Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus.

Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. In study 1, the effects of immunosuppressants, cyclosporine (CsA) and tacrolimus on serum lipids were compared in-patients undergoing renal transplantation. The study included 32 cases of renal transplantation recipients who randomized to the CsA treatment group (15 patients) and the tacrolimus group (17 patients). Before and 1 month after the transplantation, we assessed the serum lipid levels, apolipoprotein levels, the concentrations of cholesterol in the respective lipoprotein fractions and the enzyme activities related to lipid-metabolism. The serum lipid levels in both groups were significantly increased at 1 month after renal transplantation. In the CsA group, there were significant increases in cholesterol contents in very-low-density lipoprotein (VLDL), LDL2 and HDL2 fractions, whereas, in the tacrolimus group, cholesterol content was increased in VLDL and HDL2 fractions. In study 2, 1 month after renal transplantation, 19 patients with hypercholesterolemia (total cholesterol (TC) >200 mg/dl) and hypertriglyceridemia (triglyceride (TG) >150 mg/dl) were treated with simvastatin 5-10 mg/day for 6 months. Simvastatin treatment significantly decreased serum TC (240+/-29-200+/-22 mg/dl, P<0.001), low-density lipoprotein cholesterol (LDL-C; 114+/-20-99+/-17 mg/dl, P<0.05) and TG levels (217+/-103-130+/-38 mg/dl, P<0.01). In addition, there were significant decreases in very-low-density lipoprotein cholesterol (VLDL-C; 53+/-20-34+/-15 mg/dl, P<0.001). The Cmax and AUC of simvastatin were increased about eight-fold, when simvastatin was given in combination with CsA. In contrast, no significant changes in simvastatin levels were observed when combination with tacrolimus. Although simvastatin levels were increased with CsA, there were no abnormal changes in renal and liver functions, creatinine phosphokinase (CPK) levels or in incidence of adverse effects.

Biological stereoselective reduction of 3,3,5-trimethylcyclohexanone by Glomerella cingulata.

The microbial transformation of 3,3,5-trimethylcyclohexanone was investigated using the plant pathogenic fungus, Glomerella cingulata. With this organism 3,3,5-trimethylcyclohexanone gave the corresponding cis- and trans-3,3,5-trimethylcyclohexanols with the ratio of 20:1 forming the cis-isomer highly stereoselectively, upon 5 days incubation together with 3,3,5-trimethyl-2-cyclohexen-1-one (isophrone) as a minor product.

Clinicopathological evaluation in non-episode biopsies of renal transplant allograft.

Histopathological findings in renal allograft with stable function remain unclear. We therefore performed non-episode biopsy in the long-surviving renal allograft to investigate the histopathological changes. Our data show that, although arteriolopathy is characteristic of drug-induced nephropathy, it is unrelated to dosage and concentration of cyclosporine or tacrolimus in non-episode biopsy. We evaluated therefore the clinicopathological findings of arteriolopathy in this study. Non-episode biopsy was defined as follows: as serum creatinine level lower than, 2.0 mg/dl and a urinary protein level lower than 500 mg/day. A total of 65 biopsy specimens were enrolled in this study as non-episode biopsy. Twenty-nine specimens revealed arteriolopathy. There were no statistically significant differences between arteriolopathy and dosage or concentration of cyclosporine or tacrolimus. Arteriolopathy in non-episode biopsy was related to time of biopsy, kidney age, hypertension, and hyperlipidemia, suggesting that it is important for graft survival to strictly control blood pressure and blood lipid level.

Synthesis and biological activity of alpha-methylene-gamma-lactones as new aroma chemicals.

Seven kinds of alpha-methylene-gamma-lactones with an alkyl group at the C-4 position were synthesized according to a previously described method, with yields of 28-34%. These alpha-methylene-gamma-lactones had characteristic and unique odors. All alpha-methylene-gamma-lactones added a roast-like odor to materials. The antimicrobial effects of alpha-methylene-gamma-lactones were investigated by using a paper disk diffusion method. The results showed the alpha-methylene-gamma-lactones inhibited the growth of three bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas fluorescens) and two fungi (Saccharomyces cerevisiae and Aspergillus niger). In particular, alpha-methylene-gamma-undecalactone and alpha-methylene-gamma-dodecalactone exhibited potent inhibition of the growth of these microorganisms compared to butyl p-hydroxybenzoate as standard antibiotic. The umu test revealed that the alpha-methylene-gamma-lactones suppressed the SOS-inducing activity of three mutagens, furylfuramide, UV irradiation, and Trp-P-1, respectively. The antimicrobial effects and the suppressive effects of SOS induction by alpha-methylene-gamma-lactones had a tendency to intensify as the number of carbons in the side chain increased.

Moscatilin from Dendrobium nobile, a naturally occurring bibenzyl compound with potential antimutagenic activity.

A bibenzyl compound that possesses antimutagenic activity was isolated from the storage stem of Dendrobium nobile. The isolated compound suppressed the expression of the umu gene following the induction of SOS response in Salmonella typhimurium TA1535/pSK1002 that have been treated with various mutagens. The suppressive compound was mainly localized in the n-hexane extract fraction of the processed D. nobile. This n-hexane fraction was further fractionated by silica gel column chromatography, which resulted in the purification and subsequent identification of the suppressive compound. EI-MS and (1)H and (13)C NMR spectroscopy were then used to delineate the structure of the compound that confers the observed antimutagenic activity. Comparison of the obtained spectrum with that found in the literature indicated that moscatilin is the secondary suppressive compound. When using 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (furylfuramide) as the mutagen, moscatilin suppressed 85% of the umu gene expression compared to the controls at <0.73 micromol/mL, with an ID(50) value of 0.41 micromol/mL. Additionally, moscatilin was tested for its ability to suppress the mutagenic activity of other well-known mutagens such as 4-nitroquinoline-1-oxide (4NQO), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), UV irradiation, 3-amino-1,4-dimethyl-5H-pyrido[4,3b]indole (Trp-P-1), benzo[a]pyrene (B[a]P), and aflatoxin B(1) (AFB(1)). With all of the aforementioned chemicals or treatments, moscatilin showed a dramatic reduction in their mutagenic potential. Interestingly, moscatilin almost completely suppressed (97%) the AFB(1)-induced SOS response at concentrations <0.73 micromol/mL, with an ID(50) of 0.08 micromol/mL. Finally, the antimutagenic activities of moscatilin against furylfuramide and Trp-P-1 were assayed by the Ames test using the S. typhimurium TA100 strain. The results those experiments indicated that moscatilin demonstrated a dramatic suppression of the mutagenicity of only Trp-P-1 but not furylfuramide.

Biotransformation of (+)- and (-)-menthol by the larvae of common cutworm (Spodoptera litura).

(+)-Menthol was mixed in an artificial diet at a concentration of 1 mg/g of diet, and the diet was fed to the last instar larvae of common cutworm (Spodoptera litura). Metabolites were recovered from frass and analyzed spectroscopically. (+)-Menthol was transformed mainly to (+)-7-hydroxymenthol. Similarly, (-)-menthol was transformed mainly to (-)-7-hydroxymenthol. The C-7 position of (+)- and (-)-menthol was preferentially oxidized.

Effect of insulin resistance on left ventricular hypertrophy and dysfunction in essential hypertension.

BACKGROUND: In hypertensive patients, the relationships between glucose tolerance and left ventricular hypertrophy (LVH) and left ventricular diastolic function (LVDF) have been described in several reports. OBJECTIVE: In this study, we examined the relationships between insulin resistance and LVH and LVDF in hypertensive patients from the therapeutic perspective. METHODS AND RESULTS: The study participants were essential hypertensive patients with impaired glucose tolerance (IGT-HT, n = 26), hypertensive patients with normal glucose tolerance (NGT-HT, n = 39), and normotensive control individuals (n = 18). Insulin resistance was evaluated by the insulin suppression test by use of the steady-state plasma glucose (SSPG) level. Left ventricular mass index (LVMI) and LVDF, which was determined by the E:A ratio, were estimated by echocardiography. Temocapril, an angiotensin-converting enzyme inhibitor, was administered in an open, non-randomized manner with a mean dose of 2.8+/-0.2 mg/ day, and the mean administration period was 18 weeks. The systolic and diastolic blood pressure, the LVMI, and the SSPG level were significantly higher in the hypertensive patients than in the control individuals. The mean systolic and diastolic blood pressures were significantly decreased by treatment with Temocapril. Before treatment, stepwise regression analysis showed that SSPG is an independent predictor for LVMI and LVDF. After treatment, the changes in LVMI (D-LVMI; %) (-15.1+/-1.5), the changes in LVDF (D-E:A; %) (-38.2+/-4.1), and the changes in insulin resistance (D-SSPG; %) (-13.7+/-1.7) were significantly higher in the IGT-HT group than in the NGT-HT group (-11.4+/-1.1, -18.1+/-1.7, -9.4+/-1.4, respectively), and the D-SSPG was an independent predictor for D-LVMI and D-E :A. CONCLUSIONS: The results of this study indicate that insulin resistance is an important factor affecting LVH and LVDF.

Relationship between insulin resistance and cardiac sympathetic nervous function in essential hypertension.

BACKGROUND: It has been suggested that hyperinsulinemia and insulin resistance participate in the pathogenesis of hypertension, in part by activating sympathetic activity. OBJECTIVE: We aimed to examine the relationship between insulin resistance and cardiac sympathetic nervous function in patients with essential hypertension using 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy. METHODS AND RESULTS: Twenty-eight patients (18 men) with essential hypertension and 11 (seven men) control individuals with a mean age of 55.8+/-3.3 years were recruited. Patients with diabetes mellitus, congestive heart failure or coronary artery disease were excluded from this study. To evaluate insulin resistance, we used steady-state plasma glucose (SSPG; mg/dl) levels measured by the SSPG method. To evaluate cardiac sympathetic nervous function, we calculated the heart-to-mediastinum ratio from the delayed MIBG image (H:M-D) and the mean washout rate (WOR, %). There were significant differences (P<0.01) in SSPG, H:M-D and WOR between the essential hypertension and control individual groups (125 versus 103 mg/dl, 2.2 versus 2.4, and 32 versus 23%, respectively). Stepwise regression analysis showed that SSPG and plasma norepinephrine level are independent predictors for the cardiac sympathetic nervous function obtained from MIBG scintigraphy. CONCLUSIONS: These findings indicate that insulin resistance is significantly related to activation of the cardiac sympathetic nervous function associated with left ventricular hypertrophy in patients with essential hypertension.

Effect of naloxone on the bladder activity of rabbits with acute spinal injury.

BACKGROUND: Naloxone enhances bladder activity in patients with chronic spinal cord injury. However, there are few reports on naloxone for bladder morbidity in acute spinal cord injury. METHODS: We performed a prospective, controlled study of the effects of naloxone on bladder function in rabbits with and without surgical transection of the spinal cord at the 10th thoracic vertebra. Acute and chronic stages of injury were defined according to bladder function. Naloxone was given intravenously at both stages, and intrathecally at the acute stage. Bladder activity was monitored by cystometry. Blood concentrations of methionine-enkephalin were measured by radioimmunoassay. RESULTS: Spinal cord injuries were acute 1 or 2 days after surgery, and chronic after 1 or 2 weeks. Bladder capacity significantly decreased after 0.01 mg of intravenous naloxone in uninjured control rabbits, and after 0.03 mg of intravenous naloxone in rabbits with chronic-phase injuries. During the acute-injury phase, 0.3 mg of intravenous naloxone, or 0.02 mg of intrathecal naloxone, was necessary to evoke the micturition reflex. No significant changes in blood enkephalin levels were seen before or after spinal cord injury. CONCLUSION: In rabbits with acute spinal cord injury, intrathecal naloxone evoked the micturition reflex at a much lower dose than did intravenous naloxone. Intrathecal naloxone promises to become a new therapy for the acute stage of spinal cord injury for active recovery of bladder function, and could replace current therapy.

Suppression of the SOS-inducing activity of Trp-P-1 and aflatoxin B1 by meso-dihydroguaiaretic acid from Machilus thunbergii in the Salmonella typhimurium TA1535/pSK1002 umu test.

The methanol extract from Machilus thunbergii showed a suppressive effect on umu gene expression of the SOS response in Salmonella typhimurium TA1535/pSK1002 against the mutagen, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), which requires liver metabolizing enzymes. The methanol extract from M. thunbergii was successively re-extracted with chloroform, butanol and water. A suppressive compound in the chloroform extract fraction was isolated by SiO2 column chromatography and identified as meso-dihydroguaiaretic acid by GC-MS, and 1H- and 13C-NMR spectroscopy. Meso-dihydroguaiaretic acid inhibited of the SOS-inducing activity of Trp-P-1 in the umu test. Gene expression was suppressed by 62% at less than 0.18 mumol/ml, the ID50 value being 0.08 mumol/ml. Compound 1 was also assayed with aflatoxin B1 (AfB1) and showed a suppressive effect.

[Histopathological findings and clinical effects for acute rejections].

We reviewed 115 cases of acute rejection following renal transplantation. All cases were diagnosed after graft biopsy, and showed histopathological evidence of acute rejection. They were treated with administration of OKT3, 15-deoxyspergualin (DSG), anti-lymphocyte globulin (ALG) or methylprednisolone (MP). All rejections were histopathologically classified according to the Banff working classification. The clinical effects of each drug were evaluated both at 1 month and 1 year following the therapy for rejection, by measurement of serum creatinine level. The effective rate both at 1 month and 1 year was related with the Banff working classification ( p < 0.0001). At 1 month after treatment, there were no significant differences between the OKT3, DSG or ALG group and MP group in cases of borderline change and AR grade I. In cases of grade II and grade III, a significant difference was observed between the OKT3 or ALG group and MP group (p < 0.05). The DSG group showed a slightly better outcome than the MP group, although the difference was not significant. In conclusion, the Banff schema is shown to be valid for classification of acute renal allograft rejection, and it is necessary to determine the treatment for acute rejection according to histopathological classification.

Biotransformation of (+)- and (-)-Limonene by the Larvae of Common Cutworm (Spodoptera litura).

(+)-Limonene was mixed in an artificial diet at a concentration of 1 mg/g of diet, and the diet was fed to the last instar larvae of common cutworm (Spodopteralitura). Metabolites were recovered from frass and analyzed spectroscopically. (+)-Limonene was transformed mainly to (+)-p-menth-1-ene-8,9-diol (uroterpenol) and (+)-p-mentha-1,8-dien-7-oic acid (perillic acid). Similarly, (-)-limonene was transformed mainly to (-)-p-menth-1-ene-8,9-diol (uroterpenol) and (-)-p-mentha-1,8-dien-7-oic acid (perillic acid). The results indicate that there is little difference in metabolic pathway between the (+)- and (-)-forms.

Suppression of the SOS-Inducing Activity of Trp-P-1 and Aflatoxin B1 by Meso-dihydroguaiaretic Acid from Machilus thunbergii in the Salmonella typhimurium TA1535/pSK1002 umu Test.

The methanol extract from Machilus thunbergii showed a suppressive effect on umu gene expression of the SOS response in Salmonella typhimurium TA1535/pSK1002 against the mutagen, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), which requires liver metabolizing enzymes. The methanol extract from M. thunbergii was successively re-extracted with chloroform, butanol and water. A suppressive compound in the chloroform extract fraction was isolated by SiO2 column chromatography and identified as meso-dihydroguaiaretic acid by GC-MS, and (1)H- and (13)C-NMR spectroscopy. Meso-dihydroguaiaretic acid inhibited of the SOS-inducing activity of Trp-P-1 in the umu test. Gene expression was suppressed by 62% at less than 0.18 µmol/ml, the ID50 value being 0.08 µmol/ml. Compound 1 was also assayed with aflatoxin B1 (AfB1) and showed a suppressive effect.

Enantioselective accumulation of (--)-pinoresinol through O-demethylation of (+/-)-eudesmin by Aspergillus niger.

Microbial transformation of (+/-)-eudesmin by Aspergillus niger was investigated. Enantioselective accumulation of (--)-pinoresinol was shown through O-demethylation of (+/-)-eudesmin. This fungus O- demethylated both enantiomers of eudesmin, but the conversion rates for each enantiomer were clearly different.

O-demethylation of 7,7'-epoxylignans by Aspergillus niger.

Biotransformation of the 7,7'-epoxylignans, (+)-veraguensin, (+)-galbelgin and galgravin by Aspergillus niger has been investigated. These lignans were converted to their corresponding 4,4'-O-demethyl derivatives, (+)-verrucosin, (+)-fragransin A2 and nectandrin B.

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (1994). III. Secular changes in susceptibility].

Susceptibilities of Enterococcus faecalis, Staphylococcus aureus, Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Proteus mirabilis, Pseudomonas aeruginosa and Serratia spp. isolated from patients with urinary tract infections (UTIs) in 10 hospitals during June 1994 to May 1995 to various antimicrobial agents were compared with those in the same period of previous years according to a classification, uncomplicated UTIs, complicated UTIs without indwelling catheter, and complicated UTIs with indwelling catheter. No remarkable changes were found in susceptibilities of Citrobacter spp., Enterobacter spp. and Serratia spp. The susceptibilities of E. faecalis to amikacin and quinolones were better than those in 1993. As for S. aureus, susceptible strains to all drugs increased in uncomplicated UTIs. Against E. coli in 1993, the antimicrobial activities of piperacillin, cefotiam and aminoglycosides have decreased, however, in 1994, these activities have turned to the better state. As for Klebsiella spp. susceptible strains to ABPC decreased. The susceptibilities of P. mirabilis to all drugs except minocycline were good. Against P. aeruginosa in 1993, the activities of aminoglycosides have decreased, but, in 1994, these activities have turned to the better state. These data should be considered in clinical treatment of various urinary tract infections.

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (1994). I. Susceptibility distribution].

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 567 bacterial strains isolated from patients with urinary tract infections in 10 hospitals during the period of June 1994 to May 1995. Of the above total bacterial isolates, Gram-positive bacteria accounted for 26.8% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 73.2% and most of them were Escherichia coli. 1. Enterococcus faecalis. Ampicillin (ABPC) and imipenem (IPM) showed the highest activities against E. faecalis isolated from patients with urinary tract infections. The MIC90s of them were 1 microgram/ml. Vancomycin (VCM) was also active with the MIC90 of 2 micrograms/ml. Piperacillin (PIPC) and biapenem (BIPM) were also active with the MIC90s of 4 micrograms/ml and 8 micrograms/ml, respectively. The others were not so active with the MIC90s of 16 micrograms/ml or above. 2. Staphylococcus aureus including MRSA. VCM showed the highest activities against S. aureus isolated from patients with urinary tract infections. Its MIC90 was 1 microgram/ml against both S. aureus and MRSA. Arbekacin (ABK) was also active with the MIC90 of 2 micrograms/ml. The others except minocycline (MINO) were not so active with the MIC90s of 64 micrograms/ml or above. 3. Staphylococcus epidermidis. MINO showed the strongest activity against S. epidermidis isolated from patients with urinary tract infections. Its MIC90 was 0.25 microgram/ml. ABK was also active with the MIC90 of 1 microgram/ml. Cephems were active with the MIC90s of 2 approximately 16 micrograms/ml, but penicillins and quinolones were not so active with the MIC90s and 64 approximately 128 micrograms/ml. 4. Citrobacter freundii. Gentamicin (GM) showed the highest activities against C. freundii isolated from patients with urinary tract infections. Its MIC90 was 1 microgram/ml. IPM was also active with the MIC90 of 2 micrograms/ml. Cefpirome (CPR) and cefozopran (CZOP) were also active with the MIC90s of 4 micrograms/ml and 8 micrograms/ml. The others were not so active with the MIC90s of 32 micrograms/ml or above. 5. Enterobacter cloacae. IPM showed the highest activities against E. cloacae. Its MIC90 was 0.5 microgram/ml. GM and amikacin (AMK), ciprofloxacin (CPFX) and tosulfloxacin (TFLX) were also active with the MIC90s of 4 micrograms/ml. Penicillins and cephems except latamoxef (LMOX), cefmenoxime (CMX), CPR and CZOP showed lower activities with the MIC90s of 256 micrograms/ml or above. 6. Escherichia coli. Most of antimicrobial agents were active against E. coli. CPR, CZOP, IPM, carumonam (CRMN), CPFX and TFLX showed the highest activities against E. coli. The MIC90s of them were 0.125 microgram/ml or below. Cefotiam (CTM), flomoxef (FMOX) CMX, ceftazidime (CAZ), and LMOX were also active with the MIC90s of 0.25 microgram/ml. Penicillins were not so active with the MIC90s of 128 micrograms/ml or above. 7. Klebsiella pneumoniae. CRMN showed the highest activities against K. pneumoniae. Its MIC90 was < or = 0.125 microgram/ml. CZOP was also active with the MIC90 of 0.25 microgram/ml. Penicillins were not so active with the MIC90s of 128 micrograms/ml or above. 8. Proteus mirabilis. P. mirabilis was susceptible to a majority of drugs. CMX, CAZ, LMOX, CRP, cefpodoxime (CPDX), CRMN, CPFX and TFLX showed the highest activities against P. mirabilis isolated from patients with urinary tract infections. The MIC90s of them were 0.125 microgram/ml or below. MINO was not so active with the MIC90 of 128 micrograms/ml. 9. Pseudomonas aeruginosa. Most of the agents were not so active against P. aeruginosa. IPM showed MIC90 of 8 micrograms/ml. The others were not so active with the MIC90s of 16 micrograms/ml or above. CPFX showed MIC50 of 0.5 microgram/ml.