Secondary tethered cord syndrome in spinal dysraphism.

Secondary tethered cord syndrome following initial repair for spinal dysraphism is an important area of interest. In this study, 32 cases with spinal dysraphism in the lumbosacral region were enrolled, in whom radical repair with autologous material had been carried out in the early stage soon after birth. During the follow-up period of up to 19 years 10 months, surgery was considered to be indicated in 2 of the 8 lipomeningocele cases and in 6 of the 24 meningocele and meningomyelocele cases, because of the presence of tethered cord syndrome 4-19 years after the primary operation. In all 8 of these cases, MR imaging demonstrated tethered spinal cord in the form of low conus medullaris. In 6 of the 8 operated cases surgery was followed by improvement of the spinal neurological deterioration. According to our experience, early untethering for secondary tethered cord syndrome is essential. In addition, since the complications of Silastic duraplasty at untethering were all minor and the operative outcome was satisfactory, the use of silicone rubber sheeting as a dural substitute might be recommended to prevent adhesion of the spinal cord.

Somatic alterations of the DPC4 gene in human colorectal cancers in vivo.

BACKGROUND & AIMS: The chromosome region 18q21 has been shown to be frequently deleted in colorectal cancers, and such frequent allelic loss is a hallmark of the presence of a tumor-suppressor gene. The DPC4 gene, which is located at 18q21, has been identified as a tumor-suppressor gene from examination of pancreatic cancers. The aim of the present study was to determine if it might also be altered in colorectal cancers. METHODS: Mutation analyses of the DPC4 gene were performed on complementary DNA samples from 31 primary colorectal cancer specimens using a combination of polymerase chain reaction, single-strand conformation polymorphism, and DNA sequencing. RESULTS: Four missense mutations producing amino acid substitutions and a somatic 12-base pair deletion in the coding region of the DPC4 gene were detected in the 31 cancers (16%; 5 of 31). CONCLUSIONS: The DPC4 gene may play a role as a tumor-suppressor gene in a fraction of colorectal cancers; however, while allelic loss at 18q21 is very often seen in colorectal cancers, only a minority show DPC4 mutations, suggesting that there might be another tumor-suppressor gene in this chromosome region.

[Antigenicity study of paclitaxel].

The antigenic property of paclitaxel was examined using its protein mixtures (paclitaxel + OVA, paclitaxel + GSA, paclitaxel + RSA) in guinea pigs and mice in comparison with ovalbumin (OVA) and the protein conjugate of 4-aminoantipriyne (AAP). The following results were obtained: 1. When guinea pigs were sensitized with paclitaxel or paclitaxel + OVA emulsified with Freund's complete adjuvant, none of active systemic anaphylaxis (ASA), passive cutaneous anaphylaxis (PCA) and Schultz-Dale reaction were induced by challenge with paclitaxel or paclitaxel + GSA (guinea pig serum albumin). In the observation of active cutaneous anaphylaxis (ACA), no changes were observed in animals treated with paclitaxel alone as a sensitizing and/or a challenging antigen under the condition where slight delayed type hypersensitivity was elicited in animals sensitized with paclitaxel + OVA and challenged with paclitaxel + GSA. 2. When mice were sensitized with paclitaxel or paclitaxel + OVA adsorbed to alum. sera of these animals revealed a negative reaction in PCA using rats by challenge with paclitaxel or paclitaxel + RSA (rat serum albumin). 3. Protein bindings of paclitaxel with the above albumins were more than 40%. As shown above, paclitaxel was considered not to possess antigenic property under the experimental condition. In addition, the dose levels of paclitaxel employed in the present experiment were confirmed not to suppress the immune response to OVA.

[Reproductive and developmental toxicity studies of paclitaxel. (I)--Intravenous administration to rats prior to and in the early stages of pregnancy].

Paclitaxel, an antineoplastic agent, was administered intravenously to Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.1, 0.3 and 1.0 mg/kg for 63 days prior to mating and during the mating period in males, and for 14 days prior to mating and during the mating period as well as day 0 to day 7 of gestation in females. Results were as follows: 1. Body weight gains were shown a tendency to hasten in vehicle-treated male rats associated with the increased food consumption. However, the vehicle-treated group had no effect in the other parameters that were measured in this study when compared to the saline-treated group. 2. 1.0 mg/kg paclitaxel caused suppression of the body weight gains accompanied by the decreased food consumption in either male or female rats. 3. Adrenal and ovarian weights were decreased in 1.0 mg/kg dams at term. 4. The fertility indices in both sexes of 1.0 mg/kg were lower than the saline-treated group. However, the copulation indices in both sexes in 1.0 mg/kg rats were comparable to those of the saline-treated group. 5. Decreases in the number of corpora lutea, implantations and live fetuses or increases in the number of empty implantation sites and total embryo-fetal deaths were observed in 1.0 mg/kg dams. However, the fetal weights, crown-rump distances and tail lengths in live fetuses were not affected by paclitaxel treatment. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 0.3 mg/kg/day for parent animals and their fetuses.

[Reproductive and developmental toxicity studies of paclitaxel. (II)--Intravenous administration to rats during the fetal organogenesis].

Paclitaxel, an antineoplastic agent, was administered intravenously to pregnant Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.15, 0.3 and 0.6 mg/kg from day 7 to day 17 of gestation. Results were as follows: 1. The ossification of hyoid bodies was retarded in F1 fetuses by the vehicle. However, the vehicle-treated group had no effect in the other parameters that were measured in this study when compared to the saline-treated group. 2. Body weight gains and food consumption in F0 dams were not affected by paclitaxel during the gestation and lactation periods. 3. Paclitaxel failed to affect the organ weights in F0 dams. 4. Paclitaxel did not alter the prenatal development in F1 fetuses. 5. External, internal and skeletal malformations were not induced by paclitaxel. Further, paclitaxel did not affect the skeletal variations and ossification processes. 6. Paclitaxel did not alter the delivery status of F0 dams or viability and weaning indices in F1 pups. 7. The day required for presence of hair was significantly delayed in 0.6 mg/kg F1 pups at paclitaxel. However, the days required for pinnae detachment, incisor eruption, eye opening, testicular descent and vaginal opening were not affected by paclitaxel. 8. No effects on body weight gains or food consumption were observed in both male and female F1 rats. 9. Paclitaxel did not alter the developmental behavior, learning ability and memory, spontaneous motor activity or emotionality in F1 rats. 10. The reproductive performance in both male and female F1 rats were not affected by paclitaxel. 11. Paclitaxel did not alter the organ weights in both male and female F1 rats. 12. No influence on prenatal development was observed for F2 fetuses even at the highest dose level of paclitaxel. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 0.6 mg/kg/day and 0.3 mg/kg/day for dams (F0) and their offspring (F1), respectively.

[Reproductive and developmental toxicity studies of paclitaxel. (III)--Intravenous administration to rats during the perinatal and lactation periods].

Paclitaxel, an antineoplastic agent, was administered intravenously to pregnant Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.1, 0.3 and 1.0 mg/kg from day 17 of gestation to postpartum day 21. Results were as follows: 1. The vehicle-treated group had no effect in any of the parameters that were measured in this study when compared to the saline-treated group. 2. 1.0 mg/kg paclitaxel caused suppression of the body weight gains associated with the decreased food consumption in F0 dams during the lactation period. 3. Thymic, heart and uterine weights were reduced in 1.0 mg/kg F0 dams at completion of the lactation period. In addition, thymic atrophy was observed for 1.0 mg/kg F0 dams macroscopically. 4. Paclitaxel did not alter the delivery status of F0 dams or birth, viability and weaning indices in F1 pups. 5. The days required for presence of hair, incisor eruption and testicular descent were statistically delayed in 1.0 mg/kg F1 rats. 6. The latency time for olfactory orientation was prolonged in 1.0 mg/kg F1 rats on postnatal day 15. Further, the positive response rates for air righting were reduced in 1.0 mg/kg F1 rats from postnatal day 17 to day 20. 7. 1.0 mg/kg paclitaxel caused suppression of the body weight gains in male F1 rats from postnatal week 1 to week 12. Though body weight gains were decreased in 1.0 mg/kg female F1 rats from postnatal week 1 to week 7, there were no significant differences between dosed animals and saline-treated animals regarding the body weight gains and food consumption during the gestation period. 8. Paclitaxel did not affect the learning ability and memory, spontaneous motor activity or emotionality in F1 rats. 9. The reproductive performance in both male and female F1 rats were not affected by paclitaxel. 10. Splenic weights were reduced in 1.0 mg/kg male and female F1 rats at weaning. Furthermore, liver weights were decreased in 1.0 mg/kg male F1 rats after mating. 11. No influence on prenatal development was observed for F2 fetuses even at the highest dose level of paclitaxel. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 1.0 mg/kg/day and 0.3 mg/kg/day for dams (F0) and their offspring (F1), respectively.

[Cefepime (BMY-28142 diHCl/L-arginine blend): one-month repeated dose subcutaneous toxicity study in rats].

In order to investigate the toxicity of cefepime (CFPM, BMY-28142 diHCl/L-arginine blend upon repeated subcutaneous dosing), the test article was administered to Crj:CD(SD) rats of both sexes at daily dose levels of 150 (low dose), 500 (intermediate dose) and 1,500 (high dose) mg/kg/day by subcutaneous route for 28 days. Two additional groups of rats were given either saline (negative control) or L-arginine (vehicle control). Doses were equally divided and administered twice each day with an interval of approximately 5 hours between the 2 doses of a same day. A half of rats in negative control and high dose groups were retained for examination during one-month recovery period. The results obtained are summarized as follows: 1. Upon general observations, it was found that drug-related changes were restricted to the injection sites. Depilation and scab-formation of the injection sites were noted in high dose rats of both sexes and intermediate dose females. No deaths occurred during the study. 2. Slightly depressed body weight gains were observed for high dose males during the latter part of the dosing period. 3. Slightly lower food consumptions were noted for intermediate and high dose males at Week 1. 4. Slightly higher water consumptions were generally detected for high dose rats during the dosing period. 5. Hematological examinations revealed that a slight decrease in the average value of relative lymphocyte counts and a slight increase in the average value of relative segmented neutrophil counts were evident for high dose males. These findings might be attributable to the inflammatory reactions at the injection sites.(ABSTRACT TRUNCATED AT 250 WORDS)

[Reproductive and developmental toxicity studies on cefepime dihydrochloride administered subcutaneously to rats during the premating, gestation and lactation periods].

Cefepime dihydrochloride (CFPM) was administered subcutaneously daily at doses of 0, 150, 500 and 1,000 mg/kg for 63 days prior to mating and during mating to male Crj: CD (SD) rats and for 14 days prior to mating and during mating, as well as periods of gestation and lactation to female SD rats. Saline and L-arginine hydrochloride (L-arginine) were used as control articles. Daily doses of test and control articles were equally divided and administered twice a day (b.i.d.). The results obtained are summarized as follows: 1. Soft stool was observed for both male and female F0 rats at CFPM 1,000 mg/kg at the first week of administration period. Further, depilation of injection sites was found in 7 males and 12 females at the same dose level. 2. Body weight gains were suppressed in male F0 rats from Day 28 to 63 of administration period at CFPM 1,000 mg/kg. Moreover, food consumption was reduced in F0 female rats during the first week of administration period at all dose levels of CFPM. 3. CFPM failed to affect the reproductive performance in both male and female F0 rats. 4. Kidney weights were increased in both male and female F0 rats and adrenal weights were augmented in male F0 rats at CFPM 1,000 mg/kg. On the other hand, cecal enlargement were observed for F0 dams treated with CFPM. However, these changes were not considered to be unique to this drug, because they have been described with most antibiotics in this species and appears to be results of modifications in gut flora. 5. Prenatal developments in F1 fetuses were not affected by CFPM. 6. CFPM failed to affect delivery status of F0 dams or survival and lactation indices in F1 pups. 7. CFPM did not affect postnatal differentiations, developmental behaviors, learning ability and memory, spontaneous motor activity or emotionality in F1 rats. 8. Body weight gains and food consumption in both male and female F1 rats were not affected by CFPM. 9. CFPM did not alter the organ weights in both male and female F1 rats. 10. There were no significant differences between drug treated animals and controls regarding the reproductive performance and delivery status of F1 rats. 11. Influences on survival indices, body weights and organ weights were not apparently observed for F2 pups even at CFPM 1,000 mg/kg. Based on the reproductive and developmental indices, the no-effect dose level of CFPM under the present experimental condition was estimated to be 1,000 mg/kg/day against dams (F0) and their offspring (F1).

Cryopreservation of in vitro-cultured multiple bud clusters of asparagus (Asparagus officinalis L. cv Hiroshimagreen (2n=30) by the techniques of vitrification.

A culture line of asparagus forming green bulbous structures consisting of numerous multiple bud clusters designated "bud clusters" was induced from a meristem culture of asparagus (Asparagus officinalis L.cv. Hiroshimagreen, 2n=30). Small cubic segments (2 mm3) cut from bud clusters were cryopreserved using three different cryogenic protocols. Only vitrification produced very high levels of shoot formation after cooling to -196°C. Segments were treated with a vitrification solution (PVS2) at 25°C for 45 min or at 0°C for 120 min prior to a direct plunge into liquid nitrogen. After rapid warming, the segments were expelled into Murashige and Skoog medium containing 1.2 M sucrose for 10 min and then plated on agar shoot outgrowth medium. The average rate of shoot formation of vitrified segments producing normal shoots was near 90% without any preculture and/or cold-acclimation treatment. Revived segments resumed growth within 3 days and developed about three shoots per segment. In vitro-cultured bud clusters appear promising as material for cryopreserving asparagus germplasm.

[Single dose oral toxicity study of BMY-28100 in juvenile rats and dogs].

In order to investigate the single dose oral toxicity of BMY-28100 in juvenile animals, the drug was administered in single doses to 4-day-old and 14-day-old Crj: CD (SD) rats of both sexes at a dose of 2,000 mg/kg, and to 4-week-old beagle dogs of both sexes at doses of 500, 1,000 and 2,000 mg/kg by oral route. The results obtained are summarized as follows: 1. In rats, decreases of the body weight gain were observed for male and female rats treated with the drug on postnatal day 4 through 5 days and 3 days after dosing, respectively. There were no apparent drug-related toxic signs. No deaths occurred during the observation period. Enlargement of the cecum was found in a few rats of both sexes administered the drug on postnatal day 4 or 14. 2. In dogs, watery-mucous diarrhea observed at 2 to 3 hours after dosing in all dose groups was not dose-related. This finding lasted in some dogs till 4 days after dosing. An increased incidence of emesis was induced in all males at 2,000 mg/kg and all females of all dose groups except one female at 2,000 mg/kg. Body weights increased normally for all dogs, but one male at 1,000 mg/kg showed a transient decrease in food consumption. No drug-related histopathological changes were found. Based upon these results, BMY-28100 at 2,000 mg/kg induced no apparent toxic changes in the present experimental conditions. Therefore, the single dose oral toxicity of the drug in juvenile animals appeared to be very slight and generally similar to that in adults.(ABSTRACT TRUNCATED AT 250 WORDS)

[Four-week repeated dose oral toxicity study of BMY-28100 in juvenile rats].

In order to investigate the repeated dose oral toxicity of BMY-28100 in juvenile rats, the drug was administered orally to 4-day-old Crj: CD(SD) rats of both sexes at daily doses of 250, 750 and 1,500 mg/kg for 4 weeks. The results obtained are summarized as follows: 1. Soiling around the anus apparently correlated to soft stool or diarrhea was observed at 750 and 1,500 mg/kg and the incidence appeared to be dose-related. Three deaths including 1 death due to cannibalization occurred at 750 and 1,500 mg/kg, but they were considered to have been caused by misadministration. 2. Slightly depressed body weight gains were noted in the 750 and 1,500 mg/kg dose groups during early dosing period. 3. Slightly increased averages of food and water consumption observed predominantly in the 1,500 mg/kg dose group at later dosing period and the recovery period were considered as incidental and unrelated to the treatment. 4. Though average values of some blood chemical parameters were slightly suppressed or elevated compared with those of controls at the completion of the dosing and recovery periods, these differences appeared to be generally within normal ranges and to be irrelevant to the drug treatment. No definitive drug-related changes were detected in hematological examinations and urinalyses. 5. The average absolute and/or relative organ weights of the brain, thymus, lungs and liver from male rats in the 1,500 mg/kg dose group were lower than those of the corresponding organs from controls. However, these findings were not considered to be toxicologically significant because no corroborative changes were detected microscopically. 6. Macroscopic and microscopic examinations demonstrated dilatation of the cecum in a dose-related fashion. This phenomenon has been reported with other antibiotics and appears to be drug-related and reversible caused by an alteration of the gut flora. There were no other microscopic changes that were considered to be related to the administration of the drug. 7. Electron microscopic examination revealed no drug-related changes in the liver and kidneys from rats of the 1,500 mg/kg dose group. Based upon these results, the no-effect dose level of BMY-28100 was estimated to be 250 mg/kg/day for both male and female juvenile rats in the 4-week repeated dose oral toxicity study if the finding of cecum dilatation was not considered.(ABSTRACT TRUNCATED AT 400 WORDS)

[Immunological properties of BMY-28100 and cefepime].

Immunogenicity, eliciting antigenicity and cross-reactivity of new cephem antibiotics, BMY-28100 and cefepime, were studied by means of passive cutaneous anaphylaxis (PCA), passive hemagglutination (PHA) and active systemic anaphylaxis in guinea pigs, and of PCA in mice and the results were compared with those obtained with reference antibiotics. In addition, the direct Coombs' reaction of the human blood was examined in vitro for the test antibiotics as compared with reference antibiotics. The results obtained are summarized as follows: 1. Immunogenicity Immunogenicity of unconjugated antibiotics was examined using the corresponding conjugates with bovine gamma-globulin (BGG) as eliciting antigen. When used as emulsions with Freund's complete adjuvant, cephalothin (CET) and benzylpenicillin (PCG) produced IgG1 and IgM antibodies in guinea pigs. However, cefepime as well as cephalexin (CEX) did not produce these antibodies, and BMY-28100 showed slightly active sensitization only for anaphylactic shock. In BALB/c and C3H/He mice, BMY-28100 and cefepime failed to produce antibodies under the experimental condition while IgE antibody formation to CET was observed. 2. Eliciting antigenicity Unconjugated CET and PCG provoked anaphylactic signs in guinea pigs sensitized with their conjugates with rabbit serum albumin (RSA). Cefepime, however, provoked no anaphylactic shock and BMY-28100 as well as CEX showed slight signs. In the other systems examined, no reactions were observed when elicited with BMY-28100, cefepime or the reference antibiotics. 3. Immunological cross-reactivity BMY-28100 did not cross-react with the reference antibiotics. While the antiserum to the RSA conjugate of CET provoked weak cross-reaction on PHA with the BGG conjugate of cefepime, the antiserum to the RSA conjugate of cefepime failed to react with the BGG conjugate of CET. Other cross-reactivities of cefepime were not observed against the reference antibiotics. 4. In vitro direct Coombs' reaction BMY-28100 did not induce the Coombs' reaction of the human blood in vitro at the testable concentration of 10 mg/ml. Cefepime or cefazolin (CEZ) caused no reaction even at a high concentration of 80 mg/ml, while CET and PCG caused a positive reaction at 10-40 mg/ml and 60 mg/ml, respectively. As shown above, immunogenicity and eliciting antigenicity of BMY-28100 and cefepime were somewhat weaker than CET and PCG but similar to CEX, and cross-reactivities of the test antibiotics with these reference antibiotics were not observed in general. The ability of BMY-28100 to give a positive reaction in the Coombs' test was weaker than that of CET, and that of cefepime was weaker than CET and PCG and equivalent to CEZ.(ABSTRACT TRUNCATED AT 400 WORDS)

[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.

[Antigenicity study of buspirone hydrochloride in guinea pigs and mice].

Buspirone hydrochloride(buspirone) and buspirone-ovalbumin mixture were examined for their antigenicity in guinea pigs and mice in comparison with ovalbumin (OVA) and 2, 4-dinitrochlorobenzene (DNCB)-OVA conjugate. The results obtained were as follows: 1. When guinea pigs were sensitized with buspirone or buspirone-OVA emulsified with Freund's complete adjuvant (FCA), these animals showed negative reactions in active systemic anaphylaxis (ASA), active cutaneous anaphylaxis (ACA), passive cutaneous anaphylaxis (PCA), passive hemagglutination (PHA) and Schultz-Dale test. 2. When mice were sensitized with buspirone or buspirone-OVA adsorbed to alum, these animals revealed a negative reaction in PCA using rats. 3. As positive controls, guinea pigs were sensitized with OVA or DNCB-OVA emulsified with FCA, and mice with OVA or DNCB-OVA adsorbed to alum. As a result, these animals disclosed positive reactions in ASA, ACA, PCA, PHA and Schultz-Dale test. As shown above, buspirone was considered to possess neither antigenic nor haptenic properties.

[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.

Teratogenic effects of carboplatin, an oncostatic drug, administered during the early organogenetic period in rats.

In the preceding study, no teratological effects against rat fetuses were observed when carboplatin, an oncostatic platinum coordination complex, was dosed to their dams from days 7 to 17 of gestation at a dose level of 4 mg/kg/day. However, there are a few reports which show the teratogenic action of carboplatin injected from days 6 to 15 of pregnancy at a dose level of 6 mg/kg/day. In the present study, carboplatin was administered intravenously to pregnant female Crj: CD (Sprague-Dawley) rats from days 6 to 9 or 7 to 10 of gestation at a dose level of 6 mg/kg/day in order to know the teratogenicity of this drug. Carboplatin were highly embryolethal in dams when dosed from days 6 to 9 of gestation, but not in animals when injected from days 7 to 10 of pregnancy. Carboplatin also produced external, internal and skeletal anomalies in fetuses such as gastroschisis, dilatation of cerebral ventricles, cleft sternum, fused ribs, malformed thoracic vertebra when administered from days 6 to 9 of gestation, but not in conceptuses when dosed from days 7 to 10 of pregnancy. However, the delayed ossification which was ascribed to the fetal growth retardation was observed in rats treated with this drug during both administration periods. These results suggest that carboplatin is embryotoxic, inducing intrauterine death and congenital malformations in rats, when injected during the early stages of gestation including day 6 of pregnancy.

[Antigenicity study of carboplatin in guinea pigs and mice].

Carboplatin and carboplatin-ovalbumin mixture were examined for their antigenicity in Hartley guinea pigs as well as BALB/c and C3H/He mice in comparison with ovalbumin (OVA) and 2,4-dinitrochlorobenzene (DNCB)-OVA conjugate. The results obtained were as follows: 1. When guinea pigs were sensitized with carboplatin or carboplatin-OVA emulsified with Freund's complete adjuvant (FCA), these animals showed negative reactions in active systemic anaphylaxis (ASA), active cutaneous anaphylaxis (ACA), passive cutaneous anaphylaxis (PCA), passive hemagglutination (PHA) and Schultz-Dale test. 2. When mice were sensitized with carboplatin or carboplatin-OVA adsorbed to alum, these animals revealed a negative reaction in PCA using rats. 3. As positive controls, guinea pigs were sensitized with OVA or DNCB-OVA emulsified with FCA, and mice with OVA or DNCB-OVA adsorbed to alum. As a result, these animals disclosed positive reactions in ASA, ACA, PCA, PHA and Schultz-Dale test. As shown above, carboplatin was considered to possess neither antigenic nor haptenic properties. In addition, the dose levels of carboplatin employed in the present experiment were confirmed not to suppress immune reactions.

[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.