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PubMed1993

Experimental and clinical studies on the intraperitoneal administration of cis-diamminedichloroplatinum (II) for peritoneal carcinomatosis caused by gastric cancers.

The effectiveness of the intraperitoneal administration of cis-diamminedichloroplatinum (II) (DDP) on peritoneal carcinomatosis caused by gastric cancers was evaluated. Seventeen patients were treated with one of three protocols, consisting of the intraperitoneal injection (ip) of DDP at doses of 70 and 110 mg/m2, with or without sodium thiosulfate (STS) rescue. The area under the curve (AUC) of DDP for sufficient anticancer activities against cultured human cell lines in vitro was estimated at 240 micrograms h/ml, which was equivalent to the AUC gained by 110 mg/m2 ip DDP in the clinical studies. The cytotoxic activity of DDP was reduced by approximately 50% with 100-fold STS in the AUC in the experimental studies. However, this was achieved only in urine, and not in either the peritoneal cavity or in plasma in the clinical studies. Three cases of a partial response against peritoneal carcinomatosis were seen from a total of four evaluable cases treated with 110 mg/m2 DDP, and no renal toxicities were observed in those treated with the STS rescue. The results of this study led us to conclude that high-dose ip DDP treatment combined with the STS rescue would be useful chemotherapy against peritoneal carcinomatosis caused by gastric cancers.

Adult↗
PubMed1976

Radioactivity in urine and feces of mink (Mustela vison) treated with [14C] aflatoxin B1.

Excretion of radioactivity by mink (Mustela vison) during 7 days after intraperitoneal injection of two different amounts of aflatoxin B1 was studied. Male mink that received a single dose of 25 mug aflatoxin B1/kg body weight excreted an average of 89.5% of administered radioactivity (56.8% via feces, 32.7% via urine); whereas female mink excreted an average of 85% (63.6% via feces, 21.4% via urine) of administered radioactivity during the 7-day period. Male and female mink given 150 mug aflatoxin B1/kg body weight excreted an average of 76.9-80.1% of administered radioactivity during the 7 days that followed treatment with toxin. These mink excreted somewhat more of the administered radioactivity in their urine than did the mink that received the lower dose of aflatoxin (37.2 vs. 32.7% for males and 32.7 vs. 21.4% for females). Regardless of sex and dosage of toxin, most of the radioactivity ultimately excreted either through feces or urine appeared in the first 24 h after toxin was administered to mink.

Aflatoxins↗
PubMed1989

Effects of route of administration of ethanol on high-speed reaction time in young and old rats.

The blood ethanol concentrations (BECs) and reactive capacity of young (8 months) and old (24 months) male Fischer 344 rats were compared at 5, 10, 20, 45, 65, and 90 min following the administration of ethanol (EtOH). The time-dependent effects of intragastric intubation (IG; 3 g/kg) and intraperitoneal injection (IP; 1.5 g/kg) of EtOH (20% w/v) were determined. Subsequent to IG delivery, BECs rose most rapidly within the first 20 min, but did not reach peak levels until 90 min for both young (240 mg/dl) and old rats (250 mg/dl). Following IP injections, BECs escalated within 5 min to 250 mg/dl in the young, to 175 mg/dl in the old, and declined gradually to a stabilized value of 150 mg/dl (young) and 130 mg/dl (old). The old rats never achieved the high BECs seen in the young. Reactive capacity, a measure of auditory/visual reaction time, was inversely related to BECs. As BECs (IP) declined, performance improved at a similar rate in both age groups, although the old rats' performance was more impaired than that of the young. However, BEC per se was not an adequate predictor of reactive capacity. When EtOH was delivered by IG so that BECs remained high for long periods of time, reactive capacity was far less impaired compared with IP delivery in which comparable BECs were present for only a few minutes. The possibility was noted that behavioral tolerance may have developed during the 90-min post-EtOH period, and that the IP delivery method may disrupt behavior in ways independent of brain ethanol levels.

Aging↗
PubMed1993

Changes of the Na/K ATPase activity in the cerebral cortical microvessels of rat after single intraperitoneal administration of mercuric chloride: histochemical demonstration with light and electron microscopy.

Since inorganic mercury salts only poorly penetrate the cerebral microvascular endothelial cells comprising the blood-brain barrier (BBB), their neurotoxicity may be predicted to result from interference with BBB transport enzymes. In the present study, we tested the effect of mercuric chloride (HgCl2) on Na+/K+ ATPase activity, a key enzyme involved in the ion transport in and out of the brain. Routine histochemical staining in conjunction with light and electron microscopy was used to evaluate the changes in the Na+/K+ ATPase activity in cerebral cortical microvessels of rats who received a single intraperitoneal injection of 6 mg/kg HgCl2. At 1 h after HgCl2 administration, light microscopy revealed uniform reduction of the Na+/K+ ATPase reaction in all cortical layers. Electron microscopy confirmed the enzyme reaction to be very weak to completely absent in both the luminal and abluminal endothelial cell membranes, and the luminal plasmalemma showed invaginations and pinocytic vesicles indicative of changes in its transport functions. The enzyme inhibition coincided with, and was likely to contribute to, profound perivascular swelling, involving mainly the astrocytic endfeet. The enzyme activity showed a partial recovery 18 h after HgCl2 treatment, mainly in cortical layers II and III. After 5 days, the recovery of the enzyme activity appeared complete as observed by light and electron microscopy. The recovery of the microvascular Na+/K+ ATPase coincided with the appearance of a strongly positive Na+/K+ ATPase reaction in the adjacent astrocytic processes and with the diminution of perivascular swelling.

Animals↗
PubMed1982

Exogenous selenium in the brain. A histochemical technique for light and electron microscopical localization of catalytic selenium bonds.

Transcardial perfusion or intraperitoneal injections with sodium selenite result in the creation of selenium bonds that can be visualized by physical development. The present paper describes how these catalytic bonds are made visible in the tissues by surrounding them with shells of metallic silver. Based on experiments with chelating agents, the possibility that selenium-metal bonds are the catalysts is discussed. In the brain, the selenium pattern is delicate and highly laminated, the grains of silver being orderly arranged corresponding with the neuropil morphology. The precipitate is most densely packed in cortical regions. The difference in staining intensity seen in different regions of the CNS reflects the density of selenium reactive terminals. The visualized selenium bonds are predominantly located within boutons, and examination in the electron microscope reveals accumulation in the presynaptic regions. In a few places precipitates can also be found in axons, but have not been observed in perikarya or dendrites. The only non-neuronal locations of selenium were sparsely scattered, astrocyte-like neuroglia, predominantly found in the cerebellum and the hypothalamus; infrequently a few blood vessels were also stained. Sections from kidney and liver are presented as examples of localizations outside the CNS of exogenous selenium.

Animals↗
PubMed1992

A new liver-tumor model in the rat.

A new tumor model for testing and comparing the effect of different forms of treatment on liver tumors is described. Single tumors were induced in the liver of rats by the implantation of small pieces taken from a subcutaneously growing tumor. Tumor growth was determined by measuring the weight of the implanted tumors after the animals had been killed. In this way, weight curves for treated and untreated tumors could be defined. The weight of untreated liver tumors increased exponentially with time (tumor weight in milligrams = 1 + e(t-0.31)/5). In addition, tumor growth defined as the geometric mean of three perpendicular diameters was determined. Tumor-diameter curves showed a linear increase with time in the untreated groups (tumor diameter in millimeters = 0.4 t + 1.90). The model was tested by assessing the effect of intraperitoneally injected cisplatin. The dose chosen produced a marked delay in tumor growth. On the basis of the weight gain shown by the treated animals and tumor growth delay, a therapeutic index can be defined, thus enabling to compare quantitatively different forms of treatment according to their antitumor effect and toxicity.

Adenocarcinoma↗
PubMed1981

Brindled mottled mouse: morphological changes of brain and visceral organs in hemizygous males following copper supplementation.

Intraperitoneal injections of cupric chloride prevent neuronal degeneration in the hemizygous brindled mottle mouse, MO br/Y, a murine model of kinky hair syndrome (KHS) in humans. At 6-9 months after two i.p. injections, the brain of MO br/Y revealed slightly increased amounts of lipofuscin pigments in the cerebral cortical neurons, cytoplasmic inclusions in the thalamic neurons, and axonal spheroid formation in the tuber cinereum, cerebellum and brain stem. Increased numbers of mitoses, bizarre hyperchromatic giant nuclei, and numerous clear vacuoles were frequently seen in the proximal renal tubular epithelium. Numerous myelin figures were conspicuous features in these epithelial cells at ultrastructural level. Such changes were not found in the littermate controls but in the heterozygous brindled mottled mouse, MO br/ +, identical changes were noted in equal or even higher frequency. These observations suggest that cupric chloride injections effectively modify the expression of the genetic defect in MO br/ Y.

Animals↗
PubMed1988

Effect of recombinant interleukin-1 on mRNA levels in rat liver.

Levels of rat liver mRNA for the plasma proteins albumin, apolipoprotein E, transthyretin, transferrin, alpha 1-acid glycoprotein, major acute-phase alpha 1-protein, and the beta-chain of fibrinogen were measured after intraperitoneal injection of interleukin-1 alpha (IL-1). A maximum response of mRNA levels for most of the plasma proteins studied was reached between 6 and 10 h after injection of IL-1. The results suggest that at the dosage used, IL-1 alone does not elicit a typical acute-phase response of the plasma protein-synthesizing system of the liver.

Acute-Phase Proteins↗
PubMed1991

Induction of plasma exudation and inflammatory cell infiltration by leukotriene C4 and leukotriene B4 in mouse peritonitis.

Leukotriene induction of the fluid and cellular phases of the inflammatory response in the mouse was evaluated. Intraperitoneal injection of leukotriene C4 (LTC4 250 ng) led to dye extravasation but not polymorphonuclear leukocyte (PMN) infiltration, whereas injection of leukotriene B4 (LTB4 250 ng), led to PMN infiltration but not dye extravasation. The injection of both leukotrienes did not result in synergy. LTC4 did not appear to induce significant release or formation of chemotactic mediators, but the dye extravasation induced by LTC4 was inhibited by the vasoactive amine antagonist cyproheptadine and not by the eicosanoid inhibitors phenidone or naproxen. The response was markedly inhibited by the cytokine and eicosanoid inhibitors SK&F 86002 and SK&F 104493. PMN infiltration induced by LTB4 was not inhibited by SK&F 86002 or phenidone but was abrogated by colchicine treatment. LTB4 in this model did not appear to cause release or formation of vasoactive mediators. These leukotrienes appeared to be independent, complementary, and sufficient to mount a complete inflammatory response in the mouse.

Animals↗
PubMed1987

Effect of muralytic enzyme degradation of streptococcal cell wall on complement activation in vivo and in vitro.

Rats given a single intraperitoneal injection of an aqueous suspension of peptidoglycan-polysaccharide polymers derived from group A streptococcal cell wall (PG-APS) develop a severe, chronic, erosive arthritis which resembles human rheumatoid arthritis. The treatment of PG-APS-injected rats with a single intravenous injection of 0.4 mg of mutanolysin prevents the development of chronic arthritis, even when administration of the enzyme is delayed until severe acute arthritis has developed. PG-APS activates complement both in vitro and in vivo. Digestion of PG-APS with mutanolysin in vitro destroys the ability to activate both the alternate and classical pathways of human serum complement, and the loss of complement activation parallels the extent of PG-APS degradation. There is also a reduction in the in vivo complexing of C3 with PG-APS in the limbs of PG-APS-injected rats treated with mutanolysin, compared to control rats injected with PG-APS and treated with phosphate-buffered saline. This association between loss of arthropathic activity and loss of activation of complement is consistent with the hypothesis that activated complement products form a part of the inflammatory mediators involved in the acute and chronic phases of bacterial cell wall-induced arthritis. This may also partially explain how mutanolysin treatment alleviates cell wall-induced arthritis in the rat.

Animals↗
PubMed1995

Role of DL alpha-lipoic acid in gentamicin induced nephrotoxicity.

The effect of DL alpha-lipoic acid on the nephrotoxic potential of gentamicin was examined. Intraperitoneal injection of gentamicin (100 mg/kg/day) to rats resulted in decreased activity of the glycolytic enzymes-hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase. The two gluconeogenic enzymes--glucose-6-phosphatase and fructose-1,6-diphosphatase, the transmembrane enzymes namely the Na+, K(+)-ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase and the brushborder enzyme alkaline phosphatase, also showed decreased activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush border membrane damage. Decreased activity of the TCA cycle enzymes isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH) and malate dehydrogenase (MDH), suggests a loss in mitochondrial integrity. These biochemical disturbances were effectively counteracted by lipoic acid administration. Lipoic acid administration by gastric intubation at two different concentrations (10 mg and 25 mg/kg/day) brought about an increase in the activity of the glycolytic enzymes, ATPases and the TCA cycle enzymes. The gluconeogenic enzymes however showed a further decrease in their activities at both the concentrations of lipoic acid administered. These observations shed light on the nephroprotective action of lipoic acid against experimental aminoglycoside toxicity and the protection afforded at 25 mg/kg/day of lipoic acid was noted to be higher than that at 10 mg level.

Adenosine Triphosphatases↗
PubMed1991

Interferon-gamma treatment in mice experimentally infected with Trichinella spiralis.

Interferon-tau (IFN-tau) treatment of Trichinella spiralis-infected BALB/c mice was investigated. The therapeutic regimen consisted of daily intraperitoneal injection of 10(4) U murine IFN-tau for 7 days, starting at 2 weeks post-infection. Striated muscle samples (diaphragm, thigh) were collected at 4, 8 and 12 weeks after infection. The muscle larval burden, the degree of encystation and the digestion of T. spiralis larvae were investigated. Furthermore, immunohistochemical studies of the inflammatory cell infiltrate around encysted larvae were performed. The results demonstrated an influence of IFN-tau treatment on the CD4+ and CD8+ subset distribution during the immune response but revealed no difference in the degree of encystation or digestion of encapsulated larvae as compared with control values.

Animals↗
PubMed1995

Effect of chronic administration of phenytoin on regional monoamine levels in rat brain.

Phenytoin (DPH) is a widely used anticonvulsant drug but a conclusive mode of action is not yet clear. This study was undertaken to assess the effects of chronic administration of DPH on monoamine levels. DPH (50 mg/kg body weight) was administered to adult male Wistar rats by intraperitoneal injections for 45 days and the regional brain levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were assayed using high performance liquid chromatographic (HPLC) method. The experimental rats revealed no behavioral deficits of any kind nor body and brain weight deficits were observed. Increased NE levels were observed after DPH administration in motor cortex (P < 0.05), striatum-accumbens (P < 0.01) and hippocampus (P < 0.01), whereas, NE level was decreased in brain stem (P < 0.05). DA levels were increased in striatum-accumbens (P < 0.05), hypothalamus (P < 0.001) and cerebellum (P < 0.001) but decreased in brainstem (P < 0.01). In DPH treated rats, 5-HT levels were increased in motor cortex (P < 0.001) but decreased in cerebellum (P < 0.001) when compared to control group of rats. The present study suggest that chronic administration of DPH induces alterations in monoamine levels in specific brain regions. DPH seems to mediate its anticonvulsant action by selectively altering the monoamine levels in different brain regions.

Animals↗
PubMed1977

Effects of chlordiazepoxide, oxazepam, chlorpromazine, and d-amphetamine on sexual responses in male and female hamsters.

The acute effects on sexual behavior of oxazepam (16--64 mg/kg), chlordiazepoxide (8--64 mg/kg), chlorpromazine (2--8 mg/kg), and d-amphetamine (0.8--3.2 mg/kg) were examined in intact male and female golden hamsters (Mesocricetus auratus). Intraperitoneal injections were given 45 min before the first behavioral test. In 10-min tests, lordosis was observed in estrous females both before and after copulation, and mounts, intromissions, and ejaculations were observed in males. Dose-response related decrements in male sexual behavior were observed following chlorpromazine and chlordiazepoxide. All dose levels of oxazepam depressed male sexual behavior. The highest dose of chlordiazepoxide and oxazepam attenuated the onset of female sexual behavior, and all dose levels reduced postcopulatory lordosis durations. Amphetamine did not interrupt either male or female sexual behavior, and chlorpromazine disrupted male but not female behavior.

Animals↗
PubMed1990

Investigations into the route of uptake and pharmacokinetics of intraperitoneally-administered monoclonal antibodies: I. Transdiaphragmatic blockade of the terminal lymphatics in the rat.

Recent studies on the intraperitoneal administration of radiolabeled monoclonal antibodies indicate that the diaphragm and, in particular, the lymphatics associated with the diaphragm are more involved in the transport of such high-molecular-mass moieties than was earlier suspected. The current study examines the role of the diaphragm in the i.p. transport of an IgG2a murine monoclonal antibody, 5G6.4, by observing the effect on the absorption of the antibody produced when the diaphragm has been scarred. Normal, sham-operated, and diaphragmatically scarred (abrasions made with 600-grade sandpaper) female Sprague Dawley rats (150-250 g) were administered intraperitoneal injections of 125labeled 5G6.4 in a volume of 2.0 cm3. Approximately 5 micrograms antibody protein was administered in the individual 19-microCi injections per rat. Scarring was effective in partially blocking the amount of labeled antibody that crossed the diaphragm. Mean diaphragm levels (% injected dose/g) of 125I-labeled 5G6.4 from the scarred group were 16.8% lower than values from the sham-operated rats and 37.2% lower than those from the control rats. The blockade was effective in slowing the appearance of the labeled antibody in the systemic circulation. The half-time to absorption was significantly prolonged in the scarred group; mean t1/2 absorption values of 2.5 h for the control group, 5.3 h for the sham-operated group, and 9.6 h for the diaphragmatically blocked group were recorded. Scarring the diaphragm reduced the mean maximum blood concentration by 27.6% over the control group and 23.9% over the sham-operated group. The mean time to maximum blood concentration was lengthened by 93..0% over the control group and 35.3% over the sham-operated group due as a result of scarification. Presumably this impedence to absorption would increase the time that the radiolabeled antibody bathed the peritoneal space. The scarred group also had the largest "system mean residence time" (162.5 h) compared to the sham-operated (147.9 h) and control (118.7 h) groups. These values further verify the effect of surgery on the kinetics of the i.p. administered radiolabeled monoclonals. This work demonstrates that scarifying the diaphragm does alter the kinetics of the i.p. administered monoclonal antibodies and supports the concept that transdiaphragmatic lymphatic absorption is an important route of antibody clearance from the peritoneal cavity.

Absorption↗
PubMed1992

Characterization and pharmacological modulation of soluble phospholipase A2 generated during glycogen-induced rat peritonitis.

Soluble phospholipase A2 (PLA2) activity was assessed in rat peritoneal lavage fluid after an intraperitoneal injection of 6% glycogen. Enzyme activity immediately increased 5-fold above basal by 4 h. Activity decreased by only 30% at 18 h and remained at this elevated level through 72 h. The initial rise in PLA2 activity was coincident with protein extravasation but not with polymorphonuclear leukocyte infiltration, suggesting that the early PLA2 activity could be, in part, blood-derived. Mononuclear cell influx occurred later (4 h), peaked by 6-8 h but remained elevated through 72 h possibly contributing to the persistence of PLA2 activity through 20-72 h. The exudate PLA2 measured at 4-6 h (early) and 20-24 h (late), after glycogen administration, were biochemically compared. They were found to be neutral pH active, Ca(2+)-dependent and were similarly inhibited by the inhibitors, p-bromophenacylbromide, ellagic acid, gossypol and luffariellolide. Oral administration of dexamethasone to rats inhibited the appearance of PLA2 activity in the peritoneal lavage fluid as well as cellular influx and protein extravasation. Indomethacin had no effect on these parameters. These studies demonstrate that PLA2 is an integral component of glycogen-induced peritonitis and can be pharmacologically manipulated.

Animals↗
PubMed1994

Inhibitory effect of allopurinol on adjuvant arthritis in rats.

The effect of Allopurinol (ALLO), on adjuvant arthritis was studied in rats and compared with the effect of indomethacin (IND). Drugs were given by intraperitoneal injection for each day beginning from the day of adjuvant injection (day 0) and continued until the 16th day. Paw swelling was measured on days 4, 17 and 29, and secondary lesions were assessed on days 17 and 29. Polymorphonuclear leukocyte (PMNs) count was also evaluated on day 17. ALLO, at relatively high doses (25-50 mg/kg), reduced paw swelling of the adjuvant-injected extremity on day 4; lower doses (6.25-12.5 mg/kg), however, elicited the same inhibitory effect on day 17. IND (0.25 mg/kg) also prevented paw swelling on days 4 and 17. Both ALLO and IND reduced the secondary lesions on days 17 and 29 and prevented the increase in polymorphonuclear leukocytes during the development of adjuvant arthritis. Possible mechanisms of the antiinflammatory effect of ALLO in adjuvant arthritis are discussed.

Allopurinol↗