codon. Twenty nt upstream from the polyadenylation site of the gene, an uncanonical polyadenylation signal, AGTAAA, was found. Human PGPx was localized on chromosome 5 band q32 by fluorescence in situ hybridization.

Adrenomedullin increases phosphatidylcholine secretion in rat type II pneumocytes.

Adrenomedullin, a novel hypotensive peptide, has been reported to be produced in the lung as well as in the adrenal medulla. However, the effect of adrenomedullin on lung function is still poorly understood. In this study, we detected the expression of both adrenomedullin mRNA and putative adrenomedullin receptor mRNA in primary cultures of rat type II pneumocytes. Adrenomedullin increased the secretion of phosphatidylcholine, the predominant component of pulmonary surfactant, by type II pneumocytes. The increase was partly inhibited by pretreatment with the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37). Furthermore, the increased phosphatidylcholine secretion was significantly inhibited by several protein kinase C inhibitors, such as sphingosine, 2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]3-(1H-indol-3-yl) maleimide (Gö6983), 3-[1-(3-amidinothio)-propyl-1H-indoyl-3-yl]3-(1-methyl-1H-++ +indoyl-3-yl ) maleimide methane sulfonate (Ro-31-8220), and staurosporine. Our results suggest that adrenomedullin can be considered a candidate autocrine modulator of surfactant secretion in type II pneumocytes.

Modification of release rates of cyclosporin A from polyl(L-lactic acid) microspheres by fatty acid esters and in-vivo evaluation of the microspheres.

Biodegradable microspheres containing cyclosporin A (CyA, cyclosporine) were prepared using poly(L-lactic acid) (PLA) and poly(lactide-co-glycolide)(PLGA) by a solvent evaporation method. CyA was efficiently entrapped in PLA, PLGA(50/50) and PLGA(75/25) microspheres in a range of 81-85%. CyA released constantly from PLA microspheres without any lag time, whereas the drug from PLGA(50/50) and PLGA(75/25) microspheres was released after lag time of about 1 and 3 weeks, respectively. Addition of fatty acid esters enhanced the release rates of CyA from PLA microspheres. In-vivo study was performed using rats with adjuvant-induced arthritis. PLA microspheres with ethyl myristate sustained high blood levels of CyA compared with the microspheres with no additives over 4 weeks. In addition, the PLA microspheres improved the symptoms such as the decrease in body weight and the increase in paw swelling occurred by adjuvant-induced arthritis in rats. Consequently, the release rate of CyA from PLA microspheres can be improved by adding fatty acid esters and PLA microspheres with fatty acid esters seem to be a useful dosage form for autoimmune disease therapy.

Abnormal expression of apoptosis-related antigens, Fas and bcl-2, on circulating T-lymphocyte subsets in primary Sjögren's syndrome.

OBJECTIVE: To clarify the pathological role of the apoptosis-related molecules expressed on peripheral blood (PB) lymphocyte subsets in primary Sjögren's syndrome (SS). METHODS: The levels of apoptosis-regulating proteins, Fas and bcl-2, were determined in the PB lymphocyte subsets from 21 patients with SS and 14 healthy controls by 2-color flow cytometry. RESULTS: In the PB from SS patients, lymphocytopenia, especially CD4+ cell-lymphocytopenia, was prominent. As observed in previous studies, the percentages of CD4+ CD45RA+ cells were lower in the SS patients than in the controls, while activated (DR+) cells were increased in CD4+ cells from the patients. Fas+ cells were also increased in the patients' CD4+ cells and CD8+ cells, but not in their B cells or natural killer cells. Furthermore, we observed several positive correlations among the percentages of activated cells (DR+ cells or CD45RA-cells) and Fas+ cells recognized in the CD4+ and/or CD8+ cells from the patients. On the other hand, intra-cellular bcl-2 proteins measured as mean fluorescence intensity were significantly diminished in the CD4+ cells, CD8+ cells, CD19+ cells, CD45RO+ cells and Fas+ cells from 14 SS patients compared with 12 healthy controls. In addition, the numbers and/or percentages of CD4+ cells and Fas+ cells positively correlated with their expression of bcl-2 in SS patients. CONCLUSION: The abnormal balance between Fas and bcl-2 expression detected in the PB lymphocyte subsets from SS patients relates, at least partially, to the lymphocytopenia observed in the patients.

Evaluation of absorption kinetics of orally administered theophylline in rats based on gastrointestinal transit monitoring by gamma scintigraphy.

The gastrointestinal (GI) transit and absorption of orally administered theophylline, a highly absorbable drug without presystemic elimination, were investigated under fasted and fed conditions using three rats in a crossover study. To evaluate the GI transit rate for each segment in vivo, a noninvasive technique, gamma scintigraphy, was employed using a nonabsorbable compound, (99m)Tc-labeled diethylenetriamine pentaacetic acid (DTPA). Using a gamma scintigraphic technique it is possible to simultaneously evaluate the GI transit and absorption of orally administered drug in the same individual. Theophylline was simultaneously administered along with [(99m)Tc]DTPA to animals in the fasted and fed states. Each GI transit pattern, simulated using the GI transit-kinetic model with a lag time factor, was well fitted to the experimental data. Gastric emptying rate varied in each study, even under the same experimental condition. The GI transit pattern for each segment was highly variable, especially in animals in the fed state. This inconsistency in transit pattern was mainly due to the variability in gastric emptying, which was much slower in animals in the fed compared with the fasted state. However, in spite of a large variability of GI transit kinetics, the plasma concentration-time curves of theophylline were well predicted by the GI transit-absorption model using the individual GI transit parameters obtained in the study. The absorption rate of theophylline was considerably reduced in animals in the fed state, because of the reduction of gastric emptying rate. Analysis using GI transit-absorption model and gamma scintigraphic technique made it possible to estimate the variable absorption kinetics regulated by GI transit with huge variability.

Transport of phenobarbitone into the intestinal lumen and the biliary tract following i.v. administration to rats.

The exsorption of intravenously administered phenobarbitone into the lumen of the small intestine of rats has been examined by an in-situ single-pass perfusion technique. The levels of the drug in the bile were about twice that in serum. Moreover, it was shown that the drug was appreciably exsorbed into the intestinal lumen. The exsorption rates of the drug into the perfusates were not very different between isotonic phosphate buffers at pH 6.0 and 8.0. The amounts of phenobarbitone exsorbed into the perfusate and excreted into the bile were 6.47 and 0.45% of the dose for isotonic phosphate buffer at pH 6.0, and were 6.09 and 0.54% of the dose for isotonic phosphate buffer at pH 8.0.

Dose-dependency in the exsorption of theophylline and the intestinal dialysis of theophylline by oral activated charcoal in rats.

The elimination half-life of theophylline in serum after intravenous (i.v.) administration of aminophylline increased with increase in dose. Exsorption of theophylline from blood to the gastrointestinal tract was investigated after i.v. administration of aminophylline (10-50 mg kg-1) to rats by the in-situ single-pass perfusion technique. The exsorption rate of theophylline into the intestinal lumen also increased with increase in dose. When the dose of aminophylline was increased five-fold from 10 to 50 mg kg-1, the amount of theophylline exsorbed in 120 min was proportionally increased from 450 to 2300 micrograms. The average extent of theophylline exsorbed into the intestinal lumen was 12-15% after doses from 10-50 mg kg-1, while the extent of the drug excreted into the bile varied from 0.17-0.30% after doses from 10-50 mg kg-1. However, intestinal and biliary clearance of theophylline did not change significantly in the range 10 to 50 mg kg-1. Oral administration of multiple doses of activated charcoal reduced the serum theophylline levels after i.v. administration of aminophylline (50 mg kg-1) to rats. The serum half-life and the area under the serum concentration-time curve of theophylline were decreased to 52 and 50% by the charcoal treatment, respectively, while the total body clearance of the drug was increased to 188% compared with the corresponding control experiments. The volume of distribution was not significantly different between treated and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Study on transport of disopyramide into the intestinal lumen aimed at gastrointestinal dialysis by activated charcoal in rats.

The characteristics of exsorption and/or excretion of disopyramide into the gastrointestinal lumen have been investigated after intravenous administration of the drug at doses of 10 and 30 mg kg-1 to rats by the in-situ single pass perfusion technique. Disopyramide was appreciably excreted into the bile where its levels were approximately ten-fold higher than those in the serum. The exsorption rate of disopyramide and mono-N-dealkyldisopyramide (MND) into the perfusate was increased with an increase in the serum level following an increase from 10 to 30 mg kg-1 in the dose of disopyramide. The average amounts of disopyramide exsorbed into the perfusate were 17.0 and 18.4% at the dose of 10 and 30 mg kg-1, respectively, whereas those of MND were less than 1% at both doses of disopyramide. Oral administration of activated charcoal reduced the serum disopyramide levels after intravenous administration of the drug (20 mg kg-1) compared with the control treatment. By oral administration of activated charcoal, t 1/2 and AUC were decreased to 89 and 82%, respectively, and Cltot was increased to 122% compared with the corresponding control treatment. Vd was not different between the treated rats and control rats. These results suggest that the oral administration of activated charcoal can enhance the clearance of disopyramide and MND from the blood.

The effect of dinoprost on transport of water and imipramine through rat small intestinal membranes.

The relation between transmucosal fluid movement and its effect on absorption and exsorption of imipramine was studied with the in-situ single-pass perfusion technique in rats. Dinoprost (prostaglandin F2 alpha, PGF2 alpha) caused a dose-related inhibition of both absorption and secretion of water across the intestinal membrane. When PGF2 alpha was infused at a rate of 5 mumols kg-1 h-1, the absorption rate of water decreased from 51.7 to 21.5 mL h-1 and the secretion rate decreased from 48.9 to 26.8 mL h-1. Net water flux changed from net water absorption (0.9 mL h-1) to net water secretion (5.33 mL h-1) by infusion of PGF2 alpha. However, absorption and exsorption of imipramine were little affected by infusion of PGF2 alpha. The absorption rates of imipramine were 3.03 and 2.36 mg h-1 in the absence and presence of PGF2 alpha, respectively. Furthermore, the average amounts of imipramine exsorbed into the intestinal lumen in 2 h were 7.82 and 8.10% in the absence and presence of PGF2 alpha, respectively. Infusion of PGF2 alpha also enhanced motility of the small intestine compared with the control. From these results, it appears that PGF2 alpha has no effect on the absorption and exsorption of imipramine across the intestinal membrane although it is reasonable to use PGF2 alpha in the case of patients with overdoses of drugs which decrease gastrointestinal motility.

Comparison of intestinal and peritoneal dialysis of theophylline and phenobarbitone in rats.

Intestinal dialysis of drugs by oral administration of activated charcoal has been compared with peritoneal dialysis in rats. The average amounts of theophylline transported over 120 min into the intestinal lumen and the peritoneal cavity were 15.7 and 16.5% of the intravenous dose (10 mg kg-1), respectively, showing no significant difference, whereas the amount of the same intravenous dose of phenobarbitone transported from the blood into the intestinal lumen (7.8%) was significantly smaller than that entering the peritoneal cavity (12.5%). The net water flux showed that secretion predominated in the peritoneal transport whilst absorption predominated in the intestinal transport for both drugs. However, the net water flux in the intestinal lumen after intravenous theophylline (as aminophylline) was significantly smaller than that following phenobarbitone. The differences in transport across the two membranes could be due to differences in the intrinsic properties of the could be due to differences in the intrinsic properties of the membranes, such as the surface area, the thickness of the membrane and the distribution of blood vessels. Differences could also be due to differences in the pharmacological effects of the drugs.

Pharmacokinetic differences between lansoprazole enantiomers in rats.

Because limited information is available about potential differences between the pharmacokinetics and pharmacodynamics of the enantiomers of lansoprazole, the enantioselective pharmacokinetics of the compound have been investigated in rats. There was a noticeable difference between the serum levels of the enantiomers of lansoprazole and of their metabolites, 5-hydroxylansoprazole enantiomers, after oral administration of the racemate (50 mg kg(-1)) to rats. Cmax (maximum serum concentration) and AUC (area under the serum concentration-time curve) for (+)-lansoprazole were 5-6 times greater than those for (-)-lansoprazole, whereas for (+)-5-hydroxylansoprazole both values were significantly smaller than those for the (-) enantiomer. CLtot/F values (where CLtot is total clearance and F is the fraction of the dose absorbed) for (+)-lansoprazole were significantly smaller than those for the (-) enantiomer. There was no significant difference between the absorption rate constants of the lansoprazole enantiomers in the in-situ absorption study. The in-vitro protein-binding study showed that binding of (+)-lansoprazole to rat serum proteins was significantly greater than for the (-) enantiomer. The in-vitro metabolic study showed that the mean metabolic ratio (45.9%) for (-)-lansoprazole was significantly greater than that (19.8%) for the (+) enantiomer in rat liver microsomes at 5.6 microM lansoprazole. These results show that the enantioselective disposition of lansoprazole could be a consequence of the enantioselectivity of plasma-protein binding and the hepatic metabolism of the enantiomers.

Effect of activated charcoal and atropine on absorption and/or exsorption of organophosphorus compounds in rats.

Effects of activated charcoal and atropine for the removal of organophosphorus compounds, which remain in the gastrointestinal tract or have already been absorbed into the systemic circulation, were investigated in rats. Activated charcoal extensively adsorbed the organophosphates fenitrothion, tolelofos methyl, piperophos and salithion, and its immediate administration after oral ingestion of fenitrothion remarkably reduced serum fenitrothion levels, but had no effect on the serum levels of the compound which had been absorbed from the gastrointestinal tract. Thus, all of the organophosphorus compounds were poorly exsorbed (0.002-0.39% of the dose in 120 min) from the blood into the intestinal lumen probably due to their extensive protein binding and large distribution volumes. Atropine inhibited absorption of fenitrothion in the perfusion in-situ and also delayed the absorption of the compound in-vivo, but had no significant effect on exsorption of fenitrothion. The serum fenitrothion levels on treatment with both atropine and charcoal significantly decreased compared with those of the control. We conclude that, oral activated charcoal will not be able to enhance the elimination of organophosphorus compounds which have already been absorbed into the systemic circulation, but constituted useful method for the removal of the compounds remaining in the gastrointestinal tract because of its excellent adsorptive capacity.

Transport of paraquat and mexiletine from the blood into the rat intestinal lumen and peritoneal cavity.

Transport of paraquat and mexiletine from the blood into the intestinal lumen and the peritoneal cavity was examined after their intravenous administration (paraquat: 20 mg kg-1, mexiletine: 10 mg kg-1) to rats. The average amounts of paraquat transferred into the intestinal lumen and the peritoneal cavity were 1.39 and 22.8% of the dose in 120 min, respectively. The average amounts of mexiletine transferred into the intestinal lumen and the peritoneal cavity were 6.1 and 2.5% of the dose in 120 min, respectively. The transfer rate of 3H2O into the peritoneal cavity after intravenous administration (1.85 MBq) was greater than that into the intestinal lumen. In view of the hydrophilic nature of paraquat cation, a solvent drag effect due to movement of water might contribute to transport of paraquat from the blood to the peritoneal cavity. Differences in transport behaviour across the two membranes could be due to differences in the geometrical factors such as the surface area and the distribution of blood vessels. Differences might also be due to differences in physicochemistry and pharmacological effects of both substances.

Inhibition of nifedipine metabolism in dogs by erythromycin: difference between the gut wall and the liver.

The purpose of this study was to evaluate possible interaction of nifedipine with erythromycin or rokitamycin in the intestinal mucosa. Male beagle dogs were orally administered nifedipine (10 mg), with or without oral pre-medication with erythromycin (300 mg), and 300 mg erythromycin or rokitamycin twice a day for 3 days. The experiments were of randomized cross-over design with a two-week wash-out period between dosing regimens. Erythromycin pre-medication for 3 days resulted in a significant increase in the area under the serum nifedipine concentration-time curve (AUC), whereas the curve for one nifedipine metabolite (M-2) decreased significantly. When the effects of erythromycin on the metabolism of nifedipine were studied using dog liver microsomes it was found that erythromycin significantly inhibited formation of M-2 but not of the metabolite M-1. These results indicate that formation of M-2 from M-1 in the liver might be reduced by erythromycin pre-medication. To avoid possible metabolism in the gut, the dogs were then administered 8 mg nifedipine into the peritoneal cavity, with or without multiple dose pre-treatment with erythromycin for 3 days. After intraperitoneal administration of nifedipine, the maximum concentration (Cmax) of nifedipine increased significantly. After pre-administration of erythromycin the relative bioavailability of nifedipine after oral administration was increased compared with injection into the peritoneal cavity. In-vitro study using rat intestinal microsomes and the in-vivo rat intestinal loop technique also showed that pre-administration of erythromycin inhibits nifedipine metabolism in the small intestine.

[Clinical studies of a newly developed miconazole preparation for intravenous drip infusion (MJR-1761) in hematologic disease patients with deep-seated fungal infections].

The efficacy and safety of a newly developed miconazole preparation (MJR-1761) for intravenous drip infusion were evaluated in 22 patients with hematological diseases complicated by documented or suspected deep-seated fungal infections. They consisted of 15 patients with fungemia, 2 patients with pulmonary mycosis, and 5 patients with mycosis of the digestive tract. Of the 5 patients, 3 had a complication of fungemia and 1 a complication of urinary tract mycosis. Of the 22 patients, 21 were clinically evaluable. All the patients were included in safety evaluation. The effective rate was 86% (18/21) when moderately improved or better evaluations were included, and the usefulness rate was 81% (17/21) when moderately or more useful evaluations were taken into consideration. Side effects occurred in 4 patients, and abnormal laboratory values were obtained in 4 patients. All these changes, which were previously reported, improved after the discontinuation of the treatment. The results presented indicate that the miconazole intravenous drip infusion solution used in this study is as effective as conventional similar preparations. Since the infusion solution need not be diluted immediately before use, it is simple to use, and its safety may be highly rated. The purpose can be met with less volume of solution per use than before because the preparation contains as much as 200 mg of miconazole in 75 ml of solution. This preparation seems to lend itself better to clinical application than conventional similar infusion solutions.

Nucleotide sequence of a human genomic DNA fragment containing the PCNA pseudogene and its localization on chromosome 4.

A one kb human genomic DNA fragment, containing a processed pseudogene of a proliferating cell nuclear antigen (PCNA/DNA polymerase delta auxiliary protein), was isolated and sequenced. The PCNA pseudogene consisted of the 3' half of exon 4 and the 5' half of exon 5 of the PCNA gene, and shared 84% nucleotide homology with the human PCNA cDNA. The PCNA pseudogene was localized on human chromosome 4, based on data obtained from a panel of human-mouse hybrid cell lines.

[Effects of cytarabine ocfosfate on colony-stimulating factor in myelodysplastic syndrome with monosomy 7].

A 42-year-old man was admitted to our hospital because of pancytopenia in April 1992. A diagnosis of refractory anemia was made. The karyotype was normal male type on the initial study. Subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) initially increased the peripheral neutrophil count, bat in January 1993, although blast cells did not increase, neutrophils had decreased in spite of the continuation of G-CSF administration. Chromosome analysis showed 46XY, +Y, -7 at this point. By adding 50 mg of cytarabine ocfosfate (SPAC) daily, the peripheral neutrophil count again rose dramatically. However, anemia, thrombocytopenia and the chromosomal abnormality were unchanged. These results indicate that SPAC may upregulate the effect of G-CSF on granulopoiesis in patients with myelodysplastic syndrome.