Research communications in chemical pathology and pharmacology最新文献

The effects of chondroitin polysulfate (CPS), a semi-synthetic oversulfated chondroitin sulfate, on the metabolism of extracellular matrix in human skin cells were examined. CPS accelerated the production of glycosaminoglycans (GAGs) in human dermal fibroblasts in a dose dependent manner (0.1-3.0 micrograms/ml), but did not modulate the production of noncollagenous protein and collagen, or [3H]-thymidine incorporation into DNA. However, higher concentrations (> 10 micrograms/ml) of CPS suppressed the [3H]-thymidine uptake by fibroblasts. More than 80% of total synthesized GAGs were found to be hyaluronate, whereas CPS did not alter their composition. These results indicated that CPS preferentially enhances the production of GAGs in human dermal fibroblasts, and that GAGs and DNA synthesis in the fibroblasts are independently regulated. Furthermore, CPS might be a unique material able to maintain the level of GAGs in the human skin.

Two new analogs of 1,25 dihydroxy vitamin D3 (calcitriol, DHCC), the active metabolite of vitamin D3 (cholecalciferol (D3) are less active on calcium metabolism and less toxic than (DHCC). They had increased differentiation-inducing activity towards normal on human myeloblastic leukemia cell line HL-60 and on histiocytic lymphoma cell line U-937 consisting of monoblastoid cells. 1,2 tetradeconyl phorbol 1, 3 acetate (TPA) was used as a positive control in these experiments.

The effects of intramuscular injections of minute amounts of polymyxin B were studied in 42 patients with endotoxemia. Plasma endotoxin was measured by means of an endotoxin-specific Endospecy test (Seikagaku Corp., Tokyo, Japan) after pretreatment of the plasma with a new perchloric acid method that we developed. The normal value of plasma endotoxin is less than 9.8 pg/mL. Polymyxin B was administered at a dose of 12,500 U every 6 hours. Plasma endotoxin rapidly decreased to the normal range in 40 of the 42 patients. Body temperature fell significantly. APACHE II scores were also significantly improved. Tumor necrosis factor-alpha and interleukin-6 (IL-6) decreased in survivors, while tending to persist in high values in patients who died. No side effects were observed in any of the patients. In conclusion, intramuscular injections of small doses of polymyxin B were useful in the treatment of endotoxemia.

It has been suggested that oxidative processes are involved in a variety of pathological conditions, notably ischemia-reperfusion injury. Moreover, anesthetics appear to exert differential effects on the severity of such injury, these being unlikely wholly attributable to their differential effects on cardiovascular or microcirculatory status. It is possible that these variable effects of anesthetics on this type of injury may be due, at least in part, to changes in the production of free radicals and/or in their detoxification by endogenous antioxidant enzymes. We have attempted to explore the latter possibility by measuring activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione reductase in normal heart tissue and red cells obtained from rats anesthetized using a variety of agents (CO2, halothane, pentobarbital or ether). For comparison, analyses were also performed on tissues from unanesthetized animals rendered unconscious by stunning prior to sacrifice. Results indicated that myocardial SOD activity was significantly greater in halothane-anesthetized as compared with CO2-anesthetized animals. Red cell SOD activities did not show such differences. However, red cell GPX activity was found to be greater in halothane-anesthetized than in pentobarbital-anesthetized rats. In general, however, antioxidant enzyme activities measured ex vivo were minimally affected by the use of anesthetics prior to euthanasia. Our findings, therefore, do not support the proposal that the influence of anesthetics on the course of ischemia-reperfusion injury involves effects at the level of enzymatic antioxidant components.

Cinchona alkaloids significantly diminished the ability of renal cortical slices to accumulate organic cations and organic anions in vitro. Stereoisomeric differences exist in the inhibition of the accumulation of p-amino hippurate and tetraethyl ammonium. Oxygen consumption in renal cortical slices was inhibited by all four cinchona alkaloids. Cinchonine/cinchonidine were stronger inhibitors of the in vitro oxygen consumption than quinine/quinidine. Common antimalarial drug chloroquine inhibited the organic anion and cation accumulation much higher concentration than primaquine. Renal cortical slice oxygen consumption was also inhibited at much higher concentration by chloroquine than primaquine. The results indicate adverse renal effects in vitro but the significance of these findings in vivo is to be further examined.

The action of N-acetylcysteine on hepatic glycogen deposition was investigated. Emphasis was also given to the protective action of this compound against hepatic glycogen depletion by paracetamol. Rats fasted for 24 hours were injected intraperitoneally with (1) vehicle, (2) paracetamol (500 mg/kg), (3) N-acetylcysteine (1200 mg/kg) and (4) paracetamol plus N-acetylcysteine. The rats were refed immediately after the drug injections. Paracetamol inhibited glycogen deposition in the 12 hours following injection. The plasma levels of paracetamol were in the range that inhibits energy metabolism in isolated mitochondria and in the isolated perfused liver. N-Acetylcysteine increased the rate of glycogen deposition either in the presence or in the absence of paracetamol. The latter effect may be responsible, partly at least, for the protective action of N-acetylcysteine against glycogen depletion caused by toxic doses of paracetamol.

We investigated whether the anti-aversive effects of salmon calcitonin (SCT) was induced by increasing ACTH and beta-endorphin and/or by decreasing of prostaglandin E2 (PGE2) levels in plasma of mice to elucidate the mechanisms responsible for the analgesic effects of SCT. Intracerebroventricular (i.c.v.) injections of SCT inhibited acetic acid-induced aversive behavior (writhing) in a U-shaped dose response curve, the most effective dose being 0.1 IU/mouse. Intraperitoneal (i.p.) injections of acetic acid increased, but not significantly, the levels of plasma ACTH and PGE2, but not beta-endorphin, which are considered to be psychoneuroendocrines correlated with pain. SCT (0.1 IU/mouse, i.c.v.) significantly increased plasma ACTH levels (p < 0.05) and tended to increase beta-endorphin levels (p = 0.052) in acetic acid-treated mice, whereas no change in PGE2 level was observed (p > 0.1). These results suggest that the anti-aversive effects of SCT may be mediated, at least in part, by the activation of ACTH.

Nephrotoxic lesions induced by cisplatin in rats are characterized by acute tubular necrosis in the outer stripe of the medulla. The purpose of this study was to examine the potential role of changes in metal binding proteins, and iron and copper content in urine and renal tissue in cisplatin-induced nephrotoxicity. Cisplatin was administered intravenously to groups of 20 rats at single doses of 0, 1, 2.5, and 5 mg/kg and rats were sacrificed at 1, 2, 3 and 6 days after treatment. Increased serum BUN and creatinine were observed at a dose of 5 mg/kg cisplatin on day 2 through day 6. Increased urinary copper excretion coincided with necrosis and increased BUN and creatinine on day 3 in the high-dose group. Evidence of renal injury was apparent histologically as karyomegaly at all dose levels as early as 48 hours after injection of cisplatin, prior to increases in urinary copper levels. No change in the distribution of metal binding proteins (transferrin, ferritin, ceruloplasmin, and metallothionein) evaluated by immunohistochemical staining, was seen. Based upon these results, it is unlikely that changes in metal excretion play a primary role in cisplatin-induced nephrotoxicity however, changes in nuclear function indicated by karyomegaly may be involved in early renal injury.

A knowledge of the rate and extent of chemical absorption across the skin is central to both transdermal drug delivery and cutaneous toxicology. Toward gaining sufficient insight into the relevant mechanisms involved in percutaneous absorption of topically applied agents in solution to validate a predictive model, we have 1) estimated porcine stratum corneum/water partition coefficients of two 14C-labeled compounds of interest (phenol and p-nitrophenol), and 2) measured dynamic surface evaporation from dosed excised porcine skin of these two radiolabeled compounds and two 14C-labeled commonly employed vehicles (acetone and ethanol). The surface evaporation profiles were fit to a kinetic model designed to estimate the liquid/vapor parameters for application to a general biophysically-based model of percutaneous absorption. In an effort to obtain more robust estimates of model parameters, corresponding evaporation experiments were effected on the isolated perfused porcine skin flap (IPPSF) under the same experimental conditions. Stratum corneum/water partition coefficients were determined for phenol and p-nitrophenol using a stratum corneum preparation from excised porcine integument.

The effect of one intraperitoneal (i.p.) injection of ketanserin (K) (20mg/kg) on the levels of monoamines and neuropeptide Y (NPY) in some central and peripheral tissues was examined in normotensive (WKY) and spontaneously hypertensive (SHR) rats. In WKY rats, K induced a depletion of norepinephrine (NE) in the hypothalamus, the medulla, the atria and the caudal artery together with a decrease in dopamine level (DA) in the hypothalamus and in serotonin level (5-hydroxytryptamine, 5-HT) in the medulla. The reduction reached 25% to 35%. In SHR, NE and DA levels in the hypothalamus, and NPY levels in the caudal artery were lower than in WKY, while NE was higher in the adrenals. After treatment with K, NE, 5-HT, 5-HIAA (5-hydroxyindoleacetic acid) and NPY in the medulla were increased by about 30% to 50% while NE in the caudal artery was reduced by about the same value as in WKY. These results indicate that K-induced release of monoamines is not linked to NPY release. Moreover, monoamine and NPY sensitivity to K differ in SHR and WKY rats.