Evaluation of risk and benefit of oral immunomodulation using heat-killed enterococcus faecalis FK-23 preparation in healthy dogs

The risk and benefit of oral immunomodulation using heat-killed Enterococcus faecalis FK-23 preparation (FK-23) were evaluated in healthy dogs. Dogs were administered perorally 100 mg/kg of FK23 daily for 3 months. FK-23 did not affect the findings of complete blood count, leukocyte differential count, blood chemistry, serum electrolyte, radiography, or physical conditions of the dogs tested. Increase in myeloid/erythroid ratio and granulocytic lineage was found in bone marrow of the FK-23 treated dogs. Neutrophil function assessed by zymosan-dependent chemiluminescence was activated by treatment of the drug. FK-23 also stimulated in vitro lymphocyte blast transformation of PHA, Con A, and LPS. FK-23 thus appears to be a useful immunomodulating drug to stimulate non-specific host immune responses without adverse side effects.     

Hematological and bone marrow effects of ribavirin in rhesus monkeys

Ribavirin (Virazole, 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide), a broad-spectrum antiviral compound, was evaluated for effects on blood and bone marrow of rhesus monkeys when administered by intramuscular injection for 10 days in doses of 30 or 100 mg/kg/day (four monkeys/group). Both groups developed a normochromic, normocytic anemia that was mild in the low-dose group and severe in the high-dose group. A dose-related erythroid hypoplasia occurred during the treatment period. Myeloid precursors were not affected. Differential counts of erythroid precursors showed a significant decrease in late erythroid forms while early erythroid forms were either unchanged or increased. Megakaryocyte numbers were increased in both groups. Qualitative changes in marrow cells included vacuolization of erythroid precursors and of occasional white cell precursors and megakaryocytes, and the appearance of bone marrow histiocytes containing red cells in various stages of disintegration. Thrombocytosis occurred in both treatment groups, with platelet counts returning to control values after drug withdrawal. Platelet function was not affected by treatment. No drug-related changes were seen during the treatment period for total and differential leukocyte counts, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. Reticulocyte counts and mean corpuscular volume increased after treatment then returned to control values. Osmotic fragility of erythrocytes was not changed. These data show that in monkey, ribavirin causes a dose-related decrease in circulating red blood cell mass that is due in part to suppression of late erythroid precursors in bone marrow. These effects are reversible when treatment is discontinued and are not predictive of potentially serious or lasting untoward effects of ribavirin.     

Analysis of rat bone marrow by flow cytometry following in vivo exposure to cyclohexanone oxime or daunomycin HCl

The purpose of these studies was to evaluate bone marrow from male CD rats following exposure to known hematotoxins using flow cytometry (FC) and a monoclonal antibody to the cell surface antigen CD71. Rats were treated with either CHO (300 mg/kg for 10 days) or DAUN (10 mg/kg for 1 day). Control groups received the appropriate vehicle. Half of the animals from each group were euthanized at the end of the dosing schedule and the remaining animals were euthanized after a recovery period. Hematology analyses were completed prior to the onset of each study and on the day of necropsy. Marrow was isolated from the tibia, stained with R-phycoerythrin-conjugated mouse anti-rat CD71 (transferrin receptor on proliferating cells) monoclonal antibody, and then analyzed by FC for myeloid:erythroid (M:E) ratios. FC determinations of myeloid and erythroid population percentages and M:E ratios from untreated rats were confirmed by microscopic examination of marrow cytospins and selected flow cell sorts. M:E ratios for control animals determined by FC were not significantly different between the two studies (1.83 vs 1.89). CHO treatment caused a significant (p < 0.01) decrease in M:E ratios (0.96 for CHO vs 1.48 for control) at day 11 due to increased erythroid cells. M:E ratios were significantly increased (p < 0.05) with DAUN treatment at day 3 (5.07 for DAUN vs 1.70 for control) and corresponded to generalized depletion of all marrow cell lines, especially erythroid cells. After recovery, M:E ratios of CHO and DAUN rats were similar to controls. Hematological values corroborated changes in marrow myeloid and erythroid populations evaluated by this FC technique. Using FC and a monoclonal antibody to the cell surface antigen CD71, this study confirmed the reversible selective toxicity on myeloid and erythroid marrow populations following in vivo exposure to CHO or DAUN. This FC procedure provides a rapid, sensitive method for bone marrow analysis compared to conventional cytological examination.     

Leukocyte and bone marrow effects of a thiomorpholine quinazosin antihypertensive agent

PD-88823, a thiomorpholine analog of prazosin, induced a consistent dose-related suppression of granulopoiesis with subsequent neutropenia and leukopenia in rats and dogs. Rats treated at 600 mg kg-1 day-1 had neutrophil counts reduced by 44% in males and 30% in females after 13 weeks. A 4-week observation period after drug treatment resulted in a rebound in neutrophil counts to 123 and 215% of control values in males and females, respectively. White blood cell count reductions were less evident in dogs, probably because of the lower doses. In both species, the extent of bone marrow suppression was related to duration of treatment. No other hematologic changes were manifest in either species. The mechanism for bone marrow depression and subsequent granulocytopenia was not established. The lack of reported bone marrow effects by quinazosin analogs suggests that the thiomorpholine group of PD-88823 is involved in toxicity. This correlation may be important to safety considerations for future drug design.     

血卟啉衍生物对小鼠造血器官的组织学效应

每只小鼠注射HPD(ip,0.4mg.2.0mg,2.0mg×3)后,骨髓造血细胞增殖受抑。其受抑程度与剂量和注射次数有关。骨髓中以红系细胞增殖受抑最为明显;其次为粒系和巨核系细胞。脾脏先出现短时造血细胞增殖抑制,然后为红系、巨核系细胞的代偿性增殖超常。     

The hematopathology of cefonicid- and cefazedone-induced blood dyscrasias in the dog

Cephalosporin treatment in man has been associated with blood dyscrasias that include a time- and dose-related anemia, neutropenia, and thrombocytopenia, the hematopathology of which remains poorly characterized. A similar hematologic syndrome can be produced in dogs following daily intravenous injections of 540-840 mg/kg cefazedone or 400-500 mg/kg cefonicid for 1-3 months. Using this animal model, histologic and cytologic changes in blood, bone marrow, spleen, and liver were studied over the course of the cephalosporin-induced cytopenias. Peripheral blood cytologic observations included an absence, generally, of erythroid regenerative changes, increased numbers of macroplatelets, spherocytosis, erythroblastemia, and toxic neutrophil morphology. Interim and postmortem cytologic and histologic observations of bone marrow included hypoplastic and toxic changes, primarily in cytopenic dogs receiving high doses of cefonicid, and regenerative changes in hematopoietic tissue of affected cefazedone-treated animals. The latter included variable erythroid hyperplasia, increased megakaryocytes, and decreased marrow fat and was accompanied by evidence of extra-medullary hematopoiesis and increased hemosiderin and hemophagocytosis in liver and splenic tissue. The incidence and severity of these changes were dose-dependent, corresponded with the cytopenias observed peripherally, and, like the cytopenias, were fully reversible. These observations suggest that the hematologic syndrome associated with cephalosporin treatment in the dog has multiple toxicologic mechanisms, which include peripheral cytotoxic effects and bone marrow damage with depressed or ineffective hematopoiesis.     

Preclinical toxicity of a new oral anticancer drug, CI-994 (Acetyldinaline), in rats and dogs

CI-994 (acetyldinaline) is an orally active anticancer drug currently in Phase 1 clinical trials. To assess int preclinical toxicity, CI-994 was administered orally as suspensions to Wistar rats (10/sex/dose) and in capsules to beagle dogs (3/sex/dose) once daily for two weeks. Doses were 1.5,5, and 15 mg/kg for rats (9,30, and 90 mg/m², respectively), and 0.5, 2, and 5 mg/kg for dogs (10,40 and 100 mg/m², respectively) systemic exposure was dose-proportional based on toxicokinetic analysis in dogs. Severe clinical signs and mortality occurred at the highest dose in both species beginning on Day 10. Neutropenia, lymphocytopenia, thrombocytopenia, lymphoid depletion, bone marrow hypocellularity, and testicular degeneration were observed in both species, primarily at the mid- and high-dosed. Despite cotinued treatment, neutrophil counts in dogs returned to control levels in Week 2. Othere microscopic findings in rats included splenic hematopoietic depletion at all doses and epithelial cell necrosis in various tissues at 15 mg/kg. Additional bone marrow changes in dogs involved myeloid and megakaryocyte hyperplasia at 2 mg/kg and abnomal myeloid and megakaryocyte maturation at 2 and 5 mg/kg. Except for the testicular efficts in both species, all chages were reversible within a 4- week (rat) or 9- week (dog) recovery period. The results of these studies show that target organ effects of CI-944 principally involve tissues with rapidly dividing cell populations and that bone marrow suppression is the dose-limiting toxicity. CI-944 also seems to interfere with the release and/or maturation of cells in the bone marrow.     

骨髓增生异常综合征异常克隆分布及与外周血细胞变化的关系

目的探讨不同染色体异常的骨髓增生异常综合征（MDS）患者异常克隆在骨髓各细胞系列中的分布及其与外周血细胞变化的关系。方法对del（20q）,8号染色体三体和含有5q-复杂核型的MDS患者和核型正常者的骨髓涂片进行Wright-Giemsa染色,并行荧光原位杂交检测,统计其红系、粒系、淋巴系细胞的荧光信号后与临床指标相比较。结果异常克隆在MDS患者红系中的比例分别为92.4%、56.4%、57.6%、63.2%、60.2%;粒系中的比例分别为71.2%、68.1%、72.4%、44.4%和49.3%,均高于对照组;异常克隆在淋巴系中的比例除在病例2三体8的患者中高于对照组,其余均低于对照组。异常克隆分布在红系和粒系的患者,外周血细胞水平可表现为正常或降低（Hb48～132g/L,ANC0.38×109/L～2.60×109/L）。病例2三体8的患者外周血淋巴细胞比例较高。结论 MDS异常克隆主要分布于骨髓粒系和红系细胞,个别患者分布于淋巴细胞。异常克隆在骨髓细胞系列中的分布与外周血细胞变化无明显相关性。     

Antitumor activity and toxicity of novel nitroheterocyclic phosphoramidates

A series of novel nitroheterocyclic phosphoramidates has been evaluated for antitumor activity in murine and xenograft tumor models and for toxicity in mice. Significant increases in lifespan and long-term survivors were noted in L1210 leukemia and B16 melanoma models, and both complete and partial tumor regressions were observed in the MX-1 breast cancer xenograft model. All compounds exhibited some degree of toxicity to granulocyte/macrophage progenitors in the bone marrow of mice. Two drugs were selected for further toxicologic, histopathologic, and pharmacokinetic evaluations. Toxicity of potential clinical significance was observed only in the bone marrow at the highest drug dose; otherwise no significant abnormalities in blood chemistries or organ histopathology were noted. The bone marrow lesions consisted of reduced numbers of progenitor cells in the myeloid and erythroid series; platelets were not affected. The compounds were eliminated rapidly by first-order kinetics, with half-lives in the 4-12 min range. The best of these compounds exhibits excellent antitumor activity and minimal toxicity at therapeutically effective doses in mice.     

Cephalosporin-lnduced Alterations in Erythroid (CFU-E) and Granulocyte-Macrophage (CFU-GM) Colony-Forming Capacity in Canine Bone Marrow

Cephalosporin-lnduced Alterations in Erythroid (CFU-E) and Granulocyte-Macrophage(CFU-GM) Colony-Forming Capacity in Canine Bone Marrow.DELDAR,A., LEIWS, H., 3 BLOOM, J., AND WEISS, L. (1988). Fundam Appl.Toxicol 11, 450—463. Cephalosporins are among the safestantibiotics. Nevertheless, hematologic abnormalities rangingfrom mono- to pancytopenia do occur, albeit infrequently, followingtheir therapeutic use. Similar abnormalities to those reportedin people have been seen in dogs given high doses of cephalosporins.As part of a study to define the latter thoroughly, we exploredthe effects of long-term, high-dose 3 cephalosporin administrationon canine marrow erythroid (CFU-E) and granulocyte-macro-phage(CFU-GM) progenitor cells. Cefazedone (Refosporen, E. Merck,Darmstadt) was administered intravenously at doses of 540 to840 mg/kg daily to 14 healthy beagle dogs for up to 4 months,or less if hematologic effects were evident earlier. Within6 to 10 weeks, treated dogs 3 developed pancytopenia (5/14),thrombocytopenia (11/14), moderate to severe neutropenia (8/14),and/or normocytic anemia (8/14). There was evidence of immune-mediateddestruction of peripheral blood cells. All treated dogs exhibiteda significant reduction in marrow colony-forming capacity, irrespectiveof whether peripheral cytopenia was present, with 12/14showingdecreased CFU-GM and 14/14 decreased CFU-E activity.Within aweek following cessation of dosing, all affected dogs achievedhematologic remission as defined by restoration of the peripheralblood counts. However, despite this apparent recovery, bothCFU-E and CFU-GM activities of the bone marrow remained depressedfor at least another 8 months. We conclude that in dogs prolongedadministration of high doses of cefazedone induced a persistentdeficit of CFU-E and CFU-GM progenitor cells. The clinical relevanceof this, if any, remains to be established.     

Preclinical toxicity of the new antineoplastic agent, ametantrone acetate, in mice and dogs

Ametantrone acetate (anthracenedione diacetate, NSC 287513) is an experimental antineoplastic agent with activity against a comprehensive panel of solid transplantable tumors in mice and dogs were carried out to establish tolerable levels. In mice, LD10, LD50 and LD90 values were respectively, 26, 35 and 47 mg kg-1 28 days following single intravenous injection and 22, 67 and 206 mg kg-1 14 days after single intraperitoneal injection. Hemorrhage and necrosis of the small intestine occurred in intercurrent deaths. A 5-day, consecutive intraperitoneal dosing study yielded 28 day, LD10, LD50 and LD90 values of 18, 21 and 26 mg kg-1, respectively, in mice. Bone marrow hypoplasia, lymphoid depletion and focal cardiac changes were observed in animals which died during the 28-day postdose observation period. In dogs, single intravenous injections repeated twice at intervals of 3-8 weeks resulted in leukopenia and thrombocytopenia at a dose of 2.71 mg kg-1 and decreased myeloid: erythroid ratios at a dose of 0.68 mg kg-1. Five consecutive daily intravenous injections in dogs of 0.7 mg kg-1 induced significant clinical and laboratory signs of toxicity but 0.35 mg kg-1 day-1 was tolerated. In dogs, bone marrow, lymphoid tissue and gastro-intestinal tract in both sexes and gonads in the males were target organs for toxicity. Clinical signs and clinical laboratory abnormalities abated in surviving mice and dogs. The spectrum of tissue changes induced by ametantrone was qualitatively similar to that elicited with other intercalating agents.     

Effect of particle size distribution on hexamethylmelamine toxicity in rats.

Single oral dose toxicities of six hexamethylmelamine samples with different particle size distributions were evaluated in Osborne-Mendel rats. The calculated LD50 values for the 6 samples were 1706 to 2150 mg/kg )10,236 to 12,900 mg/m2). The two samples with median particle size less than 40 micron were more toxic than the other 4 samples. Among the latter samples, severity of toxic effects was not correlated with particle size. Leukocytes, lymphocytes, platelets and body weight showed dose-related decreases for all samples. Particle size appeared to have a minimal effect on these variables. The drug produced toxic effects on rapidly proliferating tissues: lymphoid, hematopoietic and germinal epithelium. At lethal doses, microscopic lesions were lymphoid tissue hypoplasia, bone marrow hypoplasia with elevated myeloid:erythroid ratios and spermatogenic arrest. The major target organs at nonlethal doses were bone marrow and germ cells, with germinal epithelium showing the most severe lesions.     

Acute and chronic dose/response effect of benzene inhalation on the peripheral blood,bone marrow,and spleen cells of CD-1 male mice

Inhaled benzene hematotoxicity to recognize stem cell progeny was studied in male CD-1 mice exposed for 6 hr/day × 5 days to one of the following mean benzene concentrations: 1.1, 9.9, 103, 306, 603, 1276, 2416, and 4862 ppm. Additional groups of mice were exposed for 6 hr/day × 5 days/week × 10 weeks to 9.6 ppm, or 6 hr/day × 5 days/week × 26 weeks to 302 ppm. Following the 5-day exposures, granulocytopenia and lymphocytopenia were observed at levels ≥ 103 ppm with no change in WBC differential. RBC counts were depressed only at the two highest exposure levels while hematocrits were variably affected and showed no clear dose/response effect. Marrow and splenic cellularities were reduced at all levels ≥ 103 ppm. Marrow lymphocytes, splenic lymphocytes, and marrow granulocytes were reduced in accordance with the reduction in total cellularity, however, splenic granulocytes and spleen weights were depressed at almost all exposure levels. Nucleated RBCs in the marrow and spleen were depressed at almost all levels ≥ 103 ppm. Exposure for 50 days to 9.6 ppm benzene, a total dose equivalent to that delivered over 5 days at 103 ppm, induced no detectable changes in the peripheral blood or bone marrow, however, increases in splenic weight and cellularity were observed. Twenty-six weeks of exposure to 302 ppm benzene resulted in lymphocytopenia and anemia. Marrow cellularity was reduced to 32% of control and was due primarily to a reduction in lymphocytes and granulocytes. Spleen cellularity and weight were reduced to 17 and 67% of control, respectively. Decreased spleen cellularity was due primarily to a reduction in lymphocytes to 5% of control. These extended exposures to 302 ppm benzene resulted in atypical cell morphology in the peripheral blood, bone marrow, and spleen.     

Mechanism of the protective action of cobamamide and leucovorin on hematopoiesis in acute blood loss

Leucovorin and cobamamide administered alone and in combination potentiate the proliferative activity of the erythroid and myeloid cells of the bone marrow. There is lack in mutual potentiation of the drugs.     

Effect of recombinant human hemoglobin on human bone marrow progenitor cells: protection and reversal of 3′ -azido-3′ -deoxythymidine-induced toxicity

Long-term therapy of AIDS patients with 3′ -azido-3′ -deoxythymidine (AZT) is limited by hematopoietic toxicity. While the mechanism(s) of this toxicity remain elusive, various strategies are being developed to reduce these toxic effects including combination therapy with non-myelotoxic anti-human immunodeficiency virus (HIV) drugs and/or administration of protective or rescue agents, such as cytokines and growth factors. Using a physiologically relevant human CD34+ bone marrow cell liquid culture system, a crosslinked human recombinant hemoglobin (rHb), currently in Phase II clinical trials, was investigated for effects on hematopoiesis and for its potential in protecting or reversing AZT-induced hematopoietic toxicity. These investigations demonstrated that 0.01, 0.1, or 1 μM human rHb did not affect the proliferation of erythroid or myeloid lineage cells. A concentration of 1 μM rHb partially protected erythroid lineage cells from an inhibition of proliferation induced by 0.1 and 1 μM AZT. Inhibition of proliferation of cells previously exposed to AZT was not reversed at this concentration. These data suggest that human rHb may be of benefit in reducing the toxic effects of AZT in the bone marrow of AIDS patients.     

Transient knock down of checkpoint kinase 1 in hematopoietic progenitors is linked to bone marrow toxicity

Checkpoint kinase 1 (Chk1) is required for both intra-S phase and G2/M checkpoints in cell cycle, and plays critical roles in maintaining genomic stability and transducing DNA damage response. Chk1 deficiency has been shown to inhibit T-cell differentiation and resulted in severe anemia in a Chk1 heterozygous mouse model. To date, there has been a good correlation between Chk1 inhibition and in vitro bone marrow toxicity among small molecule inhibitors. To better understand the role of Chk1 in hematopoiesis, we conducted transient Chk1 gene silencing in human bone marrow progenitor cells using siRNA and electroporation. At 48h post electroporation, approximately 70% inhibition of Chk1 was confirmed using real-time RT-PCR and immunoblotting, which resulted in more than 60% reduction in cell count when compared to the non-specific siRNA control on day 6 post-electroporation. This result was confirmed using a colony forming unit assay, where reduced number in both erythroid and granulocyte colonies was observed with Chk1 siRNA treatment. The Chk1 gene inhibition in bone marrow progenitor cells resulted in significant induction of apoptosis, but not cell cycle arrest, as assessed using flow cytometry. In this study an effective method to knock down a gene of interest was established in hard-to-transfect hematopoietic stem cells. Furthermore, our results support a direct role of Chk1 in maintaining normal hematopoiesis in the bone marrow.     

Zidovudine pharmacokinetics in zidovudine-induced bone marrow toxicity.

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.     

The effects of folic or folinic acid on the toxicity of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3,4-dichlorobenzyloxy)-1,3,5-triazine hydrochloride, an antifolate, in dogs.

Oral doses of 5 mg/kg/day of 4,6 diamino-1,2-dihydro-2,2-dimethyl-1-(3,4-dichlorobenzyloxy)-1,3,5-triazine hydrochloride (TAD) for 28 consecutive days were tolerated by beagle dogs. Repeated doses of 15 or 42.5–45 mg/kg/day produced emesis, hemorrhagic diarrhea, anorexia, and severe weight loss, a pattern of toxicity resembling that of antifolates. Reticulocytopenia associated with erythroid depression of bone marrow, neutrophilia, and lymphopenia occurred. Histopathologic changes included atrophy, depletion and/or necrosis of the lymphoid tissue, degenerative, inflammatory, and atrophic changes of the gastrointestinal tract, and depression of the bone marrow. Simultaneous im administration of folinic acid (0.3 mg/kg/day) with TAD, but not oral folic acid (7.5 mg/kg/day), protected beagles against TAD toxicity. The demonstration of folate and antifolate toxic antagonism suggests toxic doses of TAD inhibit the reduction of folic acid to a tetrahydro derivative and thus interfere with the transfer and utilization of the single carbon moiety which is essential for a number of metabolic pathways.     

The liquid culture filtrates of entomogenous fungus Paecilomyces tenuipes and its glycoprotein constituent protects against anemia in mice treated with 5-fluorouracil

The purpose of the present study was to investigate the efficacy of a liquid culture filtrates of the entomogenous fungus Paecilomyces tenuipes (PTCF) and its main active glycoprotein-enriched (PGF) fraction against hematotoxicity in mice treated with 5-fluorouracil (5-FU). Oral administration of PTCF (100 mg/kg/d) for 7 consecutive days after 5-FU injection significantly suppressed reductions in the red and white blood cell counts in peripheral blood, and accelerated their recoveries. From PTCF, glycoprotein-enriched fraction (PGF, >90% protein, approximately 15 kDa determined by SDS-PAGE) was separated as active ingredient that ameliorates 5-FU-induced anemia. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis of trypsinized-PGF showed 11 fragment ion peaks. Effective recoveries of erythrocytopenia and leukocytopenia were observed when PGF was co-administered with murine recombinant erythropoietin (mrEPO; 5 U/mouse). Oral administration of PGF also inhibited 5-FU-induced decreases in peripheral reticulocyte and bone marrow cell counts on day 12, and markedly hastened their recoveries on day 20, in dose-dependent manners. Reductions in erythroid progenitor colonies, such as colony-forming units (CFU)-erythroid and burst-forming units-erythroid mix, formed by bone marrow cells from 5-FU-treated mice were markedly improved by oral administration of PGF with subcutaneous mrEPO. Oral administration of PGF also increased the myeloid lineage progenitor, CFU-granulocyte-macrophages, in cultured bone marrow cells. These findings suggest that PGF isolated from P. tenuipes has the potential to protect against 5-FU-inudced erythrocytopenia and leukopenia, especially in combination with mrEPO, and also has hematopoietic activity, through stimulation of immature erythroid as well as myeloid progenitor cell differentiation.     

Maturation arrest of neutrophils-a possible reason for the leucopenia in sodium selenite induced sub-chronic selenosis in cow calves

The effect of long-term administration of sodium selenite on leucocyte indices of peripheral blood of calves was determined. Nine calves, 9-12 months old, with an average body weight of 104kg were divided into three groups. Calves of groups 2 and 3 were administered with sodium selenite at 0.1 and 0.25mg/kg body weight for 98 consecutive days. The clinical signs characteristic of selenosis viz. alopecia, cracking of hooves, intradigital lesions and discoloration of hard palate, started appearing from 45 to 60 days onwards with high dose, whereas only subtle indications of toxicosis were observed in the low-dose group. The prolonged administration of sodium selenite produced a progressive and dose-dependent decline in the circulating leucocyte count with concomitant decline in the circulating neutrophil count. There was a high negative correlation (0.94) between blood selenium levels and neutrophils. Granulocyte/agranulocyte ratio was also significantly reduced in the treated animals. Evaluation of bone marrow smears revealed a decline in the myeloid to erythroid ratio. In addition, there was also maturation arrest of neutrophils at promyelocyte or myelocyte level as shown by differential granulocyte count in the bone marrow. The results indicated that host's immune response may be adversely affected.