Relationship between the administration of nicardipine hydrochloride and the development of delirium in patients on mechanical ventilation.

A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium.

Dose-dependent promotion effects of potassium chloride on glandular stomach carcinogenesis in rats after initiation with N-methyl-N'-nitro-N-nitrosoguanidine and the synergistic influence with sodium chloride.

The modifying effects of potassium chloride (KCl) ingestion on glandular stomach carcinogenesis were investigated in male Wistar rats induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and were compared with those of sodium chloride (NaCl). A total of 120 male 6-week-old Wistar rats were divided into six groups, each consisting of 20 animals. After initiation of treatment with a MNNG solution (100 parts/million) as their drinking water for 10 weeks, rats were fed a diet supplemented with 5% NaCl, 2.5% NaCl, 2.5% NaCl plus 2.5% KCl, 5% KCl, 2.5% KCl, or a basal diet alone for the following 62 weeks. Under this experimental condition, there were no statistical differences in the final body weights between groups. The incidences of adenocarcinomas in the glandular stomachs were significantly higher in the 5% NaCl and combined 2.5% NaCl-plus-2.5% KCl groups (P < 0.05 and 0.01) than in the MNNG alone (control) group. The incidences of atypical or precancerous hyperplasias in the glandular stomachs were increased significantly by the 5% NaCl, 2.5% NaCl-plus-2.5% KCl, and 5% KCl treatments (P < 0.05 or 0.01). The multiplicities of adenocarcinomas were significantly greater in the 5% NaCl, 2.5% NaCl, and combined NaCl-plus-KCl groups (P < 0.05 or 0.01) compared with the control value. The multiplicity data for atypical hyperplasias were most striking; namely, their multiplicities were increased significantly by the treatments of NaCl or KCl (P , 0.01) in a clear dose-dependent manner and enhanced synergistically by the combined treatment of NaCl and KCl. Because the concentrations of KCl used in this study were about 1.3 times lower than those of NaCl on a molar basis, although the doses of each chemical were exactly the same on a weight-percent basis, it is suggested that the enhancing effects of KCl might not be much different from those of NaCl. The results in the present study thus indicate that, similarly to NaCl, KCl ingestion exerts dose-dependent promoting effects and a synergistic influence with NaCl when given during the postinitiation phase of two-stage glandular stomach carcinogenesis in rats.

Monooxygenation of N-acetylhistamine mediated by L-ascorbate.

In the presence of molecular oxygen and a catalytic amount of copper(II) ion, ascorbate almost completely degraded histamine (approx. 72%). The reaction was shown to occur at the imidazole group but not at the primary amino group in histamine. 4-[2-(Acetylamino)ethyl]-2,3-dihydroimidazol-2-one, a monooxygenated form of N-acetylhistamine, was first isolated as the primary product.

[Clinical experience of sivelestat sodium hydrate for severe reexpansion pulmonary edema; report of a case].

An 81-year-old man was referred to our hospital for the treatment for left spontaneous pneumothorax. A chest X-ray revealed a left-sided total pneumothorax and complete collapse of the lung. After intravenous administration of methylprednisolone, a 16 Fr chest tube was inserted, and drainage was started without negative pressure suction. Four hours after chest tube insertion, the patient's condition deteriorated. He complained severe cough and dyspnea, and pulse oximetry reading was 70%. A repeat chest X-ray demonstrated diffuse reexpansion pulmonary edema (RPE) on the left. After mechanical ventilation and intravenous infusion therapy with sivelestat sodium hydrate, methylprednisolone and ulinastatin were started, P(O2)/ Fi(O2) ratio improved rapidly. He was extubated on hospital day 6 and was discharged after pleurodesis for the pneumothorax. This case suggests that sivelestat sodium hydrate may be useful for the treatment for RPE.

Contractile and relaxant effects of phorbol ester in the intestinal smooth muscle of guinea-pig taenia caeci.

1. Effects of phorbol esters on the cytosolic Ca2+ level ([Ca2+]i) and muscle tension in the intestinal smooth muscle of guinea-pig taenia caeci were examined. 2. 12-Deoxyphorbol 13-isobutyrate (DPB, 1 microM) did not change the [Ca2+]i and tension in resting muscle. 3. In high K(+)-stimulated muscle, 1 microM DPB transiently augmented the contraction and decreased [Ca2+]i. 12-Deoxyphorbol 13-isobutyrate 20-acetate (1 microM) and phorbol 12, 13-dibutyrate (1 microM) showed similar effects to DPB whereas phorbol 12-myristate 13-acetate (1 microM) and phorbol 12, 13-didecanoate (1 microM) were ineffective. 4. DPB (1 microM) inhibited both [Ca2+]i and tension stimulated by 300 nM carbachol or 3 microM histamine. In the presence of a higher concentration of carbachol (1 microM), DPB decreased [Ca2+]i and transiently increased muscle tension. 5. In the muscle strips permeabilized with bacterial alpha-toxin, 1 microM DPB shifted the Ca(2+)-tension curve to the left. An inhibitor of protein kinase C, H-7 (30 microM), inhibited the effect of DPB. 6. DPB did not change the high K(+)-induced contraction in the muscle strips pretreated with 3 microM phorbol 12-myristate 13-acetate for 24 h. 7. These results suggest that activation of protein kinase C has dual effects; it augments contraction by increasing the Ca2+ sensitivity of the contractile elements and it inhibits contraction by decreasing [Ca2+]i.

Calcium compartments in vascular smooth muscle cells as detected by aequorin signal.

1. To examine whether cytosolic Ca2+ in smooth muscle cells distributes evenly, cytosolic Ca2+ levels were measured with two different Ca2+ indicators in the ferret isolated portal vein; a fluorescent indicator, fura-PE3, that shows the average Ca2+ level, and a photoprotein, aequorin, that preferentially shows a high Ca2+ compartment. 2. A noradrenaline (10 microM)-induced sustained contraction was associated with a sustained increase in the fura-PE3 signal, or a transient increase followed by small sustained increase in the aequorin signal. A high K(+)-induced contraction was associated with a sustained increase in both the fura-PE3 and aequorin signals. 3. A second application of noradrenaline or high K+ induced reproducible contractions and fura-PE3 signals. In contrast, the aequorin signal resulting from a second application of noradrenaline or high K+ was much smaller than the first signal. 4. Following a 13 h but not a 3 h resting period, the aequorin signal stimulated by noradrenaline or high K+ recovered, without any change in the contractile response. 5. In Ca(2+)-free solution, high K+ was ineffective, whereas noradrenaline induced only a small aequorin signal and contraction compared to those obtained in the presence of external Ca2+. After the addition of Ca2+, the first application of noradrenaline induced a large aequorin signal and a large contraction, although a second application induced a much smaller aequorin signal accompanied by a large contraction. 6. These results suggest that high K+ and noradrenaline increase Ca2+ in at least two cytosolic compartments; a compartment that is coupled to the contractile mechanism ('contractile' Ca2+ compartment; major portion of cytoplasm containing contractile elements) and a compartment that is not coupled to contractile mechanisms ('non-contractile' Ca2+ compartment; small sub-membrane area that does not contain contractile elements). On stimulation, the Ca2+ level in the 'contractile' compartment may increase to a level high enough to stimulate myosin light chain kinase but not so high as to consume aequorin rapidly. In contrast, the Ca2+ level in the 'non-contractile' compartment may increase so greatly that aequorin in this compartment is rapidly consumed. These two compartments may be separated by a diffusion barrier and, during a resting period, aequorin may slowly diffuse from the 'contractile' compartment to the 'non-contractile' compartment and thus restore the full aequorin signal. An increase in Ca2+ in the 'non-contractile' compartment seems to be dependent mainly on Ca2+ influx and partly on Ca2+ release.

Inhibitory effect of a toxin okadaic acid, isolated from the black sponge on smooth muscle and platelets.

1. Effects of okadaic acid, a toxin isolated from marine sponges, on smooth muscle contraction and platelet activation were examined. 2. Contractions in rabbit aorta induced by high concentrations of K+ and noradrenaline were inhibited by 0.1-1 microM okadaic acid in a concentration-dependent manner. Spontaneous rhythmic contractions as well as high K+-induced contraction in guinea-pig taenia caeci were also inhibited by 1 microM okadaic acid. 3. High K+-induced contraction in rabbit aorta was accompanied by increased Ca2+ influx measured with 45Ca2+ and increased cytosolic Ca2+ [( Ca2+]cyt) measured with fura-2-Ca2+ fluorescence. Okadaic acid inhibited the contraction without inhibiting Ca2+ influx and produced only a small decrease in [Ca2+]cyt. 4. In a saponin-skinned taenia, Ca2+-induced contraction was not inhibited but rather potentiated by okadaic acid. 5. Okadaic acid, 1 microM, inhibited aggregation, ATP release and increased in [Ca2+]cyt induced by thrombin in washed rabbit platelets. Okadaic acid itself did not change the platelet activities. 6. Okadaic acid did not change the cyclic AMP content of rabbit aorta although the inhibitory effects of okadaic acid were similar to those of cyclic AMP. 7. Although the mechanism of the inhibitory effect of okadaic acid was not clarified in the present experiments, it is suggested that okadaic acid acts by inhibiting protein phosphatases resulting in an indirect activation of cyclic AMP-dependent protein phosphorylation.

Enhancing effects of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) on cell proliferation and lipid peroxidation in the rat gastric mucosa.

The influence of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone, a mutagen in chlorinated water, on cell proliferation and lipid peroxidation in the glandular stomach mucosa was investigated in male 4-week-old Wistar rats. Animals were given 50 p.p.m., 25 p.p.m., 12.5 p.p.m., 6.25 p.p.m. or 0 p.p.m. of MX solution in their drinking water for 5 weeks. At the end of this period, cell proliferation in the mucosal epithelia of the gastric fundus was increased in a dose-dependent manner up to 25 p.p.m., at which dose the induction was statistically significant as compared with the control value (P < 0.05). The MX treatment was also associated with increased lipid peroxidation levels in the gastric mucosa as well as in the urine, with loose dose-dependence, although not at 50 p.p.m. Mucosal lipid peroxidation was significantly increased in animals given 25 p.p.m. as compared with controls (P < 0.05). Similarly, the levels of urinary lipid peroxidation were significantly higher in rats given 25 p.p.m. or 12.5 p.p.m. than in the controls (P < 0.05). Histopathologically, gastric erosion was noted in rats receiving 25 p.p.m. or more of MX. There were no statistical differences between groups for serum biochemical data. The results thus suggest that MX may exert a gastric tumor-promoting action in rats, even at low doses which do not give rise to toxic effects, because of the clear dose-response relationship evident at low levels.

Effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on N-nitrosobis(2-oxopropyl)amine (BOP)-initiated carcinogenesis in hamsters.

The effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) administration during the post-initiation phase of carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Female Syrian golden hamsters were given a single s.c. injection of BOP at a dose of 10 mg/kg and then administered 3 ppm (H) or 1 ppm (L) NNK in their drinking water for the following 87 weeks. Additional groups of animals received the BOP injection alone, or only the 3 or 1 ppm NNK treatments as BOP-negative controls. At week 88 of the experiment, all surviving animals were sacrificed and development of proliferative lesions was assessed histopathologically. The results showed no statistically significant influence on pancreatic adenocarcinomas or dysplastic lesions, although the incidence and the number of atypical hyperplasias in the pancreas head in the BOP/NNK (L) group was significantly increased as compared to BOP alone group values (P < 0.05). Similarly, the NNK treatments did not affect the incidences or multiplicities of neoplastic or hyperplastic lesions in the endocrine pancreas, lung, liver or kidney. Thus, the present experiment demonstrates that the tobacco-specific carcinogen NNK does not enhance BOP-induced hamster tumorigenesis when given in the promotion phase.

A novel 66-kDa stress protein, p66, associated with the process of cyst formation of Physarum polycephalum is a Physarum homologue of a yeast actin-interacting protein, AIP1.

When exposed to various stresses including heat shock, myxoamoebae, growing haploid cells of Physarum polycephalum, show marked morphological changes and consequently become disk-shaped microcysts. We have found that p66 is induced exclusively in the course of microcyst formation and has an actin-binding activity. In this study, we purified p66 to homogeneity and isolated a p66 cDNA. The deduced protein sequence contained 601 amino acids and showed 31% identity to a yeast actin-interacting protein, AIP1. Northern blot analysis revealed that the amount of p66 mRNA was significantly increased by heat shock in myxoamoebae but not in plasmodia. Thus, p66 seems to be a developmentally-expressed stress protein which regulates the rearrangement of actin organization during microcyst formation in P. polycephalum.

Hypothermic neuroprotection of peripheral nerve of rats from ischemia-reperfusion injury: intraischemic vs. reperfusion hypothermia.

The pathophysiology of ischemic fiber degeneration (IFD) is not known, but mechanisms involved during nerve ischemia differ from those during reperfusion. We have previously demonstrated hypothermic neuroprotection of peripheral nerve from IFD. We now evaluate the efficacy of hypothermia in the intraischemic vs. the reperfusion period, using our established model of ischemia-reperfusion injury. Intraischemic hypothermia resulted in significant recovery of all indices (behavior score, electrophysiology and histology, P<0.01 or 0.05) while hypothermia during reperfusion period showed less improvement, significant only for the histological score compared to normothermia group (IFD index, P<0.05). Once hypothermia was applied in the ischemic period, the resultant neuroprotection continued into the reperfusion period, even if nerve temperature was then raised during the reperfusion period. These results indicate that hypothermic neuroprotection is more efficacious during the intraischemic period than during reperfusion, when a lesser degree of neuroprotection ensued.

Effects of felodipine, nifedipine and verapamil on cytosolic Ca2+ and contraction in vascular smooth muscle.

The inhibitory effects of felodipine, nifedipine and verapamil were compared in vascular smooth muscle. In rat aorta, these inhibitors attenuated the high K(+)-induced contraction with a parallel decrease in the cytosolic Ca2+ level ([Ca2+]i). Maximal inhibition was obtained with 10 nM felodipine, 100 nM nifedipine and 10 microM verapamil. The inhibitory effects were antagonized by an increase in external Ca2+ concentration to 6.5 mM and the addition of a Ca2+ channel activator, 100 nM Bay k 8644. These inhibitors also attenuated the contraction induced by norepinephrine although these effects were weaker than those on high K(+)-induced contraction. Furthermore, these inhibitors attenuated the norepinephrine-stimulated [Ca2+]i more strongly than contraction. In contrast, none of these inhibitors inhibited the transient increase in [Ca2+]i and muscle tension induced by norepinephrine in Ca(2+)-free solution and the Ca(2+)-induced contraction in permeabilized smooth muscle. These results suggest that felodipine, nifedipine and verapamil inhibit smooth muscle contraction by inhibiting Ca2+ channels at concentrations which do not change Ca2+ release or Ca2+ sensitivity of contractile elements.

Inhibitory effects of cadralazine and its metabolite, ISF-2405, on contractions and the level of cytosolic Ca2+ in vascular smooth muscle.

The inhibitory effects of a hypotensive agent, cadralazine and its metabolite, ISF-2405, on the level of cytosolic Ca2+ ([Ca2+]cyt) and on contractions were examined in isolated vascular smooth muscle. Cadralazine slightly inhibited the transient norepinephrine-induced contraction in rabbit aorta and canine femoral, renal and mesenteric arteries and saphenous vein, and prostaglandin F2 alpha-induced contractions in canine basilar and coronary arteries. In contrast, ISF-2405 inhibited the contractions induced by prostaglandin F2 alpha in canine basilar and coronary arteries and those induced by norepinephrine in canine renal and femoral arteries and rabbit aorta. In aorta, ISF-2405 inhibited the increase in [Ca2+]cyt and muscle tension caused by norepinephrine. A Ca2+ channel blocker, verapamil, inhibited the norepinephrine-stimulated increase in [Ca2+]cyt more potently than it inhibited the increase in muscle tension, and ISF-2405 inhibited the verapamil-resistant part of the contraction. In Ca2(+)-free solution, norepinephrine induced transient increases in [Ca2+]cyt and muscle tension. ISF-2405 inhibited these changes. However, ISF-2405 did not inhibit the transient contraction induced by caffeine in the aorta. These results suggest that cadralazine is metabolized to ISF-2405 and inhibits vascular smooth muscle contraction by inhibiting receptor-mediated Ca2+ influx, Ca2+ release and Ca2+ sensitization of contractile elements.

The long-term inhibitory effect of a Ca2+ channel blocker, nisoldipine, on cytosolic Ca2+ and contraction in vascular smooth muscle.

The mechanism of the long-term inhibitory effect of a dihydropyridine Ca2+ channel blocker, nisoldipine, on contraction and cytosolic Ca2+ level ([Ca2+]i) was examined in isolated rat aorta. Nisoldipine inhibited the [Ca2+]i and muscle tension induced by high K+. The inhibitory effects were antagonized by a Ca2+ channel activator, 100 nM Bay k8644, and by a high concentration of Ca2+ (6.5 mM). Ultraviolet light, which has been shown to decompose dihydropyridines, attenuated the effects of nisoldipine. After nisoldipine had been removed from muscle bath, the inhibitory effect faded away slowly. The residual inhibitory effects on [Ca2+]i and muscle tension were antagonized by Bay k8644, high Ca2+ and ultraviolet light. These results suggest that the inhibitory effect of nisoldipine is caused by a decrease in [Ca2+]i as a result of inhibition of L-type Ca2+ channels, and that the residual inhibitory effects are caused by the same mechanism as the inhibitory effects of nisoldipine, namely the tight binding of nisoldipine to Ca2+ channels even after washout.

Mechanism of relaxing action of the antiasthmatic drug, azelastine, in isolated porcine tracheal smooth muscle.

Azelastine (1-300 microM) inhibited contractions of isolated porcine trachea induced by high K+, carbachol and endothelin-1 (ET-1) with a decrease in [Ca2+]cyt (as measured by fura-2-fluorescence). Verapamil (0.1-10 microM) also inhibited the high K(+)-induced increases in [Ca2+]cyt and contraction, although it only partially inhibited the responses evoked by carbachol or ET-1. In the absence of extracellular Ca2+ (with 0.5 mM EGTA), carbachol induced a transient increase in [Ca2+]cyt and force by releasing Ca2+ from cellular stores. Azelastine (100 microns) completely inhibited these contransient changes. In the absence of extracellular Ca2+, carbachol and 12-deoxyphorbol 13-isobutyrate (DPB) induced small sustained contractions without increasing [Ca2+]cyt. Azelastine inhibited these contractions. In muscle permeabilized with alpha-toxin, Ca2+ (0.3-3 microM) induced contraction in a concentration-dependent manner. DPB (without GTP) and carbachol or ET-1 (with GTP) enhanced the Ca(2+)-induced contraction. Azelastine partially inhibited the contraction induced by 0.3 microM Ca2+ but not the contraction induced by 3 microM Ca2+, and strongly inhibited the potentiating effects of DPB, carbachol and ET-1. Azelastine had no effect on the content of cyclic AMP or cyclic GMP. These results suggest that azelastine inhibits smooth muscle contraction by (i) decreasing [Ca2+]cyt, by inhibition of Ca2+ channels, (ii) decreasing agonist-induced Ca2+ release, and (iii) direct inhibition of contractile elements.

Alpha-lipoic acid provides neuroprotection from ischemia-reperfusion injury of peripheral nerve.

BACKGROUND: Reperfusion aggravates nerve ischemic fiber degeneration, likely by the generation of reduced oxygen species. We therefore evaluated if racemic alpha-lipoic acid (LA), a potent antioxidant, will protect peripheral nerve from reperfusion injury, using our established model of ischemia-reperfusion injury. METHODS: We used male SD rats, 300+/-5 g. Ischemia was produced by the ligature of each of the supplying arteries to the sciatic-tibial nerve of the right hind-limb for predetermined periods of time (either 3 or 5 h), followed by the release of the ligatures, resulting in reperfusion. LA was given intraperitoneally daily for 3 days for both pre- and post-surgery. Animals received either LA, 100 mg/kg/day, or the same volume of saline intraperitoneally. Clinical behavioral score and electrophysiology of motor and sensory nerves were obtained at 1 week after ischemia-reperfusion. After electrophysiological examination, the sciatic-tibial nerve was fixed in situ and embedded in epon. We evaluated for ischemic fiber degeneration (IFD) and edema, as we described previously. RESULTS: Distal sensory conduction (amplitude of sensory action potential and sensory conduction velocity (SCV) of digital nerve) was significantly improved in the 3-h ischemia group, treated with LA (P<0.05). LA also improved IFD of the mid tibial nerve (P=0.0522). LA failed to show favorable effects if the duration of ischemia was longer (5-h ischemia). CONCLUSION: These results suggest that alpha-lipoic acid is efficacious for moderate ischemia-reperfusion, especially on distal sensory nerves.

Inhibitory effect of forskolin on myosin phosphorylation-dependent and independent contractions in bovine tracheal smooth muscle.

In bovine tracheal smooth muscle, carbachol (CCh, 1 microM) and high K+ (72.7 mM) induced sustained increases in cytosolic Ca2+ level ([Ca2+]i), myosin light chain (MLC) phosphorylation and force of contraction. Forskolin (FK, 1-10 microM) inhibited the CCh-induced increase in [Ca2+]i, MLC phosphorylation and force in parallel. In contrast, FK inhibited the high K(+)-induced contraction and MLC phosphorylation without changing [Ca2+]i. In the absence of extracellular Ca2+ (with 0.5 mM EGTA), CCh (10 microM) and caffeine (20 mM) induced transient increase in [Ca2+]i and contractile force by releasing Ca2+ from cellular store. FK strongly inhibited the CCh-induced Ca2+ transient, but failed to inhibit the caffeine-induced Ca2+ transient. In the absence of external Ca2+, 12-deoxyphorbol 13-isobutylate (DPB, 1 microM) induced sustained contraction without increase in [Ca2+]i and MLC phosphorylation. FK inhibited this contraction without changing [Ca2+]i. In permeabilized muscle, Ca2+ induced contraction in a concentration-dependent manner. FK (10 microM) and cAMP (1-100 microM) shifted the Ca(2+)-force curve to the higher Ca2+ levels. CCh with GTP, GTP gamma S or DPB enhanced contraction in the presence of constant level of Ca2+. Forskolin and cAMP also inhibited the enhanced contractions in the permeabilized muscle. In the permeabilized, thiophosphorylated muscle, ATP induced contraction in the absence of Ca2+. cAMP (300 microM) had no effect on this contraction. These results suggest that forskolin inhibits agonist-induced contraction in tracheal smooth muscle by multiple mechanisms of action; 1) inhibition of MLC phosphorylation by reducing Ca2+ influx and Ca2+ release, 2) inhibition of MLC phosphorylation by changing the MLC kinase/phosphatase balance, and 3) inhibition of regulatory mechanism which is not dependent on MLC phosphorylation.

Effect of administration of anti-bursal extract or perfusate serum on the antibody production in chickens.

Antisera to bursal extracts or perfusates were prepared and the influence of such sera on antibody production in chickens was investigated by the injection of antisera during the embryonic stage. Antisera to cyclophosphamide treated bursal extracts or bursal perfusates were injected on the 15th day of embryogenesis. The level of antibodies produced by chickens treated by these antisera was equal to the controls but IgG antibodies were totally absent. These results suggested that the administration of these antisera inhibited the differentiation of IgM antibody producing cells.

Effects of hickory smoke condensate on gastric carcinogenesis in Wistar rats after treatment with N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride.

Short-term assays in vivo have suggested that hickory smoke condensate (HSC), a food flavouring, might have tumour-initiating and/or promoting activities in the glandular stomach of the rat. In the present study, the modifying effects of HSC on glandular stomach carcinogenesis after initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride (MNNG salt) were investigated in male Wistar rats. Animals were given MNNG solution (100 ppm) as drinking water and simultaneously fed the diet supplemented with 5% sodium chloride for 8 wk. Matched negative controls received neither MNNG nor sodium chloride. Rats were then fed a basal diet and given HSC solution (1 or 3%) or tap water for the following 32 wk. During the experimental period, treatment with MNNG salt and administration of HSC both brought about growth retardation although the final body weight of rats was comparable between groups. Only two rats treated with MNNG salt followed by 1% HSC developed adenocarcinoma of the stomach. HSC treatment appeared to increase the number of rats with preneoplastic hyperplasias and/or adenocarcinomas in both the fundic and pyloric mucosa, although not to a statistically significant extent. HSC administration significantly increased malondialdehyde levels in the urine and gastric mucosa, the former in a dose-dependent manner. The results suggest that HSC has little, if any, promoting effect on two-stage glandular stomach carcinogenesis in rats when given during the post-initiation phase. However, the tumour co-initiating effects of HSC require further clarification.

Carcinogenicity study of 1,1-bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane in B6C3F1 mice.

1,1-Bis(tert-butylperoxy)-3.3.5-trimethylcyclohexane (BBTC) is widely used in the manufacture of rubber. The present carcinogenicity study in B6C3F1 mice was carried out in order to assess its potential to induce tumours. BBTC was administered at dietary levels of 0 (control), 0.25 and 0.5% for 78 wk; these dose levels were selected on the basis of a subchronic toxicity study, in which body weights were depressed to less than 90% of the control group values and swelling of hepatocytes was histologically evident in animals fed 1% BBTC or more in the diet. Neoplasms were found in all groups, including the control group, but there were no significant differences between groups of either sex in mortality, tumour incidences or tumour distribution. All tumours were considered to be spontaneous because of the similarity to background data for B6C3F1 mice. This study thus provides no evidence of carcinogenicity of BBTC in B6C3F1 mice.