Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objectives of the present study were to determine the following: (a) the maximum tolerated dose (MTD) of melphalan using a 24-h continuous infusion; (b) the clinical toxicity; and (c) the pharmacokinetic characteristics of melphalan at each dose level. Twenty-one patients with refractory solid tumors were enrolled in the study. Melphalan, packaged in 3% sodium chloride, was administered i.v. over a 24-h period. Patients were assigned to one of three escalating dose levels of melphalan: (a) 20 mg/m2 (n = 5); (b) 30 mg/m2 (n = 7); and (c) 40 mg/m2 (n = 6). Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Melphalan concentrations in plasma were determined by high-performance liquid chromatography. Toxicity was evaluated after each course of chemotherapy. All of the patients were assessable for toxicity and pharmacokinetics, and 20 patients were assessable for response analysis. A total of 50 courses of melphalan was studied. The MTD was 30 mg/m2. The dose-limiting toxicity was neutropenia and thrombocytopenia. Hematotoxicity was reversible (nadir, 14-15 days; recovery, 3.5 and 12.5 days for 30 and 40 mg/m2, respectively), cumulative, and related to the administered dose and to the history of previous therapy. There were six episodes of neutropenic sepsis. Individual pharmacokinetic parameters were estimated using a Bayesian approach and linear elimination kinetics. Data were compatible with a one-compartment model. Relationships have been found between the area under the plasma concentration-time curve and doses and between Css and doses. Moreover, clearance, t1/2 elimination, and volume of distribution did not change statistically with dose, which suggests linear kinetics. Two partial responses were observed in patients with ovarian carcinoma or adenocarcinoma of unknown primary origin, and another patient had stabilization disease. In conclusion, melphalan MTD was determined to be 30 mg/m2 when administered as a 24-h infusion. Hematological toxicity was the dose-limiting toxicity. The most important nonhematological toxicity encountered was nausea and vomiting. The recommended dose for Phase II studies was 30 mg/m2.
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PMID:A phase I and pharmacokinetic study of melphalan using a 24-hour continuous infusion in patients with advanced malignancies. 1065 32

Since there is increasing evidence indicating nitric oxide [NO] would play a role in sepsis, we decided to investigate whether this multifaceted mediator is directly implicated in the process of bacterial translocation. A total of 48 rats received intraperitoneal either Zymosan A (group Z) for systemic inflammation production or sodium chloride solution (controls); they were then further subdivided into three groups of eight animals each, being given, through the tail vein: L-NAME (N-nitro-L-arginine] for inhibition of NO production; SNP (sodium nitroprusside) as NO donor; or sodium chloride as control. After 2 h, the mesenteric lymph node complex was excised, under sterile conditions, and, using standard bacteriological techniques, bacterial translocation was assessed as colony forming units per gram of tissue (CFU/g). Statistical evaluation of the bacteriological data revealed a significant increase of bacterial translocation in all rats subjected to systemic inflammation (group Z) versus controls (P = 0.01) Control rats that were subjected to L-NAME treatment exhibited a statistically significant increase (P = 0.001) in CFU/g compared to sodium chloride treated rats, while SNP treatment revealed no difference in relation to sodium chloride treated rats. Group Z rats, subjected to L-NAME treatment, similarly exhibited a statistically significant increase (P = 0.01) in CFU/g compared to sodium chloride treated rats, while SNP treatment led to a statistical increase of bacterial translocation in relation to sodium chloride treated rats (P = 0.05). The results of this study lead us to suggest that NO appears to participate in the process of bacterial translocation.
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PMID:The implication of nitric oxide in the process of bacterial translocation. 1081 26

The therapeutic efficacies of buforin II, indolicidin, and KFFKFFKFF were investigated in three rat models of septic shock: (i) rats injected intraperitoneally with 10 microg of Escherichia coli O111:B4 lipopolysaccharide, (ii) rats given an intraperitoneal injection of 2 x 10(10) CFU of Escherichia coli ATCC 25922, and (iii) rats in which intra-abdominal sepsis was induced via cecal ligation and single puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1 mg of buforin II per kg of body weight, 1 mg of indolicidin per kg, 1 mg of KFFKFFKFF per kg, and 20 mg of imipenem per kg. The main outcome measures were bacterial growth in abdominal exudate and plasma, endotoxin and tumor necrosis factor alpha (TNF-alpha) concentrations in plasma, and lethality. Treatment with all peptides resulted in significant reductions in plasma endotoxin and TNF-alpha concentrations compared with those resulting from the imipenem and saline treatments. On the other hand, imipenem treatment significantly reduced the levels of bacterial growth compared with the reductions achieved with the peptide and saline treatments. All compounds reduced the rates of death compared to that for the controls. Although the peptides demonstrated lower levels of antimicrobial activity than imipenem, they exhibited the dual properties of antimicrobial and antiendotoxin agents.
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PMID:Potential therapeutic role of cationic peptides in three experimental models of septic shock. 1206 65

The effect of sepsis on the rate of protein synthesis in the heart is poorly described. We have investigated changes in protein synthesis in the ventricles of the heart over time after cecal ligation and puncture (CLP) in rats in comparison with sham-operated and unoperated animals (ad libitum). All operated animals were starved from the time of surgery to the time of sacrifice. When operated animals were compared with ad libitum animals, ventricular weight and ventricular protein, and DNA and RNA contents were unchanged at 24 h, but were invariably reduced at 72 and 96 h. Fractional rate of protein synthesis (FSR), RNA activity, and cellular efficiency were reduced at 24 h and further reduced at 72 and 96 h. There were no differences, however, between septic and sham-operated animals. Eighteen hours after CLP, additional groups of rats were infused intravenously with 0.9% sodium chloride, parenteral nutrition (PN), or PN with glutamine, and were given a single dose of 400 microg recombinant human growth hormone (rhGH) or an equal volume of 0.9% sodium chloride. FSR was higher in animals given PN when compared with those given 0.9% sodium chloride only, and did not differ from FSR measured in unoperated animals. There was no additional benefit from the acute administration of either glutamine-enriched PN or rhGH. These results indicate that ventricular protein synthesis is markedly reduced by surgery and starvation, but that superimposed sepsis does not further influence these changes. PN can prevent the fall in cardiac protein synthesis associated with starvation, surgery, and sepsis, but neither glutamine nor rhGH produced any additional benefit.
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PMID:Influence of starvation, surgery, and sepsis on cardiac protein synthesis in rats: effects of parenteral nutrition, glutamine, and growth hormone. 1235 29

The efficacy of cationic peptides combined with betalactams was investigated in a peritonitis rat model. Intraabdominal sepsis was induced in adult Wistar rats via cecal ligation and single puncture. The study included eight drug-treated groups: each of them received intravenous polymyxin-E (1 mg/kg), buforin II (1 mg/kg), imipenem (20 mg/kg), amoxicillin-clavulanate (50 mg/kg), polymyxin-E (1 mg/kg) plus imipenem (20 mg/kg), or amoxicillin-clavulanate (50 mg/kg), and buforin II (1 mg/kg) plus imipenem (20 mg/kg), or amoxicillin-clavulanate (50 mg/kg). The study included an untreated control group that received intravenous isotonic sodium chloride solution. All compounds significantly reduced the lethality and the number of bacteria in abdominal fluid compared with saline treatment. Among compounds, imipenem showed the highest antimicrobial activity, while buforin II produced the highest reduction in plasma endotoxin and TNF-alpha levels. Overall, buforin II and imipenem association were the most effective therapeutic approach. Data presented here suggest the potential advantages of combining antimicrobial agents and compounds able to neutralize the biological effect of the endotoxin.
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PMID:Cationic peptides combined with betalactams reduce mortality from peritonitis in experimental rat model. 1244 22

From January through July of 2000, a study was conducted to evaluate clearance, immunologic responses, and potential shedding of Brucella abortus strain RB51 (SRB51) following ballistic or subcutaneous (SQ) vaccination of 7 mo old bison (Bison bison) calves. Ten bison calves were vaccinated SQ with 1.4 x 10(10) colony-forming units (CFU) of SRB51 and five calves were inoculated SQ with sterile 0.15 M sodium chloride. An additional 10 bison calves were ballistically inoculated in the rear leg musculature with 1 x 10(10) CFU of SRB51 and five calves were ballistically inoculated with an empty Biobullet. Serologic responses were monitored at 0, 2, 4, 6, 8, 12, 18, and 24 wk using the standard tube agglutination test and a dot-blot assay. Swabs from rectal, vaginal, nasal, and ocular mucosal surfaces, and blood were obtained for culture from all bison at 2, 4, 6, and 8 weeks post-inoculation to evaluate potential shedding by vaccinated bison or persistent septicemia. The superficial cervical lymph node was biopsied in eight ballistic and eight hand vaccinated bison at 6 or 12 wk to evaluate clearance of the vaccine strain from lymphatic tissues. Lymphocyte proliferative responses to irradiated SRB51 bacteria were evaluated in peripheral blood mononuclear cells (PBMC) at 4, 6, 8, 12, 18, and 24 wk after inoculation. Serum obtained from hand or ballistically vaccinated bison demonstrated antibody responses on the dot-blot assay that were greater than control bison (saline or empty Biobullet) at 2, 4, 6, and 8 wk after vaccination. Antibody titers of ballistically vaccinated bison did not differ (P > 0.05) from hand vaccinated bison at any sampling time. Blood samples obtained from all bison at 2, 4, 6 and 8 wk after vaccination were negative for SRB51. One colony of SRB51 was recovered from the vaginal swab of one ballistically vaccinated bison at 2 wk after vaccination. All other ocular, vaginal, nasal, and rectal swabs were culture negative for SRB51. Strain RB51 was recovered from superficial cervical lymph nodes of hand and ballistic vaccinated bison at 6 (two of four and two of four bison, respectively) and 12 wk (three of four and one of four bison, respectively). Serologic tests and bacterial culture techniques failed to demonstrate infection of nonvaccinated bison. Peripheral blood mononuclear cells obtained from hand vaccinated bison had greater (P < 0.05) proliferative responses to strain RB51 bacteria when compared to PBMC from nonvaccinated and ballistically vaccinated bison. Proliferative responses of PBMC from ballistically vaccinated bison did not differ (P > 0.05) at any sampling time from proliferative responses of PBMC from control bison. Serum alpha 1-acid glycoprotein concentrations, plasma fibrinogen, and total protein concentrations were not influenced by treatments. Ballistic delivery of SRB51 did not induce adverse effects or influence clearance of the vaccine strain. There were no proliferative responses of PBMC to SRB51 in bison ballistically vaccinated with SRB51; whereas bison inoculated with SRB51 by hand injection had greater proliferative responses than control or ballistically vaccinated bison. Our study suggests that ballistic delivery may require a greater dose of SRB51 to induce cell-mediated immune responses in bison that are comparable to those induced by hand injection, and that ballistic or hand delivery of 1 x 10(10) CFU of SRB51 is safe in bison calves.
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PMID:Immune responses of bison to ballistic or hand vaccination with Brucella abortus strain RB51. 1252 40

The present study was designed to investigate the antiendotoxin activity and therapeutic efficacy of sheep myeloid antimicrobial peptide (SMAP)-29, a cathelicidin-derived peptide. The in vitro ability of SMAP-29 to bind LPS from Escherichia coli 0111:B4 was determined using a sensitive limulus chromogenic assay. Two rat models of septic shock were performed: (1) rats were injected intraperitoneally with 1 mg E. coli 0111:B4 LPS and (2) intraabdominal sepsis was induced via cecal ligation and single puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1 mg/kg SMAP-29, 1 mg/kg polymyxin B or 20 mg/kg imipenem. The main outcome measures were: abdominal exudate and plasma bacterial growth, plasma endotoxin and tumor necrosis factor-alpha concentrations, and lethality. The in vitro study showed that SMAP-29 completely inhibited the LPS procoagulant activity at approximately 10 microM peptide concentration. The in vivo experiments showed that all compounds reduced the lethality when compared with control animals. SMAP-29 achieved a substantial decrease in endotoxin and tumor necrosis factor-alpha plasma concentrations when compared with imipenem and saline treatment and exhibited a slightly lower antimicrobial activity than imipenem. No statistically significant differences were noted between SMAP-29 and polymyxin B. SMAP-29, because of its double antiendotoxin and antimicrobial activities, could be an interesting compound for septic shock treatment.
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PMID:Cathelicidin peptide sheep myeloid antimicrobial peptide-29 prevents endotoxin-induced mortality in rat models of septic shock. 1471 31

The therapeutic efficacy of protegrin peptide IB-367 was investigated in three rat models of septic shock: (i) rats injected intraperitoneally with 1mg Escherichia coli 0111:B4 lipopolysaccharide, (ii) rats given an intraperitoneal injection of 2 X 10(10) CFU of E. coli ATCC 25922, and (iii) rats in which intra-abdominal sepsis was induced via cecal ligation and puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1mg/kg of IB-367, 60mg/kg piperacillin and 1mg/kg of IB-367 plus 60mg/kg piperacillin. The peptide demonstrated lower level of antimicrobial activity than piperacillin, nevertheless it exhibited the dual properties of antimicrobial and antiendotoxin agent. Finally IB-367 and piperacillin association showed to be the most effective therapeutic approach.
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PMID:Antiendotoxin activity of protegrin analog IB-367 alone or in combination with piperacillin in different animal models of septic shock. 1501 6

RNAIII-inhibiting peptide (RIP, YSPWTNF-NH2) is a quorum-sensing peptide inhibitor that prevents Staphylococcus aureus toxin production and biofilm formation. A mouse sepsis model was used to test the efficacy of RIP alone or in combination with conventional antibiotics in suppressing S. aureus-induced sepsis. Mice were injected intravenously with 3.0x10(6)CFU of S. aureus ATCC 25923 or with 3.0x10(6)CFU of S. aureus strain Smith diffuse. All animals were randomized to receive intravenously isotonic sodium chloride solution as a control, or 20 mg/kg RIP alone or combined with 20 mg/kg cefazolin, 10 mg/kg imipenem, or 10 mg/kg vancomycin immediately or 6 h after bacterial challenge. Main outcome measures were bacteremia and lethality. All compounds reduced lethality when compared to controls. Although, in general combined-treated groups had significant lower bacterial counts when associated to singly-treated groups only the combination between RIP and vancomycin with respect to cefazolin gave a statistically significant decrease in the lethality rate. Lowest lethality rates (10%) and bacteremia (<10(2)CFU/ml) were obtained when RIP was administered in combination with vancomycin. Because RIP can be synergistic with current antibiotic therapies and help to reduce S. aureus exotoxins production, it can be considered a promising agent to associate with antibiotics for further clinical research into treatment of sepsis.
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PMID:RNAIII-inhibiting peptide improves efficacy of clinically used antibiotics in a murine model of staphylococcal sepsis. 1562 27

To investigate the efficacy of pexiganan, a 22-residue magainin analog, alone and combined with betalactmas antibiotics in three experimental rat models of Gram-negative septic shock. Adult male Wistar rats were given (i) an intraperitoneal injection of 1 mg Escherichia coli 0111:B4 LPS; (ii) 2x10(10)CFU of E. coli ATCC 25922; and (iii) intra-abdominal sepsis induced via cecal ligation and puncture. For each model, all animals were randomized to receive intraperitoneally isotonic sodium chloride solution, 1 mg/kg pexiganan, 1 mg/kg polymyxin B, 20 mg/kg imipenem, 60 mg/kg piperacillin alone and combined with 1 mg/kg pexiganan. Each group included 15 animals. Lethality, bacterial growth in blood or intra-abdominal fluid, endotoxin and TNF-alpha concentrations in plasma. All compounds reduced the lethality when compared to controls. Piperacillin and imipenem significantly reduced the lethality and the number of E. coli in abdominal fluid compared with saline treatment. Pexiganan showed a slightly lower antimicrobial activity than betalactams even though it achieved a substantial higher decrease in endotoxin and TNF-alpha plasma concentrations than imipenem and piperacillin. No statistically significant differences were noted for antimicrobial and antiendotoxin activities between pexiganan and polymyxin B. Combination between pexiganan and betalactams showed to be the most effective treatment in reducing all variables measured. The use of a novel antimicrobial compound able to bind to LPS associated to potent antibiotics such as betalactams may become an important future consideration for sepsis treatment.
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PMID:Effects of pexiganan alone and combined with betalactams in experimental endotoxic shock. 1562 32


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