Showing papers on "Intraperitoneal injection published in 1995"
TL;DR: It is concluded that IL-8 is a cytokine that induces rapid mobilization of progenitor cells and pluripotent stem cells that are able to rescue lethally irradiated mice and that is able to completely and permanently repopulate host hematopoietic tissues.
286 citations
TL;DR: It is demonstrated that two major cell groups in the brain, neuronal cells and non-parenchymal cells, are responsible for the enhanced production of prostaglandins after systemic LPS treatment, and a possible role for blood vessels and leptomeninges in the genesis of fever is proposed.
258 citations
TL;DR: To monitor the fate of alginate following systemic administration, a method was developed that allowed the covalent incorporation of approximately 1 mol% tyrosinamide, which was subsequently stable on storage at 4°C for 30 days, with very little free [125I] iodide released over that period.
Abstract: Tb monitor the fate of alginate following systemic administration, a method was developed that allowed the covalent incorporation of approximately 1 mol% tyrosinamide. The product could be radioiodinated to a high specific activity, and was subsequently stable on storage at 4°C for 30 days, with very little (c 1%) free [125I] iodide released over that period. Twenty-four hours following intravenous administration, the low molecular weight fraction (<48,000) of the injected polymer was excreted in the urine while the larger polymer fraction remained in the circulation and did not readily accumulate in any of the tissues. Almost all of the dose administered by intraperitoneal injection was transferred from the peritoneal cavity to the blood compartment within 24 h, with the low molecular weight fraction of the polymer excreted in the urine. Following subcutaneous administration, the majority (-70%) of the injected dose was retained at the site of injection at 24 h.
164 citations
TL;DR: It is demonstrated that abolishing acute hepatic injury with α‐tocopherol, a free radical scavenger, also eliminated increased NF‐κB binding, and it is tempting to speculate that enhanced NF-κB expression caused by free radical production/oxidative stress may modulate liver injury, perhaps through an effect on cytotoxic cytokine synthesis.
152 citations
Journal Article•
TL;DR: Adenosine 5'-O-(3-thiotriphosphate) was also effective in causing IL-1 release but not UTP or ADP, suggesting that the ATP-mediated release of IL- 1 is a receptor-mediated phenomenon that is associated with cell lysis.
Abstract: The secretion of IL-1 from murine macrophages in vitro is an inefficient process that is distinct from those of other cytokines such as IL-6. We have therefore studied this process in vivo to see if these differences are maintained. Intraperitoneal injection of LPS in mice induced production and release of IL-6 into the extracellular fluid (peritoneal lavage). Although induction of intracellular IL-1 alpha and IL-1 beta was readily detected, these cytokines were not detected extracellularly. Injection of ATP 2 h after LPS led to the rapid extracellular release of IL-1 beta, IL-1 alpha, lactate dehydrogenase, and beta-N-acetylglucosaminidase. Western blot analysis revealed that a large proportion of the IL-1 beta was released as the 17-kDa form, whereas IL-1 alpha was unprocessed. Adenosine 5'-O-(3-thiotriphosphate) was also effective in causing IL-1 release but not UTP or ADP. This suggests that the ATP-mediated release of IL-1 is a receptor-mediated phenomenon that is associated with cell lysis.
130 citations
TL;DR: Both tPA and uPA may be used to prevent adhesion formation when delivered locally in a rat uterine horn devascularization and serosal injury model in a blinded, randomized study.
112 citations
Journal Article•
TL;DR: The hypothesis that inhibition of angiogenesis is a mechanism of action for vitamin D in the transgenic retinoblastoma mouse model is supported.
Abstract: Purpose. Vitamin D compounds have been shown to inhibit tumor growth in a transgenic retinoblastoma murine model. The mechanism of action has not been defined clearly, although an antiangiogenic action has been proposed. Methods. Transgenic retinoblastoma mice received high (0.05 fig) and low (0.025 fxg) doses of vitamin D3 by intraperitoneal injection 5 times per week for 5 weeks. Control animals were injected with mineral oil vehicle alone. At 5 months of age, the animals were killed and eyes were enucleated and processed for light microscopy. Paraffin-embedded sections were stained with an immunoperoxidase stain (GS-1) specific for mammalian vascular endodielium. Sections were graded by a single masked reviewer, and intraobserver reliability was assessed. Mean vessel counts were made for each group. Results. The high-dose group had the lowest mean vessel count (8.5), followed by the lowdose group (10.1). The control group had the highest mean vessel count (14.1). Vitamin Dtreated animals (high- and low-dose groups combined) had significantly fewer vessels (P = 0.001) than untreated controls. Conclusions. These results support the hypothesis that inhibition of angiogenesis is a mechanism of action for vitamin D in the transgenic retinoblastoma mouse model. Invest OphthalmolVisSci. 1995; 36:83-87. .Human retinoblastoma requires the presence of blood vessels to support tumor growth. Retinoblastoma cells grow in a uniform, collar-like pattern around blood vessels with necrosis at a constant radius around blood vessels. 1 It is not known whether the angiogenic stimulus is derived from tumor cells themselves or from ischemic retina. Cultured retinoblastoma cell lines, however, have been shown to produce tumor angiogenesis factors. 2 The natural progression of transgenic murine retinoblastoma indicates that tu
104 citations
TL;DR: Investigating the acute effects of both vanadyl sulfate and bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, on plasma glucose levels by several routes of administration found that the increase in potency with BMOV cannot be totally attributed to increased gastrointestinal absorption.
Abstract: Numerous studies, both in vitro and in vivo, have demonstrated the insulin-mimetic properties of vanadium. Chronic oral administration of inorganic and organic compounds of both vanadium(IV) and vanadium(V) reduced plasma glucose levels and restored plasma lipid levels in streptozotocin-diabetic rats. We investigated the acute effects of both vanadyl sulfate and bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, on plasma glucose levels by several routes of administration. Previous studies have shown that chronic administration of vanadyl sulfate has resulted in a sustained euglycemia following withdrawal of the drug. This effect was not observed following the chronic administration of BMOV; therefore, we investigated the effect of increasing the concentration of BMOV on the production of a sustained euglycemic response. An acute plasma glucose lowering effect was obtained with both vanadyl sulfate and BMOV when administered as a single dose by either oral gavage or intraperitoneal injection. In those animals that responded to vanadium treatment, plasma glucose levels were within the normal range within 2 to 6 h when given by i.p. injection or within 4 to 8 h when given by oral gavage. BMOV-treated rats that responded to treatment maintained the euglycemic effect for extended periods, ranging from 1 to 14 weeks following administration. However, vanadyl sulfate treated rats reverted to hyperglycemia within 12 to 24 h, depending on the route of administration. Intravenous administration of BMOV was effective in lowering plasma glucose levels only when administered by continuous infusion. An oral dose-response curve showed that BMOV was 2 to 3 times as potent as vanadyl sulfate. This difference in potency was observed with both oral and intraperitoneal administration, which suggests that the increase in potency with BMOV cannot be totally attributed to increased gastrointestinal absorption. Organic chelation of vanadium may facilitate uptake into vanadium-sensitive tissues. Chronic oral administration of higher concentrations of BMOV did not result in a sustained reduction in plasma glucose following withdrawal of the drug. All diabetic rats eventually responded to increased concentrations of BMOV with a restoration of plasma glucose levels to normal values; however, reversion to the hyperglycemic state occurred within 2 days of withdrawal of treatment. Chronic oral administration of BMOV did not produce a sustained euglycemic effect following withdrawal, but acute administration of the compound by either oral gavage or intraperitoneal injection did produce a long-term reduction in plasma glucose levels. Rats treated chronically with vanadyl sulfate remained euglycemic even after the drug was withdrawn. However, acute treatment produced only a transient euglycemia.
101 citations
TL;DR: In this paper, male NIH-Swiss mice intraperitoneal injection of physiological saline significantly diminished (vs. naive mice) the ratio of the number of entries into open and also open arms, and significantly prolonged time spent in closed arms.
79 citations
TL;DR: It is suggested that sustained NO synthesis may be a beneficial mechanism for the induction of LPS tolerance in rats by intraperitoneal injection of a sublethal dose of Salmonella enteritidis LPS.
Abstract: The role of nitric oxide (NO) synthesis was investigated in endotoxin (LPS) tolerance induced in rats by intraperitoneal injection of a sublethal dose of Salmonella enteritidis LPS (100 micrograms/kg intraperitoneally). Peritoneal macrophages were harvested 6 and 24 h after LPS injection and stimulated in vitro with LPS. LPS significantly stimulated arachidonic acid metabolism, as assessed by 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels, and NO production, as assessed by nitrite, in macrophages collected from control rats. In macrophages from tolerant rats LPS-stimulated 6-keto-PGF1 alpha production was significantly reduced, while nitrite production was increased compared to control macrophages (p < .001). In in vivo mortality studies, rats that were pretreated 24 h earlier with sublethal LPS were resistant to the lethal effect of a subsequent dose of LPS (15 mg/kg intravenously) in comparison to control rats (p < .001). NG-Nitro-L-arginine-methyl ester, an inhibitor of NO synthase, decreased mean survival time in control rats and abrogated the resistance to the lethal effect of LPS in tolerant rats. In contrast, molsidomine, a NO donor, improved survival in control rats but did not modify the resistance to the lethal dose of LPS in tolerant rats. The results suggest that sustained NO synthesis may be a beneficial mechanism for the induction of LPS tolerance.
75 citations
Journal Article•
TL;DR: Results indicate that plasma IGF-I in salmonid fish is under GH control and that oral administration of the hormone is followed by longer-lasting effects than those achieved by intraperitoneal injection.
Abstract: Changes in plasma insulin-like growth factor-I (IGF-I) and growth hormone (GH) levels in rainbow trout, Oncorhynchus mykiss, were investigated after either intraperitoneal or oral (intragastric) administration of salmon GH Plasma IGF-I and GH levels were measured by homologous radioimmunoassays for salmon IGF-I and GH After intraperitoneal injection of salmon GH at doses of 01 or 10 micrograms/g body weight to rainbow trout, plasma GH levels increased to a maximum after 6 h and declined rapidly thereafter Plasma IGF-I levels were elevated after 12 h, reaching maximum at 24 h and (after the higher dose of GH) remaining high at 78 h after GH injection In contrast, following intragastric administration of salmon GH at the same doses, plasma GH levels were significantly elevated 12 h after administration, reaching a maximum at 15 h and declining to basal levels at 24 h Plasma IGF-I levels increased significantly after 48 h and remained elevated (after the higher dose of GH) for more than 96 h Effects on plasma GH and IGF-I were dose-dependent notwithstanding the route of administration of GH These results indicate that plasma IGF-I in salmonid fish is under GH control and that oral administration of the hormone is followed by longer-lasting effects than those achieved by intraperitoneal injection
TL;DR: The results suggest that methimazole-induced toxicity in the olfactory mucosa is related to metabolism-dependent changes of the thiol group.
Abstract: In mice given a single intraperitoneal injection of the antithyroid drug methimazole (0.44 mmol/kg; 50 mg/kg) detachment of the olfactory neuroepithelium and necrosis of the Bowman's glands in the lamina propria was observed 24 hr after administration. Three days after administration there was an atypical epithelium throughout the olfactory region and the Bowman's glands had disappeared. Pretreatment with the olfactory cytochrome P450 inhibitor metyrapone protected against the methimazole-induced changes at this site. In mice injected with the methimazole analogues 1-methylimidazole or 4-methylimidazole (0.44 mmol/kg; 36 mg/kg) or the antithyroid drug propylthiuracil (0.22 mmol/kg; 38 mg/kg) no morphological changes were observed in the olfactory mucosa. The results suggest that methimazole-induced toxicity in the olfactory mucosa is related to metabolism-dependent changes of the thiol group.
TL;DR: The ratio of relative concentrations of radiolabel observed in the livers and flesh indicates that extremely low levels of microcystin-LR would be present in the flesh of fish afflicted with 'netpen liver disease'.
TL;DR: Experimental sepsis, induced by either cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide, resulted in impaired intestinal amino acid uptake, which may explain the lack of benefit of enteral, compared with parenteral, arginine therapy on survival from a septic insult.
Abstract: Objective : To investigate the effect of sepsis on the intestinal absorption of arginine. Design : Controlled, nonintervention study. Setting : Surgical research laboratories of Sinai Hospital of Baltimore. Subjects : Male Sprague-Dawley rats. Interventions : Experimental sepsis induced by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide. Measurements and Main Results : Sepsis assessed by peritoneal and blood cultures. Intestinal absorption estimated by measuring the transfer of 3 H-arginine by everted jejunal sacs prepared from septic and control animals (n = 6 per group) at multiple time points after the induction of sepsis (6, 12, 24, 48, and 72 hrs after cecal ligation and puncture ; 6 and 12 hrs after intraperitoneal injection of lipopolysaccharide). Induction of peritonitis in the rat by cecal ligation and puncture significantly reduced the in vitro uptake of arginine by everted jejunal sacs at 12, 24, and 48 hrs after laparotomy. Arginine transfer by everted jejunal sacs was also significantly reduced in rats as early as 6 hrs after intraperitoneal injection of endotoxin (endotoxin 273 ± 14 ; saline 377 ± 14 nmol/sac/hr). Data are expressed as mean ± SEM. Recovery from sepsis was associated with normalization of arginine transfer by intestinal sacs. Conclusions : Experimental sepsis, induced by either cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide, resulted in impaired intestinal amino acid uptake. Impaired intestinal arginine absorption may explain the lack of benefit of enteral, compared with parenteral, arginine therapy on survival from a septic insult. (Crit Care Med 1995 ; 23 :1227-1232)
TL;DR: A combination of light and electron microscopy, plus measurement of myeloperoxidase activity (a marker of neutrophil accumulation) demonstrated that the omental milky spots are the major route through which leukocytes migrate into the peritoneal cavity.
Abstract: Intraperitoneal injection of inflammatory agents in the mouse and rat causes plasma protein and leukocyte extravasation into the peritoneal cavity. Following an intraperitoneal injection of zymosan A, the milky spots of the omentum were the only abdominal sites detected where intravenously administered Monastral Blue labeled interendothelial cell gaps responsible for plasma extravasation. In addition, when colored microspheres were intraventricularly administered to quantify blood flow, the omentum was the only abdominal organ which showed an increase in blood flow during zymosan A peritonitis. A combination of light and electron microscopy, plus measurement of myeloperoxidase activity (a marker of neutrophil accumulation) demonstrated that the omental milky spots are the major route through which leukocytes migrate into the peritoneal cavity. Identical structures in the pleura likewise are the sites of protein leakage into the pleural cavity. In contrast, selective sites of protein and cellular extravasation could not be detected in the synovial lining of the inflamed knee joint.
TL;DR: In this article, the influence of peritoneal macrophage enhancement on postoperative adhesion formation in five groups of rabbits was studied, and it was concluded that enhancement of peri-itoneal Macrophages by protease peptone reduced markedly the degree of post-operative adhesive formation.
TL;DR: The results show that inhibition of serum tumor necrosis factor activity does not block the development of endotoxin-induced uveitis, but in fact, anti-tumor necrosisFactor antibody treatment exacerbates the intraocular inflammation, and suggest that tumor Necrosis factor may have other than proinflammatory properties in this uve arthritis model.
TL;DR: All the polymer-enzyme conjugates showed increased body residence time after intravenous injection in rats with respect to the native enzyme, and PVP was found to affect the pharmacokinetic properties of the enzyme after subcutaneous, intramuscular and intraperitoneal administration.
Abstract: Monofunctional hydroxy-terminated poly(N-vinylpyrrolidone) was obtained by radical polymerization in the presence of isopropoxyethanol for protein surface modification. Superoxide dismutase was modified to various degrees by reaction with PVP-OH activated by 4-nitrophenyl chloroformate with high retention of enzymatic activity. All the polymer-enzyme conjugates showed increased body residence time after intravenous injection in rats with respect to the native enzyme. The residence time depended upon the number of bound polymer chains. PVP was found to affect the pharmacokinetic properties of the enzyme after subcutaneous, intramuscular and intraperitoneal administration. The antigenicity of superoxide dismutase was reduced to one third following modification, while its immunogenicity after intravenous, subcutaneous and intraperitoneal injection totally disappeared. The conjugates exhibited increased solubility in organic solvents and increased stability towards thermal denaturation, whereas changes in the...
TL;DR: The results provide confirmation of previous reports that mitochondria from hypothyroid rats show a markedly diminished AdNT activity, which is restored to normal levels within 72 hours by intraperitoneal injection of 10 to 20 micrograms triiodothyronine (T3)/100 g body weight.
Abstract: Adenine nucleotide translocase (AdNT) levels were measured as the exchange of extramitochondrial against intramitochondrial adenosine diphosphate (ADP) in liver, spleen, and testes mitochondria isolated from normal and hypothyroid rats using the "back-exchange" and atractyloside-stop method of Pfaff and Klingenberg. The results provide confirmation of previous reports that mitochondria from hypothyroid rats show a markedly diminished AdNT activity, which is restored to normal levels within 72 hours by intraperitoneal injection of 10 to 20 μg triiodothyronine (T 3 )/100 g body weight. The latter dose was found in dose-response studies to result in maximal stimulation of AdNT in liver mitochondria. Qualitatively similar results on AdNT activity were obtained in liver mitochondria within 30 to 60 minutes following intravenous injection into hypothyroid rats of a more physiological dose of T 3 (40 ng/100 g body weight). AdNT in mitochondria isolated from spleen and testes (organs that do not exhibit a calorigenic response after administration of thyroid hormone to the whole animal) failed to respond to thyroidectomy and to administration of T 3 . More recently, we have observed that in vitro replacement of T 3 also stimulates AdNT activity in hypothyroid liver mitochondria. The enzyme adenosine triphosphate (ATP) synthase was examined as another possible candidate for direct hormonal stimulation of mitochondria. Simultaneous determinations on the same rats after intraperitoneal injection of T 3 (20 μg/100 g body weight) showed little or no effect on ATP synthase until after 37 to 85 hours, whereas enhanced activity of the translocator was regularly observed at 17 hours. These findings support the view that AdNT, which is considered to exert major control over the rate of oxidative phosphorylation, may be a direct target of T 3 action on the mitochondria. Increased nuclear transcription may be regarded as a sustained delayed effect of T 3 administration, in contrast to the early effect on mitochondrial AdNT. A bolus intravenous injection of T 3 into the hypothyroid rat increases the activity of the mitochondrial carrier AdNT within a matter of minutes as an early direct effect, as also suggested by studies of addition of T 3 in vitro to isolated rat liver mitochondria. In contrast, nuclear effects require 12 to 24 hours to show increased transcription, evidenced by increased specific mRNA directing the formation of more AdNT (Luciakova and Nelson).
TL;DR: The observation that activity-dependent gene expression in the spinal cord is effectively modulated by anticonvulsants discloses a novel therapeutic potential of these compounds.
TL;DR: Mechanisms other than direct iron toxicity, such as generation of cytotoxic free radicals, may play an important role in cerebral vasospasm and the route of administration and concentration of drugs in the perivascular region adjacent to the thrombus may be critical to their efficacy.
Abstract: Prior work in our laboratory showed that the perivascular application of deferoxamine (an antioxidant and iron-chelating agent) inhibited delayed arterial narrowing after chronic blood exposure in a rat femoral artery model of vasospasm. To determine which of these mechanisms was operant in vasospasm, we compared deferoxamine with two agents (ascorbic acid and U74389F) that have antioxidant but not iron-chelating capacity. For the systemic application of drugs in 23 rats, whole blood encased in a silastic cuff was applied to the right femoral artery of each rat; whole-blood serum (lacking erythrocytes) was similarly applied to the left femoral artery. Deferoxamine (30 mg/kg/d), ascorbic acid (1000 mg/kg/d), U74389F (30 mg/kg/d), or pH-matched control vehicle was administered three times daily by intraperitoneal injection for 7 days. After exposure to whole blood, arteries treated with intraperitoneal vehicle showed an 85% reduction in the lumen, compared with vessels exposed to erythrocyte-free serum (P < 0.001). Intraperitoneal ascorbic acid and U74389F produced moderate amelioration in arterial narrowing (53 and 61% decrease, respectively, in the lumen versus controls; P < 0.05 versus vehicle); deferoxamine had no significant effect when administered intraperitoneally. To test the efficacy of these agents by the perivascular application of drugs, whole blood was applied to both femoral arteries in each of 25 rats. Solutions of deferoxamine (10 mg/ml), ascorbic acid (50 or 100 mg/ml), or U74389F (15 or 30 mg/ml) were directly applied to the perivascular thrombus surrounding the femoral arteries, compared with vehicle applied to contralateral vessels. The perivascular application of 50 mg of ascorbic acid (36% reduction, P < 0.05), 100 mg of ascorbic acid (31% reduction, P < 0.01), or 10 mg of deferoxamine (41% reduction, P < 0.05) significantly inhibited arterial narrowing, compared with vehicle. The application of U74389F at a dose of 15 or 30 mg directly into the perivascular thrombus produced nonsignificant reduction in arterial narrowing. These data suggest that mechanisms other than direct iron toxicity, such as generation of cytotoxic free radicals, may play an important role in cerebral vasospasm. In addition, the route of administration and concentration of drugs in the perivascular region adjacent to the thrombus may be critical to their efficacy.
TL;DR: The view that superoxides play a key role in the pathogenesis of caerulein pancreatitis is supported, and that Mn-SOD in the pancreas may work as a defense against the development of this disease.
TL;DR: Comparison of tumor suppression and toxic effects of human TNF and human lymphotoxin in mice shows a higher therapeutic index of LT compared with TNF.
TL;DR: Adex1HST-1 was injected intraperitoneally into thrombocytopenia induced by administration of a chemotherapeutic agent and/or by irradiation for cancer treatment and more efficiently diminished the extent and duration than any other reported cytokine or any combination of cytokines so far.
Abstract: HST-1 (FGF-4) gene product is a member of the fibroblast growth factor family with a signal peptide and plays a crucial role in limb development. We showed previously that an intraperitoneal injection of replication-deficient adenovirus containing the HST-1 gene (Adex1HST-1) into normal mice caused a twofold increase in peripheral platelet count. To investigate whether Adex1HST-1 could effectively prevent experimentally induced thrombocytopenia in mice, we injected Adex1HST-1 intraperitoneally into thrombocytopenic mice induced by administration of a chemotherapeutic agent and/or by irradiation. A single Adex1HST-1 injection caused continuously increased levels of serum HST-1 protein for at least 30 d and increased the count of large megakaryocytes in bone marrow, which specifically recovered platelet counts and more efficiently diminished the extent and duration of thrombocytopenia than any other reported cytokine or any combination of cytokines so far. In the other peripheral hematological parameters, no discernible differences were detected. No other apparent side effects were observed. Therefore, this method could be useful for treatment and/or prevention of thrombocytopenia induced by chemotherapy and/or irradiation for cancer treatment.
TL;DR: It is suggested that IL-1 beta may stimulate synthesis and release of hypothalamic histamine in presynaptic terminals by activation of HDC and facilitate degradation of extracellular histamine byactivation of MHT.
Abstract: Dynamic involvement of hypothalamic histamine in ingestive behavior and thermogenesis induced by interleukin-1 beta (IL-1 beta) was examined in rats. Intraperitoneal injection of 0.12 nmol/rat IL-1 beta decreased food and water intake and elevated body temperature. However, depletion of neuronal histamine induced by intraperitoneal injection of 160 mumol/rat alpha-fluoromethylhistidine, a suicide inhibitor of histidine decarboxylase (HDC), attenuated the suppressive effect of IL-1 beta on food intake, facilitated the suppressive effect on drinking, and enhanced the elevating effect on rectal temperature. Intraperitoneal injection of 0.12 nmol/rat IL-1 beta increased hypothalamic histamine turnover rate. The same dose of IL-1 beta also increased activity of HDC and histamine-N-methyltransferase (HMT). These results suggest that IL-1 beta may stimulate synthesis and release of hypothalamic histamine in presynaptic terminals by activation of HDC and facilitate degradation of extracellular histamine by activation of MHT. These changes in the dynamics of hypothalamic histamine modulate IL-1 beta-induced ingestive behavior and body temperature.
TL;DR: The results suggest that the therapeutic injectable gel chemotherapy, when given intratumorally, may improve tumor response with less systemic toxicity in comparison with conventional systemic chemotherapy.
Abstract: This study provides the first evidence that treatment of human pancreatic adenocarcinoma is markedly improved by the intratumoral administration of chemotherapeutic agents in a novel drug delivery system. The effect of chemotherapeutic agents delivered in a sustained-release, protein-based, injectable gel was evaluated on the growth of human pancreatic adenocarcinoma cell line, BxPC-3. In vitro chemosensitivity of BxPC-3 cells exposed for 24 or 72 h to fluorouracil (0.01-5 mM), cisplatin or doxorubicin (0.1-50 microM) and floxuridine, vinblastine, mitomycin or paclitaxel (1.0-100 microM) was compared with that of untreated cells. In vitro chemosensitivity was also studied with fluorouracil and mitomycin in the poorly differentiated PANC-1, human pancreatic cancer cell line. Survival was determined after 7-10 days. All drugs decreased cell growth in a dose-dependent fashion. The efficacy of fluorouracil, cisplatin and doxorubicin increased with prolonged exposure, rendering these drugs most appropriate for a sustained-release preparation. For in vivo studies, athymic nude mice bearing BxPC-3 xenografts were treated either with fluorouracil, cisplatin or doxorubicin in the therapeutic injectable gel containing epinephrine or with vehicle alone administered intratumorally on days 1 and 4. After 28 days, the mice were sacrificed and tumors dissected and weighed. Tumors in mice treated with the injectable gel decreased in size by 72-79% compared with tumors in untreated controls and tumors treated with vehicle alone. Intratumoral injection of drug solution and intraperitoneal injection of drug in the injectable gel did not change tumor size compared with controls. In a drug-retention study, mice were injected intratumorally with [3H]fluorouracil either in the injectable gel or in solution. Sustained radioactivity was observed in tumors injected with the gel, and, conversely, greater radioactivity was detected in the liver and kidneys in mice receiving the radiolabeled solution. These results suggest that the therapeutic injectable gel chemotherapy, when given intratumorally, may improve tumor response with less systemic toxicity in comparison with conventional systemic chemotherapy.
TL;DR: It is concluded that TIMP‐2 mRNA expression is regulated in a distinct and partially opposite manner and could inhibit the activity of metalloproteinases and thus lead to matrix accumulation.
Journal Article•
TL;DR: A differential response of transport systems to sepsis appears to be the inverse of what is observed after a period of starvation, suggesting that not all transport systems were affected equally.
Abstract: Background Sepsis has been shown to impair the barrier function and metabolism of the intestine. This study was done to investigate the effect of sepsis on intestinal absorption of proline, leucine, glutamic acid, and aminoisobutyric acid. Study design Rats (six per group) were studied 24 hours after cecal ligation and puncture (CLP) or six hours after intraperitoneal injection of lipopolysaccharide (LPS). Controls underwent sham laparotomy or saline solution injection. Four 7-cm everted proximal jejunal sacs were prepared from each rat and filled with 800 microL Krebs' bicarbonate buffer containing 100 mumol/L of amino acid. Paired sacs (septic and control) were incubated at 37 degrees C in flasks containing the same solution trace labeled with 3H containing the same solution trace labeled with 3H amino acid. Sac contents were aspirated 60 minutes later and amino acid uptake was determined by scintillation counting. Results Twenty-four hours after CLP and six hours after LPS administration there was significant impairment in the intestinal absorption of all amino acids studied. Absorption of glutamic acid was the least affected, followed by leucine, aminoisobutyric acid, and proline. Conclusions Sepsis impairs the intestinal absorption of amino acids. The magnitude of this defect in absorption differed with the amino acid studied, suggesting that not all transport systems were affected equally. This differential response of transport systems to sepsis appears to be the inverse of what is observed after a period of starvation.
Journal Article•
TL;DR: Diallyl sulfide and phenethyl isothiocyanate demonstrated chemoprevention of tumorigenesis and N-Acetyl-l-cysteine and 1,2-oxothiazolidine-4-carboxylate did not affect the yield of either liver lesion.
Abstract: The ability of six proposed chemopreventive agents to prevent diethylnitrosamine-induced liver foci and tumors in male C3H mice was investigated. The test agents were administered by intraperitoneal injection on days 13, 14 and 15 of age and starting at 21 days of age continuously in the diet until sacrifice at 161 days of age. The mice were administered 4.0 mg/kg diethylnitrosamine by intraperitoneal injection on day 15 of age and two hours after the test agent. Diethylnitrosamine-induced 62.4 +/- 4.2 foci of altered hepatocytes and 22.1 +/- 2.1 hepatocellular adenomas, which were reduced by diallyl sulfide to 21.6 +/- 2.4 and 6.73 +/- 1.13 and phenethyl isothiocyanate to 28.2 +/- 3.4 and 5.06 +/- 1.53 foci and adenomas, respectively. Difluoromethylornithine and ellagic acid only decreased the yield of adenomas without affecting the yield of foci of altered hepatocytes and of total lesions. N-Acetyl-l-cysteine and 1,2-oxothiazolidine-4-carboxylate did not affect the yield of either liver lesion. When administered starting prior to diethylnitrosamine-initiation and continuing until sacrifice, diallyl sulfide and phenethyl isothiocyanate demonstrated chemoprevention of tumorigenesis.
TL;DR: Aspirin, in vivo slightly affected lipid peroxidation and antioxidant enzyme activity in liver homogenates and erythrocytes, irrespective of the dose and route of drug administration.
Abstract: 1. Malondialdehyde formation and antioxidant enzyme activity after oral or intraperitoneal treatment of rats with various doses of aspirin was studied. 2. Aspirin, orally, had no effect on spontaneous, Fe(II)- or Fe(II)/ascorbate-induced malondialdehyde formation in liver homogenates; orally, ascorbate-induced malondialdehyde production was inhibited but only after 5-day treatment with 500 mg/kg aspirin; after intraperitoneal injection, the drug inhibited ascorbate- and Fe(II)/ascorbate-induced production of malondialdehyde. 3. Aspirin had no effect on malondialdehyde formation in erythrocytes, irrespective of the dose and route of drug administration. 4. Aspirin increased glutathione peroxidase activity in liver after 5-day treatment with an oral dose of 500 mg/kg and decreased enzyme activity in both liver and erythrocytes, 24 hr after a single injection of the same dose. 5. Aspirin, in vivo slightly affected lipid peroxidation and antioxidant enzyme activity.