Thirteen-week dietary intake of rapeseed oil or soybean oil as the only dietary fat in Wistar Kyoto rats-change in blood pressure.

Wistar Kyoto (WKY) rats were fed a diet containing 10% rapeseed (canola) oil or soybean oil as the only dietary fat for 13 weeks. From week 5 of feeding, systolic blood pressure of the canola oil group became higher than that of the soybean oil group. The 13-week canola oil intake increased plasma levels of Na(+) and lipids, and decreased the level of K(+) compared to those in the soybean oil group. The canola oil group also showed a high density of neutrophils and a low density of platelets compared to the soybean oil group. Moreover, the activities of catalase and superoxide dismutase in the hepatic cytosol were depressed in the canola oil group. The mechanisms for the higher blood pressure are unclear. However, an increase in body fluid via activation of Na(+) pump or Na(+), K(+)-ATPase and/or a blunt endothelium-dependent vasodilation by increased superoxide might have relevance to the elevated blood pressure. The increased plasma lipids and the changes in the densities of platelets and neutrophils appear not to be critical in WKY rats. However, these would tend to promote peripheral vascular lesions in the strains, such as spontaneously hypertensive rats and stroke-prone spontaneously hypertensive rats, which are prone to present atheroscrelotic vascular injury.

Immunomodulatory activity of Withania somnifera.

Administration of an extract from the powdered root of the plant Withania somnifera was found to stimulate immunological activity in Babl/c mice. Treatment with five doses of Withania root extract (20 mg/dose/animal; i.p.) was found to enhance the total WBC count (17125 cells/mm(3)) on 10th day. Bone marrow cellularity (27x10(6) cells/femur) as well as alpha-esterase positive cell number (1800/4000 cells) also increased significantly (P<0.001) after the administration of Withania extract. Treatment with Withania extract along with the antigen (SRBC) produced an enhancement in the circulating antibody titre and the number of plaque forming cells (PFC) in the spleen. Maximum number of PFC (985 PFC/10(6) spleen cells) was obtained on the fourth day. Withania extract inhibited delayed type hypersentivity reaction in mice (Mantoux test). Administration of Withania extract also showed an enhancement in phagocytic activity of peritoneal macrophages (76.5 pigmented cells/200) when compared to control (31.5/200 cells) in mice. These results confirm the immunomodulatory activity of W. somnifera extract, which is a known immunomodulator in indigenous medicine.

Effect of methanolic extract of Enicostemma littorale on Dalton's ascitic lymphoma.

The antitumour activity of methanolic extract of Enicostemma littorale (MEL) has been evaluated against Dalton's ascitic lymphoma (DAL) in swiss albino mice. A significant enhancement of mean survival time of MEL treated tumour bearing mice was found with respect to control group. MEL treatment was found to enhance peritoneal cell counts. When these MEL treated animals underwent i.p. inoculation with DAL cells, tumour cell growth was found to be inhibited. After 14 days of inoculation, MEL is able to reverse the changes in the haemotological parameters, protein and PCV consequent to tumour inoculation.

Effects of high nitrate intake in rats.

The purpose of this study was to determine the effects of administration of high dose nitrate in drinking water on weight gain, hematological parameters and osmotic fragility in rats. We compared these parameters in 40 rats divided into four groups (one control and three treatment groups). Control animals drank filtered tap water containing a maximum of 10 mg/l nitrate while the treatment groups drank 100 mg/l, 200 mg/l and 400 mg/l nitrate-containing water ad libitum for 60 days. Animals in the treatment groups gained less weight than the control group and the differences between the control and treatment groups were statistically significant (p < 0.05). At the concentration of 100 mg/l nitrate, platelet counts and hemoglobin levels were significantly increased compared with the control group (p < 0.05). At the concentration of 200 mg/l nitrate, erythrocyte counts, hemoglobin and hematocrit levels were significantly increased compared with the control group (p < 0.05). At the concentration of 400 mg/l nitrate, platelet counts were decreased significantly when compared with the first two treatment groups (p < 0.05). There were statistically significant differences in osmotic fragility ratios between treatment groups and the control group (p < 0.05). We concluded that high nitrate intake in drinking water decreases weight gain, affects hematological parameters by inducing bone marrow activity at low doses and inhibiting it at high doses, and increases erythrocyte osmotic fragility.

Acute parietal and chief cell changes induced by a lethal dose of lipopolysaccharide in mouse stomach before thrombus formation.

The common lipopolysaccharide (LPS)-induced gastric lesions, such as erosions or ulcers, have been investigated in depth. Little is known, however, about the acute gastric lesions following a high dose of LPS. In a time-course study, ICR female mice were given a high subcutaneous dose of LPS (50 mg/kg). Mice were sacrificed at 4, 6, 12, and 24 hours after dosing and were assessed histopathologically for acute gastric lesions. The major gastric changes were seen in the fundic region and included vacuolar degeneration of parietal cells and apoptosis of chief cells. The vacuole in parietal cells was apparent as early as 4 hours postinjection (PI), and apoptosis of chief cells was apparent at 12 hours PI. Thrombus formation, in contrast, was not seen until 24 hours PI. No erosion, ulcer, or hemorrhage was seen in any gastric region in any of the treated animals at 24 hours PI. These results indicate that a subcutaneous high dose of LPS in mice causes vacuolar degeneration of parietal cells and apoptosis of chief cells before thrombus formation or subsequent ulcerative lesions.

Modulation of endocrine systems and food intake by green tea epigallocatechin gallate.

Green tea polyphenols, especially the catechin, (-)-epigallocatechin gallate (EGCG), have been proposed as a cancer chemopreventative based on a variety of laboratory studies. For clear assessment of the possible physiological effects of green tea consumption, we injected pure green tea catechins ip into rats and studied their acute effects on endocrine systems. We found that EGCG, but not related catechins, significantly reduced food intake; body weight; blood levels of testosterone, estradiol, leptin, insulin, insulin-like growth factor I, LH, glucose, cholesterol, and triglyceride; as well as growth of the prostate, uterus, and ovary. Similar effects were observed in lean and obese male Zucker rats, suggesting that the effect of EGCG was independent of an intact leptin receptor. EGCG may interact specifically with a component of a leptin-independent appetite control pathway. Endocrine changes induced by parenteral administration of EGCG may relate to the observed growth inhibition and regression of human prostate and breast tumors in athymic mice treated with EGCG as well as play a role in the mechanism by which EGCG inhibits cancer initiation and promotion in various animal models of cancer.

Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone.

Thirty-five patients with myelodysplastic syndrome (MDS) were registered on protocol MDS 96-02 and were receiving continuous therapy with pentoxifylline 800 mg 3 times a day and ciprofloxacin 500 mg twice a day by mouth; dexamethasone was added to the regimen for the partial responders and the nonresponders after 12 weeks at a dose of 4 mg by mouth every morning for 4 weeks. Amifostine was administered intravenously 3 times a week at 3 dose levels (200 mg/M(2), 300 mg/M(2), and 400 mg/M(2)) to cohorts of 10 patients each. Therapy has been continued for 1 year in responders. Twenty-nine have completed at least 12 weeks of therapy and are available for response evaluation. Of the 21 men and 8 women (median age, 67 years), 20 had refractory anemia (RA), 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). Five had secondary MDS. No differences were noted in response rates among the 3 dose levels. Seven patients did not respond at all, and 22 showed an improvement in cytopenias (76%). Three had a triple lineage response, 10 had a double lineage response, and 9 had a single lineage response (8 of 9 in absolute neutrophil count [ANC] and 1 had more than a 50% reduction in packed red blood cell transfusions). Fifteen patients responded only after the addition of dexamethasone, whereas 7 responded before. When examined by lineage, 19 of 22 showed improved ANC, 11 of 22 demonstrated more than 50% reduction in blood transfusions, improved Hb levels, or both, and 7 of 22 showed improvement in platelet counts. Interestingly, the responses were frequently slow to appear, and continued improvement in counts was seen up to 12 months of therapy and beyond. This study supports the feasibility of treating patients with MDS with the unique approach of cytoprotection and anticytokine therapies as well as the principle that prolonged commitment to treatment is desirable when noncytotoxic agents are administered. (Blood. 2000;95:1580-1587)

Adverse effects of reduced-dose d-penicillamine in children with mild-to-moderate lead poisoning.

BACKGROUND: Oral chelation therapy with d-penicillamine (d-PCN) has been proven to be effective in the treatment of mild-to-moderate lead poisoning. However, d-PCN is associated with a relatively high incidence of adverse effects when given in the standard dose of 25-30 mg/kg/d. Lower doses of d-PCN may reduce the rate of adverse effects without a significant reduction in the drug's efficacy. OBJECTIVE: To examine the incidence of rash, white blood cell and platelet count depression, and abnormal urinalysis with d-PCN when given in a dose of 15 mg/kg/d to children with blood lead concentrations <40 microg/dL. METHODS: Retrospective analysis of a clinical treatment course of children who received d-PCN during 1996 in the Lead and Toxicology Clinic of Children's Hospital, Boston. All children were treated under a reduced-dose d-PCN chelation protocol. RESULTS: During the study period, 55 children (mean age 37.4 mo) received 66 courses of d-PCN. Mean blood lead concentration before chelation was 24 microg/dL (range 15-37), with a corresponding erythrocyte protoporphyrin concentration of 42 microg/dL. After 77 days of treatment with d-PCN, blood lead concentration was reduced to mean 16 microg/dL (mean fall 35%; p = 0.005) and erythrocyte protoporphyrin was reduced to 28 microg/dL (p = 0.009). During chelation therapy, the white blood cell count fell below 5,000/mm3 in seven cases (9.7%); there were no episodes of platelet counts falling below 150,000/mm3. No cases of abnormal urinalysis were reported; three episodes of rash (4.5%) were recorded. The only patients prematurely terminated from therapy were those who developed rash; in all three cases, drug eruption was an isolated occurrence, which resolved within 48 hours of diphenhydramine therapy. All adverse effects were transient and resolved during or immediately after chelation therapy. CONCLUSIONS: Reduced-dose d-PCN appears to maintain efficacy at reducing blood lead concentrations. Reduced-dose d-PCN also appears to be associated with a rate of adverse effects lower than previously reported; observed adverse effects appear to be benign and transient.

Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression.

Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells. This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression. Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 ((60)Co) gamma-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 microg/kg/d (n = 4), or 50 microg/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10). Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 microg/kg/d, in a daily schedule (n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet < 20,000/microL) versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophils (ANC to < 500/microL) and platelets (PLT < 20,000/microL) were significantly enhanced in the MPO-treated cohorts versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression.

The dose of granulocyte-colony-stimulating factor after chemopriming treatment does not influence apheresis yield of progenitor cells: a retrospective study of 91 cases.

BACKGROUND: The optimal dose of post-chemotherapy granulocyte-colony-stimulating factor (G-CSF) administration before peripheral blood progenitor cell (PBPC) collection has not been determined as yet, although 5 microg per kg per day has been recommended as the standard dose. This study retrospectively analyzed the effect of G-CSF dose on peripheral blood CD34+ cell collection from 91 patients with hematologic malignancies. STUDY DESIGN AND METHODS: Various doses of G-CSF were administered after several chemotherapeutic PBPC mobilization regimens. According to the dose of G-CSF administered, patients were assigned to two groups. Group 1 included 46 patients who received a low dose of G-CSF (median, 3.6 [range, 2.8-4.6] microg/kg/day). Group 2 included 45 patients who received a standard G-CSF dose of 6.0 (5.5-8. 1) microg per kg per day. Patients in the two groups were matched for age, diagnosis, previous therapy, and chemotherapeutic PBPC mobilization regimens. RESULTS: No difference was observed in the median number of CD34+ cells harvested from each group. The number of leukapheresis procedures necessary to obtain a minimum of 3 x 10(6) CD34+ cells per kg was the same in both groups, and the percentage of patients who failed to achieve adequate PBPC collections was similar in the two groups. CONCLUSION: The administration of low-dose G-CSF after chemotherapy appears equivalent to administration of the standard dose in achieving satisfactory PBPC collection. This approach could allow significant savings in medical cost. A randomized and prospective study is necessary, however, to assess the validity of these conclusions.

Effect of the methanolic extract of Glinus lotoides on Dalton's ascitic lymphoma.

The antitumour activity of the methanolic extract of Glinus lotoides (MGL) has been evaluated against Dalton's ascitic lymphoma (DAL) in Swiss albino mice. A significant enhancement of mean survival time of tumour bearing mice and peritoneal cell count in normal mice was observed with respect to the control group. When these MGL treated animals underwent i.p. inoculation with DAL cells, tumour cell growth was found to be inhibited. After 14 d of inoculation, MGL is able to reverse the changes in the haemotological parameters, protein and packed cellular volume consequent to tumour inoculation.

Toxicology and humoral immunity assessment of octamethylcyclotetrasiloxane (D4) following a 28-day whole body vapor inhalation exposure in Fischer 344 rats.

Octamethylcyclotetrasiloxane, D4, is a low viscosity, silicone fluid consisting of four dimethyl-siloxy units ((CH3)2SiO)4 in a cyclic structure. It is primarily used as a building block in the industrial synthesis of long chain silicone polymers. The combination of D4 with decamethylcyclopentasiloxane (D5) is commonly referred to as cyclomethicone which has a wide range of applications as a formulation aid in personal care products. To extend the existing database regarding the biological activities of D4, a 28 day whole body vapor inhalation study was conducted using Fischer 344 rats at 0 (room air), 7, 20, 60, 180 and 540 ppm for 6 hours/day, 5 days/week. Parameters measured included body weights, organ weights, gross pathology, histopathology, serum chemistries, and urinalysis. In addition to these standard toxicological endpoints, the ability of D4 exposed animals to mount an IgM antibody response was evaluated by a splenic antibody forming cell (AFC) assay and a serum enzyme-linked immunosorbant assay (ELISA). The results of this 28-day inhalation study indicate that D4 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. In addition, there were no exposure related histopathological alterations at any site for any exposure group. A statistically significant increase in liver weight and the liver to body weight ratio was observed in both male (180-540 ppm) and female (20-540 ppm) rats, which was not observed in the 14-day recovery group animals. There were no other significant organ weight changes. Although statistically significant changes were observed in several hematological and serum chemistry parameters in both the terminal and 14-day recovery animals, the changes were marginal and within the normal range of values for the rat. Under these experimental conditions, there were no alterations noted in immune system function at any of the D4 exposure levels.

Effects of red chilli (Capsicum frutescens L) on rats.

The effects of red chilli were examined in 12-w-old male Wistar rats fed a commercial diet mixed with ground Capsicum frutescens L fruits at levels of 2% and 10% (w/w) for 8 w. When compared with controls, the general health, body weight gain, feed intake and feed efficiency were not adversely affected on the rats on feed with 2% Capsicum, while the feed intake and growth rate were depressed and exfoliation of the intestinal epithelium into the lumen and cytoplasmic fatty vacuolation and necrosis of the centrilobular hepatocytes occurred in rats at 4 and 8 w on feed with 10% Capsicum. This correlated with changes in hematology, serum enzyme profiles and other serum constituents.

Effects of combinations of endosulfan, dimethoate and carbaryl on immune and hematological parameters of rats.

IgG and IgM levels and hematological parameters (red and white blood cell counts, thrombocyte, monocyte, lymphocyte and granulocyte counts and hemoglobin concentrations) were determined in albino rats exposed to combinations of endosulfan, dimethoate and carbaryl. Two and 3 combinations of 100- and 1000-fold acceptable daily intake (ADI) of endosulfan (ADI = 0.00612 mg/kg), dimethoate (ADI = 0.0204 mg/kg) and carbaryl (ADI = 0.0101 mg/kg) were administered po to male albino rats for 3.5 mo. Animals were immunized s.c. with tetanus toxoid in Freund's complete adjuvant 20 d before terminating exposures. At 100-fold ADI dosing, administration of each of the pesticides alone did not cause any difference in the parameters, but numbers of white blood cells and monocytes increased in rats given endosulfan + dimethoate while numbers of red blood cells increased with dimethoate + carbaryl. Rats given 1000-fold ADI endosulfan + dimethoate + carbaryl had significant differences in almost every parameter, while IgG, IgM white blood cells and lymphocytes decreased, and monocytes and % granulocytes increased from single endosulfan dosing. Lymphocyte counts were reduced by single dimethoate or carbaryl dosing. Endosulfan + dimethoate + carbaryl produced the most effective changes in comparison to single dosing or other pesticide combinations.

Toxicity of Commiphora myrrha to goats.

An investigation was made of Commiphora myrrha used in traditional medicine for the treatment of various ailments. Twelve 6-mo-old male Nubian goat kids were assigned to 4 groups: undosed controls, C myrrha-dosed at 0.25 g plant resin/kg/d, C myrrha-dosed at 1 g resin/kg/d and C myrrha dosed at 5 g plant resin/kg/d. Results of hepatorenal function tests were correlated with clinical and pathological changes. The use of 1 or 5 g plant resin/kg/d caused grinding of teeth, salivation, soft feces, inappetence, jaundice, dyspnea, ataxia and recumbency. Death occurred between 5 and 16 d. Enterohepatonephrotoxicity was accompanied by anemia, leucopenia, increases in serum ALP activity and concentrations of bilirubin, cholesterol, triglycerides and creatinine, and decreases in total protein and albumin. The oral dose of 0.25 g plant resin/kg/d was not toxic.

Safety of 25-hydroxyvitamin D3 as a source of vitamin D3 in layer poultry feed.

A target animal safety study investigated the effects of providing 25-hydroxyvitamin D3 (25-OH-D3) in laying hen feed at levels ranging from 0.5 to 10 times the level commonly used for vitamin D3 supplementation in the poultry industry. Following a 28-day preconditioning period, 5 groups of laying hens were fed commercial diets containing 68.9 micrograms of vitamin D3/kg feed (control) or 41.25 (0.5x), 82.5 (1x), 412.5 (5x), or 825 (10x) micrograms of 25-OH-D3/kg feed. The study compared the effects of the control level of vitamin D3 and the various test levels of 25-OH-D3 on health, performance, hematology, and 25-OH-D3 tissue concentrations in laying hens from 0 to 112 d of treatment and on health, performance, gross pathology and histopathology from 113 to 224 d of treatment. Gross pathologic and histopathologic examination of selected tissues after 224 d revealed no lesions attributable to vitamin D toxicity at any level of test material. Concentrations of 25-OH-D3 in edible tissues at 112 d were similar for birds in the control and 1x groups. On the basis of all variables monitored, including body weight gain and feed conversion, the 10x level of 25-OH-D3 produced clear toxicity (but no mortality), the 5x level caused limited threshold toxicity, and the 1x level induced no toxicity. These results indicate that 25-OH-D3 is safe for use in laying hen feed as a source of vitamin D3 at 82.5 micrograms/kg feed (1x), with a margin of safety of approximately 5x between the proposed 1x level and the 5x level (412.5 micrograms/kg feed) that constitutes threshold toxicity in layers.

Some pharmacological and toxicological studies on Balanites aegyptiaca bark.

The aqueous extract of Balanites aegyptiaca bark, which is used in Sudanese folk medicine in the treatment of jaundice, was without effect when studied on rabbit intestine, rabbit aortic strip, rat stomach strip, rat uterus and rat phrenic nerve-diaphragm in a dose up to 10 mg/mL gut bath. In a larger dose (25 mg) the extract decreased significantly the contractility and the rate of the isolated perfused rabbit heart. Administration of the aqueous extract to biliary duct-ligated rats, showed a dose-dependent significant decrease in serum bilirubin level. The chronic and subchronic toxicity investigations indicate the safety of the aqueous extract at a dose level which showed a significant decrease in serum bilirubin level in experimental obstructive jaundice in rats.

Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats.

Tamoxifen is widely used to treat oestrogen-dependent carcinoma of the breast. Previous long-term studies have shown that oral administration of tamoxifen induces hepatoproliferative lesions and hepatocellular tumours in rats. 4-hydroxytamoxifen is an active metabolite of tamoxifen undergoing clinical evaluation for the treatment of various non-malignant breast diseases by topical application. In the present study, 4-hydroxytamoxifen was administered daily by cutaneous application for 101 weeks to groups of 50 female Sprague-Dawley rats at 20, 140 or 1000 microg/kg/day. The product was applied with no occlusive bandage and oral ingestion was avoided by application of an Elizabethan collar for 6 h after administration. Treatment with 4-hydroxytamoxifen was clinically well tolerated and induced changes such as decreased food consumption and body weight gain, uterine and ovarian atrophy, mucification of vaginal epithelium and reduced mammary development, all of which were attributed to its pharmacological action. Mortality was significantly lower in the treated animals. The number of animals with palpable masses was similarly reduced. The incidence of mammary tumours and hypophyseal tumours was markedly lower in 4-hydroxytamoxifen-treated animals. The incidence of chronic tubulo-interstitial nephropathies, a common cause of mortality, was also lowered. There was no evidence of a carcinogenic action of 4-hydroxytamoxifen on the liver, genital organs or skin. Plasma levels of 4-hydroxytamoxifen were stable over the duration of the study and were proportional to the administered dose, exceeding clinical plasma levels by 60-fold at the high dose-level. In conclusion, 4-hydroxytamoxifen is not carcinogenic in the rat and reduces the incidence of spontaneous mammary and hypophyseal tumours.

Reversible contraception with chloroform extract of Carica papaya Linn. seeds in male rabbits.

The contraceptive efficacy and reversibility of the chloroform extract of the seeds of Carica papaya in adult male rabbits were investigated. Eighteen adult male rabbits were divided into three groups of six animals each; Group I--control, Group II--administered chloroform extract of the seeds of Carica papaya at 20 mg/animal/d for 150 d by gavage, and Group III--administered the seed extract at 50 mg/animal/d for 150 d. Body weight and organ weight, semen analysis, sperm morphology by scanning electron microscopy, semen biochemistry, histology of the testis, haematology, serum clinical biochemistry, and the fertility status of the control and the treated animals were evaluated. Body weight and the weight of the testis, epididymis, seminal vesicles, and prostate did not show appreciable changes. Sperm concentration showed a gradual decline, reached severe oligospermia (fewer than 20 million/mL) after 75 d treatment, and attained uniform azoospermia after 120 d treatment. Sperm motility and viability were severely affected after 45 d treatment and reached less than 1% after 75 d treatment. The morphology of the spermatozoa by scanning electron microscopy revealed membrane damage in the acrosome, bent midpiece, coiled tail, and detached head and tail. The levels of fructose, glycerylphosphorylcholine, acid phosphatase, and lactate dehydrogenase in the seminal plasma were unaltered. Histology of the testis revealed arrest of spermatogenesis beyond the level of spermatocytes. No toxicity was evident from the haematology and serum biochemistry parameters. The libido of the treated animals was unaffected and the fertility rate was zero. The effects were comparable in both the dose regimens (Groups II and III) and were restored to normal 45 d after withdrawal of the treatment.

Effect of methotrexate on distraction osteogenesis.

To assess the potential of using distraction osteogenesis to reconstruct bone deficient limbs after limb salvage for musculoskeletal sarcomas, the authors examined the effect of methotrexate on distraction osteogenesis in a rabbit tibial lengthening model. Eighteen rabbits underwent tibial corticotomy and application of a ring external fixator. Rabbits were assigned randomly to one of two groups in which either methotrexate (n = 12) or placebo (n = 6) was administered during a 21-day distraction period. Serum methotrexate levels and complete blood cell counts were monitored during distraction, and radiographs of the tibia were obtained weekly. Half of the animals from each group were sacrificed at the end of distraction, and the remaining animals were sacrificed after 6 weeks of neutral fixation when bone normally bridges the gap. Using methotrexate at serum concentrations similar to those used clinically for the treatment of human osteosarcomas, the authors were unable to show significant radiographic, histologic, or chemical differences in the effect of this antineoplastic drug on distraction osteogenesis in the rabbit model.