Methionine-induced acidosis in the weanling rat

Whole body balances of non-metabolizable base (NB) were studied in weanling rats fed a cereal-based diet with or without added l -methionine. In response to l -methionine loading (2.5 mmol day^-1) the rats exhibited a significant reduction in rates of food intake (109 vs. 160 g per 8 days) and body growth (3 vs. 52 g per 8 days); fractional oxidation of absorbed dietary amino acid sulphur increased from 0.28 to 0.64; and mean urinary sulphate excretion increased from 2.3 to 14.8 mmol per 8 days. Mean rates of renal excretion of NB and filtered titratable organic acid decreased from 20 to ?11 mmol per 8 days and from 22 to 8 mmol per 8 days. Balances of calcium and NB remained at reference values despite a decrease in whole blood ‘base excess’ from ?1.0 to ?6.4 mmol 1–¹. The concentration of NB in plasma rose but slightly. It is concluded that L-methionine loading in the weanling rat leads to extracellular non-carbonic acidosis subject to renal compensation. This acidosis is due not to retention of H⁺ released by ionization of endogenous sulphuric acid but possibly to accumulation of (acid) organic metabolites of methionine which are efficiently conserved by the kidneys. The rise in sulphuric acid production leads to an adaptive decrease in fractional reabsorption of filtered sulphate. Even during inhibited growth, absorbed dietary NB is retained and deposited in the skeleton, probably as calcium carbonate.     

Effect of ketoconazole and terbinafine on the pharmacokinetics of caffeine in healthy volunteers

The effects of single oral doses of ketoconazole 400 mg and terbinafine 500 mg on the hepatic microsomal system have been investigated in 8 healthy male volunteers. Microsomal activity caffeine was assessed by following the metabolism of 3 mg/kg bodyweight i.v. administered 1 h after the drug. The inhibitory effect of terbinafine was more pronounced than that of ketoconazole: clearance was decreased from 1.34 ml.kg-1.min-1 in controls to 1.06 and 1.21 ml.kg-1.min-1, respectively, and the corresponding half-life was increased from 5.8 h in controls to 7.6 and 6.7 h, respectively. The apparent volume of distribution remained unchanged. The serum levels of the antimycotics were within the therapeutic range in each subject. Although all three substances are metabolised by microsomes, the kinetic parameters (Cmax, half-life, elimination constant) of the antimycotics were poorly if at all correlated with the elimination of caffeine.     

Correlation between soluble transferrin receptor and serum ferritin levels following bone marrow transplantation for thalassemia

Abstract: This study analyzes the serum transferrin receptor (sTfR) levels in a series of 230 ex-thalassemics with a follow-up of 1 to 9 years after bone marrow transplantation (BMT) for homozygous β thalassemia. Ex-thalassemics are individuals, cured of homozygous β thalassemia by BMT, who maintain different degrees of iron overload acquired during the pretransplant period. Both in experimental and clinical conditions, sTfR concentrations have been shown to be a quantitative measure of body iron status. This study was carried out to assess whether the level of sTfR may be of help in determining the extent of iron overload in ex-thalassemics. Patients who received the marrow from their HLA-identical sibling donor heterozygous for β thalassemia, namely heterozygous ex-thalassemics, displayed significantly higher levels of sTfR than patients transplanted from their normal sibling donors (normal ex-thalassemics). This finding suggests that increased erythropoiesis, albeit in part ineffective in heterozygous ex-thalassemics, is responsible for the sTfR increment. Both heterozygous and normal ex-thalassemics had significant lower sTfR levels than their heterozygous (p < 0.003) or normal (p < 0.0001) donors, respectively. These differences may be ascribed to the presence of iron overload in ex-thalassemics in comparison to their normal or heterozygous donors who did not present excess of iron in the body. A significant inverse correlation between sTfR and serum ferritin levels (r = –0.54, p < 0.0001) was found when normal ex-thalassemics were considered. In heterozygous ex-thalassemics, the lack of correlation between these two parameters may be explained by the enhanced erythropoietic activity of individuals with thalassemic trait. These results suggest that the level of sTfR may be a useful indicator of iron overload in normal ex-thalassemics.     

Formation of pyridinium species of haloperidol in human liver and brain

Recent interest in the neurotoxicity of haloperidol is based on its oxidation in rodents to the pyridinium derivative, HPP⁺, a structural analog of the neurotoxin, 1-methyl-4-phenylpyridinium (MPP⁺). Recently, we reported that HPP⁺ and a newly identified reduced pyridinium, RHPP⁺, were present in blood and urine of haloperidol-treated schizophrenics and that the concentrations of RHPP⁺ exceeded those of HPP⁺. In this study, we examined pathways for formation of RHPP⁺ in subcellular fractions of human liver (n=5) and brain (basal ganglia;n=5). The major pathway was reduction of HPP⁺ (20 µM) to RHPP⁺ in cytosol (0.17–0.39 and 0.03–0.07 µM RHPP⁺/g cytosolic protein per h in liver and brain, respectively). The reactions were inhibited significantly by menadione and in brain also by daunorubicin. The inhibition profile, cytosolic location and strict NADPH dependence suggest that the enzymes involved are ketone reductases. A second pathway was oxidation of reduced haloperidol (50 µM), a major metabolite of haloperidol in blood and brain, to RHPP⁺. In liver microsomes, 0.17–0.63 µmol RHPP⁺ was formed /g microsomal protein per h. A potent inhibitor of the pathway was ketoconazole (IC₅₀, 0.8 µM), which suggests that P-450 3A isozymes could be involved. In brain mitochondria but not microsomes, reduced haloperidol (120 µM) was oxidised to RHPP⁺ at a small but significant rate (0.005–0.020 µmol RHPP⁺/g mitochondrial protein per h) which was not attenuated by SKF 525A, quinidine, ketoconazole, or monoamine oxidase inhibitors. Further studies are warranted to establish the biological importance of these metabolites in vivo.     

Favorable effects of epidural analgesia on hemodynamics,oxygenation and metabolic variables in the immediate post-anesthetic period

Fourteen adult patients undergoing elective major abdominal surgery were divided into two groups. One group received epidural and general anesthesia (epidural group), and 20 ml of 0.125% bupivacaine and 2 mg of morphine were administered epidurally about 30 min before the end of the operation for post-anesthetic analgesia. The other group (control group) received general anesthesia alone with nitrous oxide, oxygen and enfiurane. Flow-directed pulmonary arterial and radial arterial catheters were inserted preoperatively, and hemodynamic, respiratory, neuroendocrine and metabolic variables were measured serially. The data were compared during anesthesia and the immediate post-anesthetic recovery period. In the control group, the plasma epinephrine level in the post-anesthetic recovery period increased about four times over the anesthetic period. Oxygen consumption was increased and mixed venous oxygen saturation was decreased significantly. There was a close linear correlation between oxygen consumption (Y) and plasma epinephrine (X) level: Y = 285.7X + 90.5 (P < 0.01, r = 0.72). On the other hand, plasma epinephrine, oxygen consumption and mixed venous oxygen saturation did not change significantly in the epidural group in the post-anesthetic recovery period. There was also a close linear correlation between oxygen consumption (Y) and oxygen delivery (X): Y = 0.22X -32.0 (P < 0.01, r = 0.89). We conclude that the surgical stress and anesthetic reversal may seriously influence neuroendocrine responses and subsequently increase plasma epinephrine. Tissue oxygenation and metabolic imbalance may occur due to the rapid increase of epinephrine in the postanesthetic recovery period. Epidural analgesia at this period may play a more important role and have a more favorable effect on the tissue metabolism.     

Kupffer cell activation in the survival discrepancy between liver grafts from enterally and parenterally fed donors

Abstract This study was designed to investigate the effects of differences in the route of nutritional support of the donor on cold ischemia/reperfusion injury. Participation of Kupffer cells in these effects, based on the analysis of hepatic energy metabolism in early phases of reperfusion was also investigated. Orthotopic liver transplantation was performed between Large-White pigs weighing 20–30 kg after a 4-h cold preservation of the graft in Euro-Collins solution at 4°C. One group was fed orally with a standard laboratory diet (FED group, n = 5), a second group was fasted and given 20% glucose intravenously (12 kJ/kg per day) (PEF group, n = 5), and a third group was fed orally with a standard laboratory diet and given GdCI₃ (10 mg/kg) intravenously 24 h before operation (FEDGD group, n = 5). These treatments were given for 7 days prior to harvesting. The survival time was significantly longer in the PEF (34.8 ± 5.5 days) and FEDGD (28.0 ± 11.9 days) groups than in the FED (9.8 ± 2.0 days) group ( P < 0.05). The serum hyaluronic acid elimination rate determined from 1 to 2 h after reperfusion was significantly lower in the FED group than in the other two groups ( P < 0.001). The glycogen content of the livers 1 h after reperfusion in all three groups had been consumed rapidly, but the ATP content of the livers was significantly reduced in the FED group alone ( P < 0.01). Hepatic FFA clearance (C_FFA) was moderately increased in all three groups in the early phase after reperfusion, but it was higher in the FED group than in the other two groups, with significant differences 1 and 2 h after reperfusion ( P < 0.05). In conclusion, parenteral nutrition of the donors reduced cold ischemia/reperfusion injury which is related to Kupffer cell activation and, thus, was better than enteral nutrition for donor management.     

五种螯合剂对大鼠体内微量元素影响的观察

观察了５种常用螯合剂对大鼠体内微量元素排出量、组织分布的变化。结果表明，５种螯合剂可不同程度地增加机体必需微量元素Ｚｎ、Ｃｕ、Ｍｇ和Ｃａ经尿液排出量。ＥＤＴＡ和ＤＴＰＡ的影响尤为明显。ＥＤＴＡ和ＤＴＰＡ可使Ｚｎ经尿液的排出量增加１６－５２倍，ＤＴＰＡ使肝脏Ｚｎ含量减少１５．９％（Ｐ〈０．０５），肝脏Ｃｕ含量下降６０％（Ｐ〈０．０５）。ＥＤＴＡ和ＤＴＰＡ注射后，肾中Ｚｎ含量明显增高，相当对照大鼠３．     

Iodomethylated fatty acid metabolism in mice and dogs

The myocardial uptake of fatty acids labeled with radioactive iodine and injected i.v. can only be evaluated with SPECT if their oxidation kinetics is slow enough. For this reason, we evaluated different iodomethylated fatty acids in mice and dogs to determine which of them shows the highest myocardial uptake and the slowest oxidation. The most suitable was found to be 16-iodo-3-methyl hexadecanoic acid (mono ) since its myocardial fixation was the same as that of the reference, i.e. 16-iodo-9-hexadecenoic acid (IHA), whereas it was degraded more slowly. Thirty min after injection of mono into dogs, the decrease in myocardial activity with respect to the maximum was two fold less than after IHA injection. The myocardial uptake of the two dimethylated fatty acids studied, i.e. 16-iodo-2,2-methyl hexadecanoic acid and 16-iodo-3,3-methyl hexadecanoic acid, was less than that of IHA in mice and dogs. In the latter, the myocardial uptake was so small that we were unable to study the time course of its activity. Consequently, these dimethylated fatty acids are not suitable for the study of the myocardial uptake of fatty acids in man.     

Prodrugs for Improved Oral β-Estradiol Bioavailability

Prodrugs of -estradiol (1) were prepared with the objective of improving its oral bioavailability. -Estradiol-3-acetylsalicylate (2), -estradiol-3-salicylate (3), and -estradiol-3-anthranilate (4) were synthesized. With these prodrugs the 3-phenolic hydroxy group of estradiol was protected, so that first-pass conjugative metabolism could be reduced. Prodrug hydrolysis rates in dog and human plasma in vitro were determined. Deacetylation of estradiol-3-acetylsalicylate was much more rapid than its hydrolysis to estradiol. In dogs, oral estradiol bioavailability after administration of 2 and 4 was 17-fold and 5-fold higher, respectively, than after oral 1.