Human serum paraoxonase concentration predicts cardiovascular mortality in hemodialysis patients.

AIMS: Human serum paraoxonase (PON1) is associated with high-density lipoprotein, and inhibits oxidative modification of low-density lipoprotein. Therefore, PON1 is supposed to contribute to the prevention of atherosclerosis. We and other investigators have shown that the enzymatic activities and concentrations of PON1 were decreased in maintenance hemodialysis (HD) patients. However, the effect of PON1 status on the long-term outcome of HD patients has not been reported. In this study, we examined the association between baseline PON 1 status and cardiovascular mortality in an observation study of an outpatient HD population. PATIENTS AND METHODS: The relation between baseline cardiovascular risk factors and clinical events was investigated, during 6 years of follow-up, in 81 HD patients (50 males and 31 females) whose enzymatic activities, concentrations and genetic polymorphisms of PON1 had been determined in a previous study. RESULTS: During follow-up for 6 years, we recorded 42 deaths, including 24 fatal cardiovascular events. In univariate analyses, baseline PON1 concentration was associated with not only cardiovascular mortality (p < 0.005), but also all-cause mortality (p < 0.001) during the period of follow-up, as were age, preexisting cardiovascular disease (CVD) and hemoglobin concentration. In a multivariate Cox regression analysis, PON1 concentration retained significant associations with cardiovascular mortality (p < 0.05) and all-cause mortality (p < 0.005) even after correction of known risk factors for CVD or mortality in HD patients. Using Kaplan-Meier survival curves, we assessed the association between low and high concentrations of PON1 divided according to the median value (7.52 U/ml). Significantly increased cardiovascular mortality (log rank 6.125, p = 0.01) and all-cause mortality (log rank 7.113, p < 0.01) were detected in the patients with low PON1 concentrations. CONCLUSIONS: These data suggest that low PON 1 concentration may be an independent predictor of cardiovascular mortality in maintenance HD patients.

Effects of ubenimex on erythroid progenitors (CFU-E and BFU-E) in human bone marrow.

Ubenimex (UBX, bestatin) is known to be an immunomodulator and host-mediated antineoplastic agent. Effects of UBX on human bone marrow erythroid progenitors (erythroid colony-forming units, CFU-E; and erythroid burst-forming units, BFU-E) were investigated in vitro. UBX enhanced CFU-E and BFU-E growth in the nonseparated bone marrow mononuclear cell fraction at concentrations from 0.005 to 5 micrograms/ml. The enhancements of CFU-E and BFU-E were independent of the concentration of erythropoietin added to culture system. In the T-cell-depleted bone marrow fraction, UBX also increased CFU-E and BFU-E growth, but it failed to stimulate these cells in the nonphagocytic and nonadherent bone marrow fraction. These findings indicate that UBX may stimulate erythroid progenitors mediated through monocytes and macrophages.

Toxicological study of etoposide (VP-16) in rats with special emphasis on testicular alteration.

Etoposide (VP-16) was administered intravenously to rats for 3 months. Testicular alterations induced by etoposide (VP-16) at 0.5 and 1.5 mg/kg/d were thoroughly assessed with light and electron microscopy. Light microscopic analyses demonstrated disorganization and moderate depletion of germinal epithelium at 0.5 mg/kg/d, and complete germ cell depopulation at 1.5 mg/kg/d. Ultrastructural studies revealed degenerative changes in spermatogonia and early spermatocytes, appearance of large spermatids with multi-nuclei, and nuclear alterations and cytoplasmic vacuolation in Sertoli cells. Moreover, the basement membrane of the seminiferous tubule showed wavy lamellae and infolding to the seminiferous epithelium. Leydig cells manifested no significant ultrastructural changes. The small intestine and ovaries were not affected. The 2-month recovery period following cessation of treatment led to the recovery of these testicular alterations at the 0.5 mg/kg/d dose, but not at the 1.5 mg/kg/d dose. Judging from these results, etoposide (VP-16) induced damage primarily in spermatogenic cells, followed by Sertoli cells and the basement membrane in seminiferous tubules. Though reversible at intermediate doses, higher doses of VP-16 might produce irreversible testicular lesions.

X-ray microanalysis of monoaminergic terminals in the nucleus tegmentalis dorsalis of the chicken.

X-ray microanalysis after aldehyde-chromate-dichromate treatment served to confirm the presence of monoaminergic terminals in the nucleus tegmentalis dorsalis (NTD) of the chicken. The monoaminergic terminals were represented as neuronal elements with electron-dense vesicles (EDVs) of several different shapes as seen in Eponembedded semi-thin sections. Conventional electron microscopic observations of the adjacent ultra-thin sections showed the EDVs to be comprised of spherical medium-sized (about 80 nm in diameter), large dense-cored (about 120 nm) and elongated granular vesicles (100-220 nm) in the same nerve varicosities. It is probable that the NTD, being a center of catecholaminergic efferent projections, may also receive direct monoaminergic inputs from an unknown area of the brain and/or from recurrent collaterals of the same catecholamine-containing neurons in the NTD.

Catecholamine-containing neurons in the mesencephalic tegmentum of the chicken. Light, fluorescence and electron microscopic studies.

The nucleus tegmentalis dorsalis (NTD) which may be homologous with the mammalian locus coeruleus was investigated in the chicken by means of light, fluorescence and electron microscopy. Results are summarized as follows: 1) Numerous neurons emitting green fluorescence by the Falck-Hillarp method were observed in the NTD of the chicken. By consecutive light and fluorescence microscopy on the same section it was established that these catecholamine(CA)-containing neurons clearly coincided with the cell group named nucleus tegmentalis dorsalis by Jungherr (1945). This procedure further showed that there were also non-fluorescent neurons in the NTD. 2) On the basis of electron microscopic observation, two types of neurons were recognized in the NTD: medium-(15-25 microns) and small-sized (10-15 microns) neurons. Medium-sized neurons had a round to oval nucleus with several deep infoldings and abundant organelles. From combined fluorescence and electron microscopic examination, they obviously corresponded with CA-containing neurons demonstrated by the Falck-Hillarp method. Small-sized neurons had a round nucleus surrounded by pale cytoplasm. They corresponded with non-CA-containing neurons. 3) From morphometric analysis, it was clear that CA-containing neurons contained a well-developed rough-surfaced endoplasmic reticulum and many lysosome-like dense bodies, unlike non-CA-containing neurons. This study was undertaken as the basis of a research program to elucidate the catecholaminergic projections from the NTD.

Bulbar catecholaminergic neurons projecting to the thoracic spinal cord of the chicken. Evans Blue labeling study in combination with catecholamine histofluorescence.

This study was undertaken to map the location of cell groups in the chicken brain stem that project to the thoracic spinal cord by retrogradely transported Evans Blue (EB). The majority of EB-labeled neurons are located in an area between the nucleus vagus motorius (NVMD) and hypoglossus ventralis dorsomedialis, the nucleus raphis, the nucleus vestibularis ventrolateralis, the nucleus tegmentalis dorsalis (NTD) and the reticular formation. However, this procedure demonstrates that no cell bodies within the nucleus tractus solitarii project to the spinal cord, unlike those of mammals. It is possible that this difference may be involved in the existence of the diaphragma. Additionally, catecholamine (CA)-containing cells in the brain stem projecting to the thoracic spinal cord were investigated with the aid of a technique demonstrating both CA and EB fluorescence in the same neuron. The doubly labeled cells are constantly found to be located within such areas as the lateral reticular formation at the level of the NVMD, the ventrolateral reticular formation at the level of the nucleus abducens major, the NTD and the ventrolateral reticular formation at the level of the NTD. The doubly labeled neurons are most numerous in the medial part of the NTD in transverse section, reflecting a similar tendency in the mammalian locus coeruleus.

Effect of a polymorphism of endothelial nitric oxide synthase gene in Japanese patients with IgA nephropathy.

BACKGROUND: Nitric oxide (NO) is synthesized by endothelial cell NO synthase (ecNOS) on vascular endothelium, and it plays a key role in the regulation of blood flow and pressure. A polymorphism of the ecNOS gene was recently shown to be associated with the development of cardiovascular disease. PATIENTS AND METHODS: We investigated the ecNOS gene polymorphism in 68 Japanese patients with IgA nephropathy (IgAN) and 134 normal controls. RESULTS: The genotype distributions were not different between the normal controls and the IgAN patients (ecNOS4b/b: ecNOS4b/a: ecNOS4a/a = 106:27:1 and 50:18:0, respectively). There was no significant difference in the renal histopathological grading between the patients with ecNOS4b/a and ecNOS4b/b. However, among the subgroup of patients whose duration of illness was two or more years, the advanced histopathological grading was more frequent in the patients with the ecNOS4b/a genotype (than in those with the ecNOS4b/b (p = 0.04)). The incidence of hypertension was also higher in the patients with the ecNOS4b/a genotype (50% in ecNOS4b/a versus 12% in ecNOS4b/b, p = 0.04). CONCLUSION: These results suggest that the ecNOS4b/a genotype (or ecNOS4a allele) of the ecNOS gene polymorphism may be involved in the progression of IgAN.

Fluvirucins A1, A2, B1, B2, B3, B4 and B5, new antibiotics active against influenza A virus. IV. Taxonomy on the producing organisms.

The morphology, chemotaxonomy, and cultural and physiological characteristics were examined on the five strains of actinomycetes which produce antiviral antibiotics, fluvirucin congeners. All strains have meso-2,6-diaminopimelic acid in the cell wall. Four strains, Q464-31, L407-5, R359-5 and R516-16, belong to the maduromycetes since they have madurose in the whole cell. The remaining one strain, R869-90, has rhamnose but no madurose, and is a nocardioform actinomycete. These five strains were classified and designated as follows: Strain Q464-31 (fluvirucin A1 producer): Microtetraspora tyrrhenii sp. nov. (Actinomadura pusilla group). Strain L407-5 (fluvirucin B2 producer): A maduromycete. Strain R359-5 (fluvirucin B1 producer): Microtetraspora pusilla (Actinomadura pusilla group). Strain R869-90 (fluvirucin A2 producer): Saccharothrix mutabilis. Strain R516-16 (fluvirucins B2, B3, B4 and B5 producer): A maduromycete.

Antineutrophil cytoplasmic antibody in patients with primary Sjögren's syndrome.

The incidence, specificity and clinical significance of positivity for serum antineutrophil cytoplasmic antibody (ANCA) was investigated in 60 patients with primary Sjögren's syndrome (SjS). The indirect immunofluorescence (IIF) technique and an enzyme-linked immunosorbent assay (ELISA) were used to measure ANCA. Purified myeloperoxidase (MPO), lactoferrin (LF), cathepsin-G (CTG) and elastase (HLE) served as ANCA antigens for the ELISA. Ten (16.7%) of the 60 SjS patients showed positivity by IIF for perinuclear, but not cytoplasmic, ANCA. Four of the 60 sera were shown to be positive for LF, four for MPO, 0 for CTG and 0 for HLE by ELISA. There was no correlation between ANCA positivity and clinical features. ANCA in patients with SjS might be an epiphenomenon of polyclonal B-cell activation.

Anti-neutrophil cytoplasmic antibody in patients with systemic lupus erythematosus is unrelated to clinical features.

To investigate the incidence, the specificity and clinical significance of positivity for serum anti-neutrophil cytoplasmic antibody (ANCA) in 31 patients with systemic lupus erythematosus (SLE), the indirect immunofluorescence (IIF) technique and enzyme-linked immunosorbent assay (ELISA) were used to measure ANCA. Purified myeloperoxidase (MPO), lactoferrin (LF), cathepsin-G (CTG) and elastase (HLE) served as ANCA antigens for ELISA. Thirteen (42%) of the 31 SLE patients showed positivity for perinuclear, but not cytoplasmic, ANCA by IIF. Five of 31 sera were positive for MPO, 10 for LF, 1 for CTG and 0 for HLE by ELISA. Patients positive for ANCA had a higher score of SLE disease activity index (SLEDAI) than those without ANCA. There was no correlation between ANCA positivity, clinical manifestations, or organic involvement. While the ANCA in patients with SLE reflected disease activity, it was unrelated to organic involvement.

Localized polyarteritis nodosa in the forearm and epididymis.

We report localized polyarteritis nodosa in a 31-year-old man who had painful nodules in the left forearm and scrotum. Histopathological findings of both tissues revealed distinct arteritis. However, he had no clinical evidence of any systemic disease. We finally diagnosed this case as a localized polyarteritis nodosa occurring in both the left forearm and epididymis. This form of polyarteritis nodosa has not been reported in the literature.

Positivity for antinuclear antibody in patients with advanced rheumatoid arthritis.

Some patients with rheumatoid arthritis (RA) as well as those with other collagen diseases are positive for antinuclear antibody (ANA). We investigated the frequency of positivity for ANA in 104 patients with RA and evaluated the clinical features and laboratory data in the ANA-positive and -negative groups. The presence of ANA in sera was studied by indirect immunofluorescence using HEp-2 cells as the antigen substrate. Sera with a positive fluorescence at a dilution of 1:20 were considered to be positive for ANA. Of the 104 patients, 39 (37.5%) were positive for ANA. The staining pattern in the positive cases varied, but most were speckled (64.1%) and homogeneous (48.7%). A small number showed a nucleolar (20.5%) or a centromere (10.3%) pattern. None showed a shaggy pattern. The ANA titer was lower in RA patients compared with those with other collagen-related diseases such as systemic lupus erythematosus or progressive systematic sclerosis. None of the patients positive for ANA with either a nucleolar or centromere staining pattern had progressive systemic sclerosis or the CREST syndrome. One patient each had Raynaud's phenomenon and pulmonary fibrosis. There was no correlation between ANA positivity and indicators of joint inflammation. The prevalence of ANA positivity in patients with advanced or prolonged disease was higher than those with early stages or short durations. There was no correlation with drug therapy.

[Reproduction studies of carboplatin (I)--Intravenous administration to rats prior to and in the early stages of pregnancy].

Carboplatin, an oncostatic drug, was administered intravenously to male Crj: CD (Sprague-Dawley) rats for 63 days and to female rats of the same strain for 14 days prior to mating at dose levels of 1, 2 and 4 mg/kg/day. These animals were then mated under the consecutive administration of this drug and the females confirmed to be copulated were further dosed from day 0 through 7 of gestation. The summarized results obtained are as follows: 1. Carboplatin 2 mg/kg and higher suppressed body weight gains accompanied by the decreases in food and water consumption in male rats. Further, body weight gains were suppressed in female rats followed by the decreases in food consumption at the same dose levels. 2. Though there were no differences between dosed animals and controls regarding the organ weights, the incidence of necrosis of the tails around the injection site was increased in male rats at 4 mg/kg. 3. Carboplatin failed to affect the reproductive ability of both sexes. 4. As for fetuses, the mortality was elevated at 2 mg/kg and higher and the number of live fetuses reduced at 4 mg/kg, but the influences on prenatal development were not apparently observed for live fetuses even at the highest dose level. Based on these results, the no-effect dose level of carboplatin under the present experimental condition was estimated to be 1 mg/kg/day against parent rats of both sexes and their offspring.

[Reproduction studies of carboplatin (II)--Intravenous administration to rats during the period of fetal organogenesis].

Carboplatin, an oncostatic drug, was administered intravenously to pregnant Crj: CD (Sprague-Dawley) rats from day 7 through 17 of gestation at dose levels of 1, 2 and 4 mg/kg/day. The summarized results obtained are as follows: 1. Carboplatin 4 mg/kg suppressed the maternal body weight gains from day 13 through 20 of gestation. 2. Uterine weights were reduced in F0 dams at term at carboplatin 4 mg/kg. 3. Carboplatin 4 mg/kg brought the inhibition of fetal growth accompanied by the lowered values in fetal weights, crown-rump distances and tail lengths. Furthermore, the elevated incidences of unossified 5th and 6th sternum , as well as retarded ossification of sacrococcygeal vertebrae were also noted in this dose level. 4. The birth rate was reduced in neonates (F1) at carboplatin 4 mg/kg. 5. Body weight gains in male F1 rats were suppressed at carboplatin 4 mg/kg from 4 to 8 weeks of age. 6. Carboplatin 4 mg/kg decreased the brain weights on an absolute basis in female F1 rats, but failed to affect their postnatal differentiations, early behavioral developments, learning ability, motor activity or emotional development. 7. Reproductive ability in F1 rats of both sexes were not affected by carboplatin. 8. Influences on prenatal development were not apparently observed for F2 fetuses derived from F1 rats whose dams had ever received carboplatin during the organogenetic period. Based on these results, the no-effect dose level of carboplatin under the present experimental condition was estimated to be 2 mg/kg/day against dams and their offspring.

[Reproduction studies of carboplatin(III)--Intravenous administration to rats during the perinatal and lactation periods].

Carboplatin, an oncostatic drug, was administered intravenously to pregnant Crj: CD (Sprague-Dawley) rats from day 17 of gestation through day 21 of postpartum at dose levels of 1, 2 and 4 mg/kg/day. The summarized results obtained are as follows: 1. Maternal body weight gains were suppressed during the former part of the lactation period at carboplatin 2 mg/kg and higher. 2. Thymic weights were decreased and lung weights were increased in dams (F0) at carboplatin 2 mg/kg and higher. Further, ovarian weights were reduced in dams (F0) at carboplatin 4 mg/kg. 3. Carboplatin failed to affect the parturition of F0 dams. 4. Carboplatin did not affect the viability of newborns (F1), and postnatal differentiations, early behavioral developments, learning ability, motor activity or emotional development in F1 animals. 5. Carboplatin 4 mg/kg brought a suppression of pituitary weights after mating in F1 male rats and decreases of adrenal and genital organ weights at weaning in F1 female rats, but failed to affect their reproductive ability. 6. Influences on prenatal development were not apparently observed for F2 fetuses derived from F1 rats whose dams had ever received carboplatin during the perinatal and lactation periods. Based on these results, the no-effect dose level of carboplatin under the present experimental condition was estimated to be 1 mg/kg/day against dams and 2 mg/kg/day against their offspring.

[Acute toxicity study of buspirone hydrochloride in mice, rats and dogs].

Buspirone hydrochloride (abbr. to BH), an anxiolytic drug, was examined for its intravenous, subcutaneous or oral acute toxicity using Crj: CD-1 (ICR) mice, Crj: CD (Sprague-Dawley) rats and beagle dogs of both sexes. The results obtained were summarized as follows: 1. Drug-related toxic signs included decreased activity and convulsions accompanied with salivation and opisthotonus in mice and rats treated with BH regardless of administration routes, and tremors and clonic convulsions accompanied with salivation in dogs treated with BH orally. 2. Pathological examinations revealed distention of the stomach in dead rats treated with BH orally, and hypersecretion of gastric juice and alterations (viz. edema, necrosis and petechia) on the superficial mucous membrane in the gastropyloric region in dead dogs treated with BH orally. 3. The cause of death was considered to be due to respiratory insufficiency in every species of animals examined. 4. LD50 values (mg/kg) were as follows: [table: see text] 5. No sex differences were observed in every species of animals regardless of administration routes on the basis of toxicological parameters examined.

[Reproductive and developmental toxicity studies of buspirone hydrochloride (I)--Oral administration to rats during the period of fetal organogenesis].

Buspirone hydrochloride (buspirone), an anxiolytic drug, was administered orally to pregnant Crj: CD (Sprague-Dawley) rats from day 7 through 17 of gestation at dose levels of 2, 12 and 75 mg/kg/day. The summarized results obtained are as follows: 1. Decreased activity was observed for F0 dams at buspirone 75 mg/kg. Further, the suppression of maternal body weight gains accompanied by the reduction of food consumption was shown during the administration period at the same dose level. 2. Liver weights were increased in F0 dams at term at buspirone 12 mg/kg and higher. Besides, brain, pituitary, adrenal and ovarian weights were increased in F0 dams at term at buspirone 75 mg/kg. 3. Buspirone 75 mg/kg brought the inhibition of fetal growth followed by the lowered values in fetal weights, crown-rump distances and tail lengths. Furthermore, the elevated incidence of skeletal abnormalities such as nodular and wavy ribs and unossified 5th and 6th sternum , as well as retarded ossification of cervical vertebrae, forelimbs and hindlimbs were also noted in this dose level. Also, the retarded ossification was observed at 12 mg/kg. 4. Buspirone failed to affect the parturition of F0 dams. 5. Buspirone did not function the viability of newborns (F1), and postnatal differentiations, learning ability, motility, motor activity or emotional development in F1 animals. 6. Body weight gains were depressed in female F1 rats from 4 to 9 weeks of age and food consumption was decreased in male F1 rats from 6 to 8 weeks of age at buspirone 75 mg/kg. 7. Buspirone 75 mg/kg produced suppressions of brain weights at 10 weeks of age in male and female F1 rats and lung weights at weaning in male F1 rats. Spleen weights were increased in female F1 rats at 10 weeks of age at the same dose level. However, buspirone failed to affect their reproductive ability. 8. F2 neonates derived from F1 rats whose dams had ever received buspirone during the period of fetal organogenesis showed no changes in observation items at birth. Based on these results, the no-effect dose level of oral buspirone under the present experimental condition was estimated to be 2 mg/kg/day against dams and their offspring.

[Reproductive and developmental toxicity studies of buspirone hydrochloride (II)--Oral administration to rats during perinatal and lactation periods].

Buspirone hydrochloride (buspirone), an anxiolytic drug, was administered orally to pregnant Crj: CD (Sprague-Dawley) rats from day 17 of gestation through day 20 of postpartum at dose levels of 2, 12 and 75 mg/kg/day. The summarized results obtained are as follows: 1. Decreased activity was observed for F0 dams at buspirone 75 mg/kg. Further, the suppression of maternal body weight gains accompanied by the reduction of food consumption was shown during the administration period at buspirone 12 mg/kg and higher. 2. Brain and adrenal weights were increased in F0 dams at buspirone 12 mg/kg and higher. Besides, lung and pituitary weights were augmented in F0 dams at buspirone 75 mg/kg. 3. Buspirone 75 mg/kg brought the increased number of stillbirths in F1 neonates. 4. Buspirone 75 mg/kg lowered the viability of newborns (F1) on postnatal day 3 and prolonged the days required for pinnae detachment, presence of abdominal hair and eye opening in offspring (F1), but failed to function their learning ability, motility, motor activity or emotional development. 5. Body weight gains were depressed in both male and female F1 rats at buspirone 12 mg/kg and higher. Food consumption was also decreased in both sexes at the same dose levels. 6. Heart weights were decreased in female F1 rats after mating at buspirone 12 mg/kg and higher. Further, buspirone 75 mg/kg brought a suppression of brain weights at 10 weeks of age in male and female F1 rats, but failed to affect their reproductive ability. 7. F2 neonates derived from F1 rats whose dams had ever received buspirone during the perinatal and lactation periods showed no changes in observation items at birth. Based on these results, the no-effect dose level of oral buspirone under the present experimental condition was estimated to be 2 mg/kg/day against dams and their offspring.

[Toxicity studies of VP 16-213 (V)--Intravenous three-month toxicity in rats].

VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to Crj : CD (Sprague-Dawley) rats of both sexes at dose levels of 0.05, 0.15, 0.5 and 1.5 mg/kg/day for three months with the object of examining its toxicity and the reversibility of toxic effects. For the purpose of comparison, vincristine (abbr. to VCR) was administered in the same manner at a dose level of 0.02 mg/kg/day. The summarized results obtained are as follows: VP 1.5 mg/kg brought anemia as well as suppression of body weight increase and food intake, and 0.5 and 1.5 mg/kg increased water consumption. However, no drug-related deaths occurred. VP 0.5 and 1.5 mg/kg predominantly decreased red blood cell count and white blood cell count accompanied with lowered lymphocyte fraction which was agreeable to the findings on bone marrow. VP 1.5 mg/kg increased platelet count. VP 1.5 mg/kg lowered total serum protein content and elevated A/G ratio. VP 0.15 mg/kg and higher decreased testicular weight; 0.5 and 1.5 mg/kg brought thymic atrophy, suppression of spermatogenesis, tubular atrophy and hydropic change in testis. VP 1.5 mg/kg induced decrease of sperms in number and appearance of giant cells in epididymis. Above-described changes excluding the findings on testis and epididymis were shown to be generally reversible. Most of the findings for a reference drug, VCR, were qualitatively comparable to those for VP. Based on these results, the non-effect dose level of VP under the present experimental condition was estimated to be 0.05 mg/kg/day against male rats and 0.15 mg/kg/day against female rats.

[Toxicity studies of paclitaxel. (I)--Single dose intravenous toxicity in rats].

Paclitaxel, an antineoplastic agent, was given to Crj: CD (SD) rats of both sexes at 38, 50, 65 and 85 mg/kg by single intravenous administration to investigate its acute toxicity. The results obtained are summarized as follows: 1. Tachypnea and decreased activity with prone position were noted for vehicle and all paclitaxel groups, and alopecia for all paclitaxel groups. 2. Deaths occurred for one out of 5 males and 2 out of 5 females at 85 mg/kg. One female died of respiratory insufficiency induced by vehicle on Day 0. One female and one male died of the systemic toxicity of paclitaxel such as hypoplasia of the bone marrow and lymphoid depletion of lymphatic organs on Days 6 and 12, respectively. 3. On Days 4 and 5, all paclitaxel groups showed decreases of reticulocyte and white blood cell counts, as well as decrease of differential count of neutrophils. These changes were generally recovered by a week after dosing. 4. Histopathological examinations revealed atrophy of the thymic medulla, hypoplasia of the bone marrow and lymphoid depletion of the spleen for a few males at 85 mg/kg, and hypospermatogenesis and tubular atrophy of the testes for all paclitaxel groups. Based on these results, 85 mg/kg of paclitaxel was lethal to rats, and hematopoietic, lymphoid and male reproductive systems were primarily affected under this condition.