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Dissociation between the time course of ethanol and extracellular dopamine concentrations in the nucleus accumbens after a single intraperitoneal injection.

BACKGROUND: Dopamine release in the nucleus accumbens has been linked to the reinforcing effects of ethanol, but the time course or relationship of this response to ethanol concentrations in the brain has not been studied. METHODS: Various doses of ethanol (0-2.0 g/kg) were administered intraperitoneally to male Sprague Dawley rats, and dopamine and ethanol were simultaneously analyzed in dialysate samples from the nucleus accumbens. A separate study to compare the ethanol-induced dopamine response in male and female rats was carried out by using a 1 g/kg intraperitoneal dose of ethanol. RESULTS: In male rats, 1 and 2 g/kg ethanol significantly increased dialysate dopamine by 40% over basal, whereas 0.25 and 0.5 g/kg ethanol produced a nonsignificant 20% increase. Dialysate ethanol concentrations exhibited a curvilinear decline after reaching peak levels for the lower doses but showed a linear decrease after 1 and 2 g/kg. There was a dissociation between the time courses of extracellular dopamine and ethanol after 1 and 2 g/kg ethanol treatment. The dopamine response returned to basal within 90 min, whereas the ethanol concentrations remained elevated. In a separate study that compared male and female rats, the ratio of the dopamine response over basal to the dialysate ethanol concentrations was significantly decreased at 60 min after an injection of 1 g/kg. However, there were no differences between males and females. CONCLUSIONS: The dissociation between dopamine and ethanol levels may reflect the development of acute tolerance to ethanol-induced dopamine release in the nucleus accumbens within the time course of a single acute injection. Given the strong links between dopamine and ethanol reinforcement, our findings may be relevant for understanding the time course of ethanol's reinforcing effects in vivo.

Animals↗

Airway hyperresponsiveness induced by repetitive intraperitoneal injection of lipopolysacharide and the involvement of inflammation and nitric oxide in guinea pigs.

OBJECTIVE: Airway hyperresponsiveness (AHR) is involved in bronchial asthma and chronic obstructive pulmonary disease (COPD) and produces respiratory symptoms. Lipopolysaccharide (LPS) has been found to be significantly related to the severity of asthma. However, its clinical mechanism still remains controversial. This study investigated the in vivo effect of repetitive intraperitoneal administration of lipopolysaccharide (LPS) on airway hyperresponsiveness (AHR) in guinea pigs and the possible involvement of inflammation, nitric oxide (NO) and nitric oxide synthase (NOS). METHODS: There were two exposure groups for intraperitoneal LPS injection: (1) LPS was given at a dose of 1 mg x kg(-1), followed by sterile saline (NS) 1 ml x kg(-1) 8 h later every 24 h; (2) LPS was given at a dose of 0.5 mg x kg(-1) two times with an interval of 8 h every 24 h. Each exposure regime was repeated 4 times. Control animals were given NS and 6 naive guinea pigs were used as baseline control. Determinations were made 24 h after each exposure. RESULTS: Persistent AHR occurred 24 h after the third and fourth exposures to LPS in the first exposure group (at one dose), but occurred earlier after the exposures to LPS in the second exposure group (at divided doses). The numbers of total cells and neutrophils were elevated initially but subsided subsequently in LPS-treated groups. No evidence of morphological changes in the small airways was found 24 h after any of the exposures. The Ca(2+)-dependent and Ca(2+)-independent NOS activities (mainly produced by iNOS) in the BALF, as well as the production of NO, were significantly elevated 24 h after any of third and fourth exposures in LPS-treated groups. CONCLUSIONS: Our results demonstrate that repetitive intraperitoneal LPS can induce persistent AHR which occurs earlier when the frequency of injection increase, and an elevation of NO production and iNOS activity may be involved in is systemic-LPS-induced AHR.

Animals↗

A pathophysiological study of abdominal organs following intraperitoneal injections of chloral hydrate in rats: comparison between two anaesthesia protocols.

Chloral hydrate (CH) is used as an anaesthetic agent in laboratory rats. Side effects occurring with high concentrations have mainly occurred in abdominal organs. The objective of the present study was to minimize these side effects following intraperitoneal administration of CH using lower concentrations. Animals were evaluated using different procedures including a general necropsy, intraperitoneal white cell counts, histology and duodenal peristalsis and acetylcholine-induced contractions. Results clearly show that lower concentrations of CH while keeping the same anaesthetic dose (400 mg/kg) will minimize the irritancy of CH on abdominal organs while providing the same level of anaesthesia.

Abdominal Muscles↗

Effects of intraperitoneally injected lithium, imipramine and diazepam on nitrate levels in rat amygdala.

Nitric oxide (NO) has been studied in relation to the etiologies of various neurologic and psychiatric diseases. However, little is known about whether clinically available psychotropic drugs affect the NO system in the brain. Using an in vivo brain microdialysis method, the effects of intraperitoneally administered lithium, imipramine and diazepam on levels of , a marker of in vivo NO production, were investigated in the rat amygdala. Lithium significantly reduced, while imipramine raised, levels as compared with controls. These observations suggest that lithium and imipramine induce opposite effects on NO-related systems in the brain.

Amygdala↗

Granulocyte colony-stimulating factor administered as a single intraperitoneal injection modifies the lethal dose95/30 in irradiated B6D2F1 mice.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that stimulates the proliferation of progenitor myeloid cells. We have previously demonstrated that recombinant human G-CSF (rhG-CSF) significantly improves survival of lethally irradiated B6D2F1 mice when administered as a single intraperitoneal dose of 1 mg/kg 2 hours after a lethal dose (LD)95/30 irradiation. In our model, rhG-CSF is also able to modify the LD95/30 in irradiated animals and 1.1 has been found to be the dose modification factor (the ratio of LD95/30 for mice treated with rhG-CSF to that for control animals).

Animals↗

Elevation of retinyl ester level in the lungs of rats following repeated intraperitoneal injections of retinoic acid or retinoyl glucuronide.

Retinoic acid (RA) is involved in the development of both the conducting airway and alveolar portions of the lung. RA plays a key role in the induction of the formation of alveolar septa. Retinoyl beta-glucuronide (RAG), an endogenous retinoid, acts like RA, but is much less cytotoxic. We examined the effect of daily intraperitoneal doses of RA and RAG (1.66 micromol/kg) in dimethyl sulfoxide (DMSO) and cotton seed oil on the stores of retinol and retinyl ester (RE) in the lung of rats. In two separate experiments, one involving normal rats, and the other involving elastase-treated rats, there was up to a 9-fold increase in REs content in the lungs of rats that received RA or RAG for 12 days as compared to Control rats. The accumulation was most profound when RA was injected in DMSO and least when RAG was injected in cotton seed oil. The reason for the accumulation of REs in the lung is not clearly known.

Animals↗

Induction of humoral manifestations of autoimmunity following intraperitoneal injection of complete Freund's adjuvant in mice.

Several animal models of arthritis are produced using complete Freund's adjuvant (CFA) alone or with collagen as an arthritogen. Successful induction of arthritis is reported to require that the adjuvant mixture be administered by intradermal or subcutaneous routes. The resulting arthritis is caused by primarily cellular immune responses. Data presented in this paper show that giving CFA by intraperitoneal (I.P.) inoculation results in a humoral autoimmune response, with no obvious signs of arthritis. This humoral autoimmune response is characterized by production of autoantibodies to nuclear and cytoplasmic antigens, elevated levels of circulating immune complexes, and in approximately 25% of mice, rheumatoid factor.

Animals↗

Biopersistence of synthetic mineral fibers as a predictor of chronic intraperitoneal injection tumor response in rats.

In December 1997 the European Commission (EC) adopted Directive 97/69/EC (O.J. L 343/19 of 13 December 1997), in which criteria were established for the classification and labeling of synthetic mineral fibers. This directive was derived based upon an extensive program evaluating current scientific knowledge on fiber pathogenicity and its relationship to the biopersistence of long fibers. Within this context, the biopersistence of fibers longer than 20 microm was found to be a good predictor of the lung burden and early pathological changes in chronic inhalation studies with fibers as well as of the tumor response in chronic intraperitoneal studies with fibers. The analysis that provided the scientific basis for the relationship of biopersistence to the chronic intraperitoneal (ip) results is presented in detail. Analysis of the relationship of biopersistence clearance half-times to ip tumor response shows a statistically significant relationship of ip tumor response to not only the number of fibers injected, but also the median length of the fibers injected and their solubility (clearance half-time). The results show that the biopersistence half-times as determined by intratracheal instillation (T(1/2) of WHO fibers or weighted T(1/2) of fibers with L > 20 microm) and as determined by inhalation (weighted T(1/2) of fibers with L > 20 microm) are equivalent predictors of the ip results. From these ip studies, fibers that can be exonerated from classification as carcinogens in Europe have a relative tumorigenic potency in the ip cavity of between 66 and 2500 times less than fibers that have been shown to produce a significant increase in tumors following chronic inhalation exposure. In addition, based upon the ip results, there is no statistical difference between the EC and the other fiber exoneration criteria, such as the German Gefahrstoffverordnung of 1999.

Animals↗

A comparison of clinical, histopathological and cell-cycle markers in rats receiving the fungal toxins fumonisin B1 or fumonisin B2 by intraperitoneal injection.

Fumonisins B1 and B2 (FB1 and FB2) are fungal secondary metabolites produced by members of the genus Fusarium. Although FB1 is usually detected in greater quantities, FB2 frequently co-occurs in contaminated feeds and foods and contributes to the total toxin load. In the present study, the comparative toxicity of FB1 and FB2 was examined in male Sprague-Dawley rats administered toxin (0.75 mg/kg body weight) or vehicle control intraperitoneally (ip) for 2, 4 or 6 consecutive days. Clinical changes, including elevated serum cholesterol, alanine aminotransferase (ALT), creatinine and protein, were slightly more pronounced in FB1-treated rats. The most consistent hematological change was an increase in vacuolated bone marrow cells, which was more pronounced in FB1-treated rats. Histopathological changes were similar in FB1- and FB2-treated rats and included single cell necrosis in kidneys and liver, cytoplasmic vacuolation in adrenal cortex and lymphocytolysis in thymus. In the liver mRNA expression for the cyclin kinase inhibitor p21 gene was significantly increased in FB1- and FB2-treated rats, compared to controls. Expression of mRNA for the cyclin D1 gene was significantly depressed in FB2-treated rats. Hepatic cyclin E mRNA was elevated in response to FB1 and FB2 compared to controls. In FB2-treated animals this corresponded with decreased liver p27 mRNA expression. Hepatic proliferating cell nuclear antigen (PCNA) transcription was elevated in FB1- but not FB2- treated rats. Changes in liver microsomal protein levels of p27, cyclin E and PCNA were similar to changes in gene expression. In contrast, cyclin D1 protein levels were elevated in rats treated with FB1 and, to a lesser extent, FB2. The data indicate that FB1 and FB2 can alter the expression of genes associated with the cell cycle, and indicate a need for a further understanding of the mechanistic basis of FB1 and FB2 toxicity.

Animals↗

[Gene c-Fos expression in brain of rats resistant and predisposed to emotional stress after intraperitoneal injection of the ACTH(4-10)analog--semax].

The effect of the ACTH(4-10) analog Semax on immediate early gene c-Fos expression was studied in Wistar rats with high and low resistance to emotional stress under the usual conditions and during psychoemotional loading. Fos-immunoreactive cells in the were counted automatically with the help of a computer. It was shown that under the usual conditions the intraperitoneal Semax injection induced immediate early gene c-Fos expression in the lateral septal region in rats predisposed to emotional stress and in the paraventricular hypothalamus in rats of both groups. Preliminary Semax injection decreased the stress-induced c-Fos expression in the paraventricular hypothalamus and medial septum in rats predisposed to emotional stress and tended to reduce the number of stress-induced c-Fos-immunopositive cells in the lateral septum and basolateral amygdala in both groups of animals. The obtained data suggest that Semax differently affects the immediate early c-Fos gene expression in the brain of rats resistant and predisposed to emotional stress and this effect reflects the antistressor properties of the regulatory peptide.

Adrenocorticotropic Hormone↗

Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer.

PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.

Adenoviridae↗

Characteristics of cells present in peritoneal fluids of mice injected intraperitoneally with Bordetella pertussis.

Peritoneal fluids obtained from mice after the intraperitoneal administration of Bordetella pertussis vaccine, heated vaccine, an extract of the organisms, killed Escherichia coli, or thioglycolate medium were examined in terms of total cells and percentage that adhered to glass cover slips during 2-h incubation period. All these substances were found to increase the number of leukocytes in peritoneal fluid within 1 to 2 days after the injection. This increase appeared to be due to an influx of macrophages and polymorphonuclear leukocytes with relative proportions at a given time dependent upon the material involved in the induction of the response. The initial increases after pertussis vaccine seemed to be due mainly to an influx of monomuclear cells, whereas with E. coli neutrophils constituted the major portion of the cell population. The percentage of peritoneal cells that attached to glass was also found to be markedly reduced in preparations obtained from mice after the injection of B. pertussis or E. coli. There appeared to be differences in persistence of this phenomenon, with preparations containing the histamine-sensitizing factor being the most active in affecting adherence properties. Thus these data would suggest that the action of B. pertussis on macrophages (or precursors) and neutrophils is not expressed in terms of suppression of emigration properties, as has been reported by others for lymphocytes, but is manifested in the alteration of glass-adherence characteristics. Within experimental limitations, it is believed that macrophages are possibly more involved in terms of altered function than are the polymorphonuclear cells.

Animals↗

Pharmacokinetics and tissue uptake of D-alpha-tocopherol in sheep following a single intraperitoneal injection.

D-alpha-Tocopherol in an emulsible base was administered i.p. to four groups of five sheep each at doses of 0, 1250, 2500, and 5000 IU. Blood was sampled regularly until slaughter at 7 d after administration. Plasma and tissue concentrations of D-alpha-tocopherol were measured by HPLC. Pharmacokinetic analysis of plasma concentrations, for the three tested doses, showed an absence of significant difference for lag time to absorption (.9 to 2.5 h), half-time of absorption (15 to 30 h), plasma half-life (31 to 42 h), and time of maximal concentration (18 to 31 h). In contrast, dose had a significant effect on area under the tocopherol plasma curve and on the maximal concentration. For both parameters, statistical evidence indicated nonlinearity for disposition of D-alpha-tocopherol, but without biological significance; by 7 d after dosing, amounts of residue of tocopherol were highest in the pancreas and adrenal glands (approximately 65 and 47 micrograms/g, respectively, for the 5000 IU dose) and lowest in neck muscle (approximately 4 micrograms/g for the 5000 IU dose). Kidney had an intermediate level of tocopherol. The intraperitoneal route is an efficient route for tocopherol administration in sheep.

Absorption↗

Amphetamine in rat brain after intraperitoneal injection of N-alkylated analogues.

Three N-alkylated analogues of amphetamine were administered intraperitoneally to male Sprague-Dawley rats and whole brain levels of amphetamine (AM) and the N-alkyl analogue were determined one hour after injection of the N-alkylated compounds. The drugs administered were the N-2-cyanoethyl-(I) (fenproporex), the N-3-chloropropyl-(II) (mefenorex) and the N-n-propyl-(III) derivatives of AM: the first two of these are used clinically as anorexiants, and the latter has been used extensively to study aspects of metabolism of AM-like compounds. Analysis of AM, I, II and III was performed using electron-capture gas chromatography with a capillary column after reaction of compounds with pentafluorobenzoyl chloride under aqueous conditions. In a second comparative study, equimolar doses (0.05 mMole/kg) of I or AM were administered intraperitoneally to the rats and brain levels determined after one hour. Results indicate extensive N-dealkylation occurs for compounds I, II and III in the rat.

Amphetamine↗

Effect of intraperitoneally injected fluoride on plasma calcium in suckling and adult rats.

Sodium fluoride 10, 20 or 40 mg/kg body weight was given intraperitoneally to rats (6-11 days old and 90-95 days old). Blood analyses showed an initial increase in plasma fluoride concentration. The subsequent decrease in fluoride was paralleled by a decrease in total plasma calcium. These plasma concentrations were normal at blood collection 4 days after fluoride injection. The baby rats differed from the older rats in that their initial plasma calcium was higher and that the drop in plasma calcium concentration was less pronounced than in the old rats. A diet low in calcium and phosphate enhanced the effects of fluoride on total plasma calcium. The data indicate that the effect of large doses of fluoride on lowering the plasma calcium level is modified by the calcium intake.

Aging↗

Studies of activated microglia and macrophages in lumbosacral spinal cord following an intraperitoneal injection of 6-aminonicotinamide into adult rats.

The anterior horns of the lumbosacral segment of the spinal cord in rats showed an extensive lesion following an intraperitoneal administration of 6-amino-nicotinamide (6-AN). Neuronal chromatolysis was observed in some of the large efferent neurons 1-7 days after the injection of 6-AN. The capability in their uptake of fluorogold and its retrograde transport was comparable to those in the normal rats. Small neurons presumably internuncial cells underwent degeneration. 8 weeks after 6-AN injection, all the surviving neurons appeared normal. 1 day after 6-AN injection microglial cells appeared activated as evidenced by the hypertrophy and expansion of their processes. A large number of macrophages were observed in the lesioned site 7 days after the administration of 6-AN. The activated microglia and macrophages showed intense immunoreactivity with the monoclonal antibody OX-42. The immunoreactivity declined with time so that by 4 weeks after the injection of 6-AN very weak immunoreactivity was seen on some very branched cells. A similar pattern of immunoreactivity was observed with the monoclonal antibodies OX-18 and OX-6. It was concluded from this study that neuronal chromatolysis and neuronal degeneration induced the expression of CR3 receptors (marked by OX-42) and MHC encoded antigens (marked by OX-18 and OX-6) in activated microglia and macrophages. With time the immunoreactivity decreased so that by 4 weeks after the administration of 6-AN only faint immunoreactivity was observed on some branched cells.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Aminonicotinamide↗