Granulocyte Colony-Stimulating Factor Ameliorates Endothelial Activation and Thrombotic Diathesis Biomarkers in a Murine Model of Hind Limb Ischemia.

Novel therapies in peripheral arterial disease, such as granulocyte colony-stimulating factor (GCSF) administration, might result in anti-atherosclerotic effects. In this study, we used 10-week-old male ApoE-/- mice, which were fed an atherosclerosis-inducing diet for four weeks. At the end of the four weeks, hind limb ischemia was induced through left femoral artery ligation, the atherosclerosis-inducing diet was discontinued, and a normal diet was initiated. Mice were then randomized into a control group (intramuscular 0.4 mL normal saline 0.9% for 7 days) and a group in which GCSF was administrated intramuscularly in the left hind limb for 7 days (100 mg/kg). In the GCSF group, but not in the control group, we observed significant reductions in the soluble adhesion molecules (vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1)), sE-Selectin, and plasminogen activator inhibitor (PAI)-1 when they were measured through ELISA on the 1st and the 28th days after hind limb ischemia induction. Therefore, GCSF administration in an atherosclerotic mouse model of hind limb ischemia led to decreases in the biomarkers associated with endothelial activation and thrombosis. These findings warrant further validation in future preclinical studies.

The effect of experimental periodontitis, experimental diabetes and their combination on the serum levels of adiponectin, leptin, IL-6, IL-18, MCP-1, RANTES and sICAM-1 in rats.

AIM: Periodontitis is often associated with diabetes mellitus and may be considered one of the chronic complications of this disease. Increasing evidence indicates that periodontal disease (gingivitis and periodontitis) has an adverse effect on glycemic control and participates in the pathophysiology of complications related to type 2 diabetes mellitus. Thus, this study aimed to evaluate the influence of obesity on clinical periodontal parameters of patients with type 2 diabetes mellitus with stage II or III periodontitis grade C after conventional periodontal treatment. METHODS: For this study, 36 patients, aged 25 to 65 years, were evaluated; 20 patients with type 2 diabetes mellitus and moderate to severe periodontitis (Non-Obese Group) and 16 patients with type 2 diabetes mellitus with obesity and moderate to severe periodontitis (Obese Group). These patients underwent conventional periodontal treatment and were evaluated using plaque index, probing depth, clinical attachment level, bleeding on probing and gingival crevicular fluid analysis, as well as laboratory tests of glycated hemoglobin, fasting glycemia, total cholesterol, and fractions of triglycerides. Periodontal and laboratory parameters were evaluated at baselineand six months. RESULTS: The results showed improvements in periodontal and clinical laboratory parameters(p less than 0.05) in the evaluated periods; however, the non-obese group presented significantly better results when compared to the obese group. CONCLUSION: It can be concluded that the presence of obesity may hinder the improvement of periodontal clinical parameters after conventional periodontal treatment in patients with diabetes mellitus and periodontitis.

Liver regeneration: immunohistochemical study of intrinsic hepatic innervation after partial hepatectomy in rats.

BACKGROUND: We examined the intrinsic hepatic innervation after partial hepatectomy (PH) in rats and the presence and pattern of neural sprouting in regenerating liver. METHODS: Male Wistar rats (age 9-13 weeks-w, weight 204-356 g), were submitted to two-thirds PH. Rats were sacrificed at postoperative days (d) 1, 3, 5, 7, at 2 and 4 w, and at 3 and 6 months (m) (6-7 animals/group, control group n = 4). Immunohistochemistry for the pan-neural marker protein gene product 9.5 (PGP9.5) and growth-associated protein 43 (GAP-43), a marker of regenerating nerve axons, was performed on tissue sections from the R1 lobe of the regenerating liver. Portal tracts (PTs) with immunoreactive fibers were counted in each section and computer-assisted morphometric analysis (Image Pro Plus) was used to measure nerve fiber density (number of immuno-positive nerve fibers/mm2 (40x)). RESULTS: Immunoreactivity for PGP9.5 was positive in all groups. The number of PGP9.5 (+) nerve fibers decreased from 0.32 +/- 0.12 (control group) to 0.18 +/- 0.09 (1d post-PH group), and gradually increased reaching pre-PH levels at 6 m (0.3 +/- 0.01). In contrast, immunoreactivity for GAP-43 was observed at 5d post-PH, and GAP-43 (+) PTs percentage increased thereafter with a peak at 3 m post-PH. GAP-43 (+) nerve fiber density increased gradually from 5d (0.05 +/- 0.06) with a peak at 3 m post-PH (0.21 +/- 0.027). At 6 m post-PH, immunoreactivity for GAP-43 was not detectable. CONCLUSIONS: Following PH in rats: 1) nerve fiber density in portal tracts decreases temporarily, and 2) neural sprouting in the regenerating liver lobes starts at 5d, reaches peak levels at 3 m and disappears at 6 m post-PH, indicating that the increase in hepatic mass after PH provides an adequate stimulus for the sprouting process.

Effects of direct infusion of bone marrow-derived progenitor cells and indirect mobilization of hematopoietic progenitor cells on atherosclerotic plaque and inflammatory process in atherosclerosis.

BACKGROUND: We sought to investigate the effects of lin-/sca+ cells, endothelial progenitor cells (EPCs) and granulocyte colony-stimulating factor (G-CSF) administration on atherosclerotic plaque progression. METHODS: Apolipoprotein E-deficient (apoE(-/-)) mice were splenectomized and treated with high-cholesterol diet for 6 weeks in order to induce atherosclerotic plaque development. Bone marrow-derived Lin-/sca-1+ cells were isolated and further cultured to early growth endothelial progenitor cells (EPCs). Mice were divided in four groups (n=10/group) and received two intravenous injections of 5×10(5) cells (lin-/sca-1+ or EPCs), or granulocyte colony-stimulating factor (G-CSF 100 µg/kg/day) for 7 days or normal saline. The same interventions were administered to animals, which had undergone unilateral hind-limb ischemia. Effects on inflammatory parameters, lesion severity, and atherosclerotic plaque area size were assessed. RESULTS: The administration of both G-CSF and progenitor cells significantly decreased the levels of IL-6, 6 weeks after the initiation of treatment. Atherosclerotic lesion area was reduced by G-CSF (atherosclerotic plaque area percentage 22.94%±3.68, p=0.001), by lin-/sca-1+ (23.27%±5.98, p=0.002) and cultured EPCs (23.16±4.86%, p=0.002) compared to control (32.75%±7.05). In the atherosclerotic mice that underwent limb ischemia, the atherosclerotic plaque area, was not significantly different between the treatment groups cultured EPCs-treated mice and the control group (p=NS, for all). CONCLUSIONS: Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells decreased plaque progression and levels of inflammatory molecules in a murine model of atherosclerosis. Treatment with G-CSF, lin-/sca-1+, or EPCs may exert beneficial effects on vascular inflammation and atherosclerotic plaque progression. However, the effects are diminished in an ischemic setting.

Infusion of lin-/sca-1+ and endothelial progenitor cells improves proinflammatory and oxidative stress markers in atherosclerotic mice.

BACKGROUND: The effects of direct infusion or indirect mobilization of progenitor cells on atherosclerotic plaque development and progression are not clear. We sought to investigate the effects of hematopoietic progenitors lineage negative/stem cell antigen-1 positive (lin-/sca-1+) cells, endothelial progenitor cells and G-CSF administration on the inflammatory and oxidative component of atherosclerosis. METHODS: Splenectomized ApoE(-/-) C57BL/6J mice (6-8 weeks of age) fed with a high-fat, cholesterol-rich diet for 6 weeks, were divided in four groups (n=10/group) and received two intravenous injections of 5 × 10(5) cells (lin-/sca-1+ or EPCs), or granulocyte colony-stimulating factor (G-CSF 100 µg/kg/day) for 7 days or normal saline. sVCAM-1 (Vascular cell adhesion protein 1), sICAM-1 (soluble intercellular adhesion molecule-1), sE-Selectin, Metalloproteinase 9 (MMP-9), Plasminogen activator inhibitor (PAI-1), Interleukin 6 (IL-6), oxidized LDL (ox-LDL) levels and lipid PEROX were evaluated at the day of the first infusion, 7 days later and 6 weeks post-treatment with ELISA. RESULTS: The administration of both G-CSF and progenitor cells significantly decreased the levels of sICAM-1, sVCAM-1,sE-Selectin, IL-6, ox-LDL and lipid Perox 6 weeks after the initiation of treatment. No significant effects of lin-/sca-1+ cells, EPCs and G-CSF on PAI-1 and MMP-9 levels were observed. The effects of all treatments on the levels of pro-inflammatory molecules and oxidative stress parameters 7 days post-treatment were not significant. Interestingly, the levels of sICAM-1and sE-selectin were increased 7 days post-treatment. CONCLUSIONS: Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells significantly decreased the levels of proinflammatory molecules and oxidative stress parameters in a murine model of atherosclerosis. The principal novelty of this work is that treatment with hematopoietic progenitors, EPCs or G-CSF may exert beneficial effects on vascular inflammation and atherosclerotic plaque development.

The effect of autologous platelet-rich plasma on bronchial stump tissue granulation after pneumonectomy: experimental study.

Objectives. Recent advances in perioperative management, antibiotics, and surgical materials, including mechanical staplers, have decreased the operative risk of pulmonary resection. However, bronchopleural fistula can still occur in some instances, the occurrence often being lethal. This study investigated whether platelet-rich plasma (PRP) promotes granulation of the bronchial stump after pneumonectomy. Methods. Ten pigs were randomized into two groups: (A) control or non-PRP group (pneumonectomy) and (B) PRP group (pneumonectomy and PRP application). PRP was obtained by spinning down the animal's own blood and collecting the buffy coat containing platelets and white blood cells. Results. Increased platelet concentration triggered the healing process. The percentage of granulation tissue formed at the stumps was significantly higher in the PRP group of animals. This observation was confirmed when statistical analysis using Mann-Whitney U test was performed (P = 0.0268). Conclusions. PRP is easily produced with minimal basic equipment and is useful in accelerating granulation of the bronchial stump, although the timing and optimum number of applications in humans require further study. Autologous PRP is a safe, feasible, and reliable new healing promoter with potential therapeutic effects.

The influence of simvastatin in rats mandible and femur bone mass under Freund's adjuvant arthritis.

OBJECTIVES. Complete Freund's Adjuvant (CFA)-induced arthritis in rats has been used widely as a model of rodent arthropathy and polyarthritis followed by osteoporosis, decreased bone formation and increased bone formation. Osteoporosis is characterized by rapid reduce of bone mass affecting more than 100 million people worldwide. Periodontitis a chronic inflammatory, of multifactorian origin disease has been associated with general osteoporosis. Protective bone-specific anabolic and antiresorptive effects of HMG-CoA reductase inhibitors have also been evaluated in normal and osteoporotic bone. AIM. The aim of the study was to investigate mandible and femur bone density in Freund's adjuvant induced arthritis rats under the influence of simvastatin. METHODS. Three groups (A, B, C) of 7 Wistar male rats each aged 3 months, (292±48.38 g) were used. A control. Group B and C subjected experimental arthritis via complete Freund's adjuvant injected in right paw. Group C was treated with simvastatin 0.5 mg/kg/daily po 14 days. Femur, mandible were isolated and sizes parameters, biochemical serum findings and BMD were estimated. RESULTS. CFA established by paw diameter, adrenals and spleen weight increase and thymus weight decrease, while biochemical serum findings were also affected. Reduced femur, mandible weight and general bone mass parameters BMD evaluated via DEXA occurred and restored under simvastatin treatment. CONCLUSIONS. CFA induced mandible and femur injuries are repaired by ssimvatatin treatment that could be therapeutically useful.

Histometric assessment of the effect of diabetes mellitus on experimentally induced periodontitis in rats.

OBJECTIVE: The aim of this interventional animal study was to assess histologically the effect of experimental diabetes in rats with experimental periodontitis in terms of alveolar bone loss and the effect of experimental periodontitis on glucose levels in diabetes. MATERIALS AND METHODS: Forty-seven Wistar rats were studied: 12 healthy controls (C), 10 with experimental diabetes (D), 12 with experimental diabetes and experimental periodontitis (DP) and 13 with experimental periodontitis (P). Diabetes was induced by streptozotocin injection and periodontitis was induced at the right second maxillary molar by ligation. Serum glucose levels were measured at specific time points. Sixty-one days after ligation, the rats were sacrificed. Histometric analysis assessed alveolar crest level. For ligated groups, alveolar bone loss was expressed as the difference in alveolar crest level between right and left maxillary molars. RESULTS: Diabetes alone did not statistically significantly affect alveolar crest level. The combination of diabetes and periodontitis caused greater alveolar bone loss (946.1 +/- 719.9 microm) than periodontitis alone (639.7 +/- 294.2 microm); however, the difference did not reach statistical significance. Periodontitis did not significantly increase glucose levels in diabetic rats. The average glucose levels were 545.4 (499 - 563) and 504.5 (445 - 560) mg/dL for diabetic and diabetic ligated rats, respectively. CONCLUSION: Within its limits, this study demonstrated that the severity of alveolar bone loss in periodontitis was not significantly aggravated by diabetes and the serum glucose levels in diabetes were not affected by periodontitis.

Intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 at the early stages of atherosclerosis in a rat model.

BACKGROUND: Members of the immunoglobulin superfamily of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM-1) and intercellular cell adhesion molecule (ICAM-1), participate in leukocyte adhesion to the endothelium and play an important role in all stages of atherosclerosis. The aim of the study was to examine the expression of VCAM-1 and ICAM-1 in the aorta of rats at the early stages of atherosclerosis and the correlation with their plasma concentrations. MATERIALS AND METHODS: Male rats (n=44), 10 weeks of age, were divided in 4 groups. Groups A and C (n=12) were fed with rich cholesterol diet for 12 and 16 weeks, respectively. Group B (regression group, n=12) was fed for the first 12 weeks with rich cholesterol diet and for another 4 weeks with normal diet. Group D (control group, n=8) was fed with normal diet for 12 weeks. We measured the serum lipid profile, the concentration of soluble ICAM-1 and the immunohistochemical expression of ICAM-1 and VCAM-1 in the endothelium, media and vasa vasorum of the aorta. RESULTS: There were significant differences (p<0.05) in the expression of ICAM-1 between group C (maximum time of rich cholesterol diet) and all other groups in the 3 groups of the aorta studied. There was regression of the expression of ICAM-1 in group B and significant differences (p<0.05) between group B and all the other groups, except group D in the expression of ICAM-1. There were no significant differences in the expression of VCAM-1 between any groups. The serum concentration of soluble ICAM-1 positively correlated with the expression of the molecule in the vasa vasorum (r=0.35, p<0.05) and fibroblasts/smooth muscular cells (r=0.34, p<0.05) of the aorta. CONCLUSION: A cholesterol diet plays a role in the expression of ICAM-1 but not in that of VCAM-1 in the rat aorta. The expression of ICAM-1 in the aorta regresses after the withdrawal of a cholesterol-rich diet. Soluble ICAM-1 is a reliable measure of ICAM-1 expression in the aorta, vasa vasorum and fibroblasts/smooth muscle cells.

Adiponectin and interleukin-6 levels in insulin-treated diabetic rats with experimental periodontitis.

The aim of the study was to compare the serum levels of adiponectin and interleukin-6 (IL-6) in insulin-treated diabetic rats with or without periodontitis. Forty male Wistar rats were randomly divided into 2 groups (20 rats each): a) insulin-treated diabetic group (control, DI) and b) insulin-treated diabetic periodontitis group (test, DIP). Diabetes was induced, and insulin treatment was initiated on day 5. On day 16, periodontitis was induced in the DIP group. All rats were euthanized on day 77. Adiponectin and IL-6 were assessed on days 16 and 77. At the end of the experiment, 14 and 11 rats survived in the DI and DIP groups, respectively. Adiponectin levels were statistically significantly higher at the end of the experiment compared with levels on day 16 in the periodontitis group (p < 0.05), but not in the control group. At the end of the experiment, adiponectin levels were statistically significantly higher in the periodontitis group compared with the control group (p < 0.05). Within-group and between-group comparisons of IL-6 levels showed no statistically significant difference. In conclusion, serum adiponectin was increased in insulin-treated diabetic rats with periodontitis in comparison with insulin-treated diabetic rats, while IL-6 levels did not differ between groups.

Adiponectin and interleukin-6 levels in insulin-treated diabetic rats with experimental periodontitis

The aim of the study was to compare the serum levels of adiponectin and interleukin-6 (IL-6) in insulin-treated diabetic rats with or without periodontitis. Forty male Wistar rats were randomly divided into 2 groups (20 rats each): a) insulin-treated diabetic group (control, DI) and b) insulin-treated diabetic periodontitis group (test, DIP). Diabetes was induced, and insulin treatment was initiated on day 5. On day 16, periodontitis was induced in the DIP group. All rats were euthanized on day 77. Adiponectin and IL-6 were assessed on days 16 and 77. At the end of the experiment, 14 and 11 rats survived in the DI and DIP groups, respectively. Adiponectin levels were statistically significantly higher at the end of the experiment compared with levels on day 16 in the periodontitis group (p < 0.05), but not in the control group. At the end of the experiment, adiponectin levels were statistically significantly higher in the periodontitis group compared with the control group (p < 0.05). Within-group and between-group comparisons of IL-6 levels showed no statistically significant difference. In conclusion, serum adiponectin was increased in insulin-treated diabetic rats with periodontitis in comparison with insulin-treated diabetic rats, while IL-6 levels did not differ between groups.

Pharmacokinetics of intravitreal bevacizumab (Avastin®) in rabbits.

PURPOSE: To describe the pharmacokinetics of intravitreal bevacizumab (Avastin®) in rabbits. METHODS: The right eye of 20 rabbits was injected intravitreally with 1.25 mg/0.05 mL bevacizumab. Both eyes of four rabbits each time were enucleated at days 1, 3, 8, 15, and 29. Bevacizumab concentrations were measured in serum, aqueous humor, and vitreous. RESULTS: Maximum vitreous (406.25 µg/mL) and aqueous humor (5.83 µg/mL) concentrations of bevacizumab in the right eye were measured at day 1. Serum bevacizumab concentration peaked at day 8 (0.413 µg/mL) and declined to 0.032 µg/mL at 4 weeks. Half-life values in right vitreous, right aqueous humor, and serum were 6.61, 6.51, and 5.87 days, respectively. Concentration of bevacizumab in the vitreous of the noninjected eye peaked at day 8 (0.335 ng/mL) and declined to 0.218 ng/mL at 4 weeks. In the aqueous humor of the noninjected eye, maximum concentration of bevacizumab was achieved at day 8 (1.6125 ng/mL) and declined (to 0.11 ng/mL) at 4 weeks. CONCLUSION: The vitreous half-life of 1.25 mg/0.05 mL intravitreal bevacizumab was 6.61 days in this rabbit model. Maximum concentrations of bevacizumab were reached at day 1 in both vitreous and aqueous humor of the right eye and at day 8 in the serum. Very low concentrations of bevacizumab were measured in the fellow noninjected eye.

Comparison of fibrate, ezetimibe, low- and high-dose statin therapy for the dyslipidemia of the metabolic syndrome in a mouse model.

BACKGROUND AND AIM: The treatment-of-choice for the optimal management of the dyslipidemia of the metabolic syndrome (MetS) is not clearly defined. We compared the efficacy of 4 drug regimes for the management of this dyslipidemia in a mouse model. MATERIALS AND METHODS: A total of 60 C57Bl6 mice comprised the study group. The first 10 received standard mouse food for the whole experiment (control group). The remaining 50 mice received atherogenic diet for 14 weeks until the development of the MetS. The mice were then divided into 5 groups: the 1st group continued receiving atherogenic diet, while the other 4 groups received atherogenic diet plus ezetimibe (10 mg/kg per day), fenofibrate (100 mg/kg per day), low-dose atorvastatin (10 mg/kg per day), or high-dose (40 mg/kg per day) atorvastatin, respectively, for another 8 weeks. RESULTS: High-dose atorvastatin treatment achieved the best lipid profile compared with low-dose atorvastatin, ezetimibe, and fibrate therapy. The lipid profile of mice receiving atherogenic diet plus high-dose atorvastatin treatment was similar with mice on regular chow. CONCLUSIONS: High-dose atorvastatin treatment resulted in optimization of the lipid profile in the presence of a high-fat atherogenic diet in a mouse model. Our results suggest that high-dose atorvastatin treatment may be the optimal treatment option for the dyslipidemia associated with MetS. Nevertheless, verification of these results in humans is required before any definite conclusions can be drawn.

Serum leptin, adiponectin and tumor necrosis factor-α in hyperlipidemic rats with/without concomitant diabetes mellitus.

We compared the lipid profiles and serum levels of leptin, adiponectin and tumor necrosis factor-α (TNF-α) in rats with/without hyperlipidemia and with/without concomitant diabetes mellitus. Forty 10-wk-old male Wistar rats were divided into four groups. Groups A and C received standard food for 12 wks. Groups B and D received a high-fat diet enriched with 2% additional cholesterol. Moreover, insulin-deficient (type I) diabetes mellitus was induced in rats in groups C and D with intraperitoneal injections of streptozotocin. Fasting serum leptin levels were decreased in diabetic groups (groups C and D) compared with controls. Fasting serum adiponectin levels were decreased in groups C and D compared with group A. Serum TNF-α levels were augmented in groups B and D, those fed with an atherogenic diet. By contrast, TNF-α levels were decreased in group C. Our data suggest that serum leptin, adiponectin and TNF-α levels may serve as markers of obesity and type I diabetes mellitus.

A surgical rat model of sleeve gastrectomy with staple technique: long-term weight loss results.

BACKGROUND: Sleeve gastrectomy (SG) is one of the surgical procedures applied for treating morbid obesity consisting of removing the gastric fundus and transforming the stomach into a narrow gastric tube. The aim of this experimental study is to create a functional model of SG and to present the long-term weight loss results. METHODS: Twenty adult Wistar rats were fed with high fat diet for 12 weeks before being divided randomly in two groups of ten rats each. One group underwent SG performed with the use of staples, and the other group underwent a sham operation (control group). The animals' weight was evaluated weekly for 15 weeks after the operation. RESULTS: All animals survived throughout the experiment. After the operation both groups started to lose weight with maximum weight loss on the seventh postoperative day (POD) for the sham-operated group and on the 15th POD for the SG group. Thereafter, both groups started to regain weight but with different rates. By the fourth postoperative week (POW), the average weight of the sham group did not differ statistically significantly compared to the preoperative weight, while after the eighth POW, rats' average weight was statistically significantly increased compared to the preoperative value. On the other hand, average weight of the SG group was lower postoperatively until the end of the study compared to the preoperative average weight. CONCLUSION: We have created a surgical rat model of experimental SG model, enabling the further study of biochemical and hormonal parameters.

Effects of nimodipine administration on small bowel mucosa under conditions of laparotomy and consequent 48-hour starvation in a rat model.

BACKGROUND/AIMS: The combination of starvation and surgical trauma induces disturbances to the intestinal mucosal structure and function, as well as changes in mucosal barrier function in the rat small bowel. The aim of the present study was to evaluate the effects of nimodipine administration, on intestinal mucosal structural changes and enterocyte apoptosis, following laparotomy and subsequent postsurgical starvation (PSS) in the rat. METHODS: Thirty Wistar rats were divided into two experimental groups: A: Control group (n=15), where the animal models underwent laparotomy and consequent 48-hours PSS and B: Nimodipine group (n=15), where the rats underwent laparotomy, followed by intraperitoneal nimodipine administration and consequent 48-hour (h) PSS. Small bowel mucosal structural changes and enterocyte epithelial apoptosis were determined 48 h following laparotomy. RESULTS: Nimodipine rats (group B) demonstrated a significant decrease in small bowel villous height in jejunum (p=0.016) and ileum (p=0.002). Similarly, crypt depth decreased in jejunum (p<0.001) and ileum (p<0.001). Nimodipine group exhibited significantly higher apoptotic index in ileum compared to control rats (p=0.006). CONCLUSION: Nimodipine did not protect the intestinal mucosa from damage caused by surgery and consequent PSS and had obvious damaging effects on intestinal mucosa with derangements to its structure and subsequent mucosal atrophy.

Colistin offers prolonged survival in experimental infection by multidrug-resistant Acinetobacter baumannii: the significance of co-administration of rifampicin.

The effect of colistin on bacterial eradication and survival was tested in experimental infection by multidrug-resistant Acinetobacter baumannii. The thigh infection model was applied in 86 neutropenic Wistar rats. Six rats were used for the induction of neutropenia and for the selection of the dose regimen of colistin; the remainder was equally divided into four groups: A, controls; B, rifampicin; C, colistin; and D, both agents. Therapy was administered 5 h after bacterial challenge; 5mg/kg of rifampicin was administered intravenously and 3mg/kg of colistin intramuscularly. Survival was recorded in 10 animals of each group. The remaining 10 rats per group were killed 4h after therapy; blood and tissue samples were sampled. Median survival of animals of groups A, B, C and D was 2.00, 2.50, 4.00 and 4.00 days, respectively (P=0.0048 between A and C and P=0.0012 between A and D. Mortality rates after 6 days of follow-up were 100, 100, 100 and 70%, respectively (P=0.018 between groups). Statistically significant decreases of bacteria were found in blood, liver, lung and spleen of group B compared with A; in lung of group C compared with A; and in blood and liver of group D compared with A. Colistin was effective in prolonging survival in an experimental thigh infection by multidrug-resistant A. baumannii in neutropenic rats. Its activity was enhanced after co-administration with rifampicin. These results mandate the application of colistin in the event of infections by multidrug-resistant pathogens and the need for its co-administration with rifampicin.