Exploration of Mental Health Issues of Students among University Health Science Academics in Japan.

Academic educators in universities are well positioned to detect early signs and symptoms of unexplained behaviour change in students that could be the beginning of mental health issues. The purpose of this research was to explore the attitudes, beliefs, knowledge and practices of university academics in Japan towards health science students with psychological/mental health issues. This study used a qualitative descriptive design. Three focus groups using a semi-structured interview guide were conducted with 15 academics teaching health science students. Data were collected between March to October 2019. Themes revealed three areas of interest: 1) Reflection on mental health issues in Japan with sub-themes "family issues"; "society expectations and changes", and "stigma"; 2) Reflection on students' mental health issues with sub-themes "student behaviors", "staff involvement", "barriers encountered"; and, 3) Potential supports with sub-themes "university assistance", "communication and connection", and "interventions and prevention." The findings provide insight and can benefit student populations across diverse cultural university settings. Further research to investigate academic staff support with early recognition of mental ill-health and ability to provide information and advice to students is warranted. Recommendations include mental health education for academics and for students to encourage healthy university campuses and well-being within the community.

Mott transition by an impulsive dielectric breakdown.

The transition of a Mott insulator to metal, the Mott transition, can occur via carrier doping by elemental substitution, and by photoirradiation, as observed in transition-metal compounds and in organic materials. Here, we show that the application of a strong electric field can induce a Mott transition by a new pathway, namely through impulsive dielectric breakdown. Irradiation of a terahertz electric-field pulse on an ET-based compound, κ-(ET) 2Cu[N(CN) 2]Br (ET:bis(ethylenedithio)tetrathiafulvalene), collapses the original Mott gap of ∼30 meV with a ∼0.1 ps time constant after doublon-holon pair productions by quantum tunnelling processes, as indicated by the nonlinear increase of Drude-like low-energy spectral weights. Additionally, we demonstrate metallization using this method is faster than that by a femtosecond laser-pulse irradiation and that the transition dynamics are more electronic and coherent. Thus, strong terahertz-pulse irradiation is an effective approach to achieve a purely electronic Mott transition, enhancing the understanding of its quantum nature.

Enhancement of Photoinduced Charge-Order Melting via Anisotropy Control by Double-Pulse Excitation in Perovskite Manganites: Pr_{0.6}Ca_{0.4}MnO_{3}.

To control the efficiency of photoinduced charge-order melting in perovskite manganites, we performed femtosecond pump-probe spectroscopy using double-pulse excitation on Pr_{0.6}Ca_{0.4}MnO_{3}. The results revealed that the transfer of the spectral weight from the near-infrared to infrared region by the second pump pulse is considerably enhanced by the first pump pulse and that the suppression of crystal anisotropy, that is, the decrease of long-range lattice deformations due to the charge order by the first pump pulse is a key factor to enhance the charge-order melting. This double-pulse excitation method can be applied to various photoinduced transitions in complex materials with electronic and structural instabilities.

Relaxation dynamics of photoexcited excitons in rubrene single crystals using femtosecond absorption spectroscopy.

The relaxation dynamics of an exciton in rubrene was investigated by femtosecond absorption spectroscopy. Exciton relaxation to a self-trapped state occurs via the coherent oscillation with 78 cm(-1) due to a coupled mode of molecular deformations with phenyl-side-group motions and molecular displacements. From the temperature dependence of the decay time of excitons, the energy necessary for an exciton to escape from a self-trapped state is evaluated to be ~35 meV (~400 K). As a result, a self-trapped exciton is stable at low temperatures. At room temperature, excitons can escape from a self-trapped state and, subsequently, they are dissociated to charged species. The exciton dissociation mechanism is discussed on the basis of the results.

Probing ultrafast spin-relaxation and precession dynamics in a cuprate Mott insulator with seven-femtosecond optical pulses.

A charge excitation in a two-dimensional Mott insulator is strongly coupled with the surrounding spins, which is observed as magnetic-polaron formations of doped carriers and a magnon sideband in the Mott-gap transition spectrum. However, the dynamics related to the spin sector are difficult to measure. Here, we show that pump-probe reflection spectroscopy with seven-femtosecond laser pulses can detect the optically induced spin dynamics in Nd2CuO4, a typical cuprate Mott insulator. The bleaching signal at the Mott-gap transition is enhanced at ~18 fs. This time constant is attributable to the spin-relaxation time during magnetic-polaron formation, which is characterized by the exchange interaction. More importantly, ultrafast coherent oscillations appear in the time evolution of the reflectivity changes, and their frequencies (1400-2700 cm-1) are equal to the probe energy measured from the Mott-gap transition peak. These oscillations can be interpreted as the interference between charge excitations with two magnons originating from charge-spin coupling.

Novel electronic ferroelectricity in an organic charge-order insulator investigated with terahertz-pump optical-probe spectroscopy.

In electronic-type ferroelectrics, where dipole moments produced by the variations of electron configurations are aligned, the polarization is expected to be rapidly controlled by electric fields. Such a feature can be used for high-speed electric-switching and memory devices. Electronic-type ferroelectrics include charge degrees of freedom, so that they are sometimes conductive, complicating dielectric measurements. This makes difficult the exploration of electronic-type ferroelectrics and the understanding of their ferroelectric nature. Here, we show unambiguous evidence for electronic ferroelectricity in the charge-order (CO) phase of a prototypical ET-based molecular compound, α-(ET)2I3 (ET:bis(ethylenedithio)tetrathiafulvalene), using a terahertz pulse as an external electric field. Terahertz-pump second-harmonic-generation(SHG)-probe and optical-reflectivity-probe spectroscopy reveal that the ferroelectric polarization originates from intermolecular charge transfers and is inclined 27° from the horizontal CO stripe. These features are qualitatively reproduced by the density-functional-theory calculation. After sub-picosecond polarization modulation by terahertz fields, prominent oscillations appear in the reflectivity but not in the SHG-probe results, suggesting that the CO is coupled with molecular displacements, while the ferroelectricity is electronic in nature. The results presented here demonstrate that terahertz-pump optical-probe spectroscopy is a powerful tool not only for rapidly controlling polarizations, but also for clarifying the mechanisms of ferroelectricity.

Slight promotion effects of intermittent administration of testosterone propionate and/or diethylstilbestrol on 3,2'-dimethyl-4-aminobiphenyl-initiated rat prostate carcinogenesis.

In order to determine the effects of intermittent hormonal manipulation on the promotion stage of rat prostate carcinogenesis, testosterone and/or estrogen were administered to F344 rats for 40 weeks after 20-weeks treatment with the prostate carcinogen, 3,2'-dimethyl-4-aminobiphenyl. For this purpose testosterone propionate (TP) and diethylstilbestrol (DES) were introduced into silastic tubes, 2- and 0.5-cm long, respectively, and implanted into the subcutis for seven repeated cycles of 30 days treatment and 10 days withdrawal. Intermittent administration of TP resulted in suppression of ventral prostate adenocarcinoma development and slight but non-significant increases in the incidences of invasive carcinomas of the lateral prostate and seminal vesicles. Intermittent administration of DES completely suppressed tumorigenesis in all sites and the combination of TP and DES generally inhibited prostate tumor development. Thus, under the present experimental conditions, no strong enhancing effects of cyclic hormonal manipulation were observed on rat prostate carcinogenesis. Indeed, the opposite appeared to be the case.

Highly metastatic hepatocellular carcinomas induced in male F344 rats treated with N-nitrosomorpholine in combination with other hepatocarcinogens show a high incidence of p53 gene mutations along with altered mRNA expression of tumor-related genes.

The carcinogenic and metastatic processes are thought to consist of a sequence of steps, and animal models featuring highly metastatic lesions are clearly necessary to allow analysis of the whole process of transformation from preneoplastic changes to high grade metastatic tumors, and to access effectiveness of therapeutic treatments of advanced cancers in vivo. The purpose of the present study was to establish a model and to screen for reported genetic alterations in induced lesions. In the present study, it was confirmed that lung metastasis of hepatocellular carcinomas (HCCs) induced in male F344 rats by N-nitrosomorpholine (NNM), given in the drinking water at a dose of 120 ppm for 24 weeks, was significantly enhanced by additional carcinogenic pretreatments and that a single i.p. injection of 100 mg/kg body weight N-diethylnitrosamine (DEN) alone was sufficient for that purpose. Molecular biological analyses of the induced lesions revealed point mutations in the p53 gene in 60.9% of HCCs, and elevated expression of mRNAs for p53, c-myc, c-fos, TGF-alpha, TGF-beta1, alpha-fetoprotein, GST-P, and GGT, and decreased mRNA expression of EGF and EGFR in HCCs when compared to controls. No obvious association of gene alterations with metastatic potential of primary tumors was found except for an increase in the incidence of p53 mutations. Since the process of metastasis is thought to be sequential and selective, further comparative analysis of metastatic and primary lesions should clarify the mechanisms involved in the multi-step process of metastasis.

[Thirteen-week oral toxicity study of propiverine hydrochloride in dogs].

A subacute oral toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out at dose-levels of 0, 1, 3, 9, and 27 mg/kg/day using male and female beagle dogs. They were treated for 13 weeks, followed by 5 weeks recovery period. The results obtained from the present study were as follows. 1. In the observation of general symptoms, mydriasis was observed in females receiving 3 mg/kg/day or more and in males receiving 9 mg/kg/day or more, every day, intermittently or sporadically. The incidence of mydriasis varied greatly in individuals. However, this sign disappeared within administration period. 2. Body weight gain was slightly suppressed in males and females receiving 27 mg/kg/day. 3. There were no significant changes in food consumption, water consumption, hematology, urinalysis and fecal occult blood, and no remarkable changes in ophthalmology, electrocardiogram. 4. Serum biochemical findings showed a decrease in Total cholesterol (T. cho), Free cholesterol (F. cho), Triglyceride (TG), Phospholipid (PL), Total protein (TP), Albumin (ALB), alpha 1-Globulin (alpha 1-GLO) and Calcium (Ca), and an increase in Alkaline phosphatase (Al P), gamma-Glutamyltranspeptidase (gamma-GTP) activities and Choresterol ester ratio (EST/T) in males and females receiving 27 mg/kg/day. Further, a decrease in lipoprotein-T. cho, -TG and -PL were noted, on the other hand, lipoprotein-T. cho, -TG and -PL in the liver tissue increased. Similar slight changes were observed in males and females receiving 9 mg/kg/day. 5. Pathological examination revealed an enlargement of hepatocytes in a few animals receiving 3 mg/kg/day. In males and females receiving 9 mg/kg/day or more, yellowish liver, a increase in liver weights, an enlargement of hepatocytes with fatty degeneration and the appearance of eosinophilic inclusions in the hepatocytes were observed. Furthermore, some males and females receiving 27 mg/kg/day showed a slight cellular infiltration in glisson's sheaths, proliferation of the bile ducts and deposition of lipid droplets. Histochemical examination of liver tissue showed an increase in Al P and gamma-GTP activities in addition. Electronmicroscopically, the proliferation of smooth endoplasmic reticulum, increases in myelin-like inclusions and small lipid droplets in the hepatocytes were noted and these changes suggested the induction of drug-metabolizing enzyme in the liver. 6. After 5 weeks recovery period, above-mentioned changes were disappeared and it was suggested that these were reversible ones. 7. From the above results, the non-effective dose and the toxic one were estimated to be 1 mg/kg/day and 9 mg/kg/day for males and females, respectively.

[Single-dose toxicity studies of tazobactam/piperacillin and tazobactam].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. Singe-dose toxicity studies in TAZ/PIPC and TAZ were carried out using mice and rats of both sexes and male dogs. The results were as follows. 1. A common clinical sign in mice and rats administered TAZ/PIPC or TAZ by all routes was soft stool. Other signs in mice and rats included a decrease in spontaneous motor activity and/or a decreased respiratory rate for the intraperitoneal (i.p.), subcutaneous (s.c.) or intravenous (i.v.) route. The animals administered by the i.v. route showed tremor for mice and clonic convulsion for rats before death. Hyperemia, hemorrhage or edema of the lung, and hemorrhage of the digestive tract were observed in these animals at necropsy. An enlargement of the spleen was seen in some of the surviving animals treated with TAZ/PIPC. 2. In dogs, TAZ/PIPC caused vomiting, and TAZ caused vomiting, respiratory abnormality, soft stool and diarrhea by the intravenous (i.v.) administration. 3. TAZ/PIPC or TAZ caused clinical signs such as the loss of hair at the injection site for the s.c. route, and necrosis of the tail for the i.v. route in mice and rats, also caused limping of the injected anterior limb in dogs. Necrosis and hemorrhage at the injection site, and peritonitis by the i.p. injection were observed at necropsy. These findings were due to the irritation of TAZ/PIPC or TAZ.(ABSTRACT TRUNCATED AT 250 WORDS)

[A six-month intraperitoneal repeated dose toxicity study of tazobactam/piperacillin and tazobactam in rats].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. A six-month intraperitoneal repeated dose toxicity study of TAZ/PIPC and TAZ including a one-month recovery period were carried out using male and female rats. The doses were 200, 400 and 800 mg/kg/day for TAZ/PIPC, and 40, 80 and 160 mg/kg/day for TAZ. The results were as follows. 1. No test article-related deaths occurred during the study period. No effect on clinical finding of survival rats was evident. 2. There was no dose-related increases of food consumption in both the males and females given TAZ/PIPC and PIPC. Slight reductions in body weight gain occurred in males given 800 mg/kg/day of TAZ/PIPC. 3. Decreases in erythrocyte, hemoglobin and hematocrit, and increases in reticulocytes were seen only at study termination in the group given 800 mg/kg/day of TAZ/PIPC. Increases in reticulocytes were seen only at study termination in the females given 80 or 160 mg/kg/day of TAZ. 4. A decrease in triglyceride levels was observed in the males given 800 mg/kg/day of TAZ/PIPC or 160 mg/kg/day of TAZ. 5. The ophthalmoscopic examination or urinalysis show no test article-related changes. 6. Enlarged ceca in all groups of animals given TAZ/PIPC and in the females given 160 mg/kg/day of TAZ were observed. 7. An increase of relative organ weight in liver was noted in the males and females given 800 mg/kg/day of TAZ/PIPC, in the males given 80 or 160 mg/kg/day of TAZ and in the females given 160 mg/kg/day of TAZ. 8. In the hepatocytes, accumulation of PAS-positive materials which was identified histochemically and ultrastructurally as glycogen, was present in the males given 800 mg/kg/day of TAZ/PIPC and in the males given 80 or 160 mg/kg/day of TAZ. 9. After a one-month recovery period, the changes of liver had generally disappeared, suggesting that they were reversible. 10. From the histopathological changes of liver, the no-toxic dose level in both the males and females was 400 mg/kg/day and 40 mg/kg/day for TAZ/PIPC and TAZ, respectively.

[A 52-week chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) in dogs].

A chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187), a new protease-inhibiting agent, was carried out using male and female beagle dogs. FUT-187 was orally administered to the dogs at dose levels of 7.5, 15, 30 and 60 mg/kg/day for 52 weeks, followed by 5 weeks' recovery period. Results are summarized as follows: 1. In general conditions, vomiting, salivation and the passage of mucousy stools were observed in dogs given 15 mg/kg/day or more, and diarrhea was observed at 30 mg/kg/day or more. One male given 15 mg/kg/day showed transient pallidity of the oral mucosa, and another male in the same group showed apnea and abdominal breathing. In addition, one male given 30 mg/kg/day was euthanatized due to extreme weakness, as weight loss and pallid oral mucosa, and another male in the same group died after showing acute toxic symptoms such as hyperpnea, tonic convulsion and ataxic gait. 2. Weight gain was slightly suppressed in females given 60 mg/kg/day. No significant changes in food consumption were observed. 3. Hematological examination revealed no statistically significant changes. Decreases in RBC counts, Ht values and Hb concentrations, and increased reticulocyte counts were observed in one male of 15 mg/kg/day group, which also showed pallid oral mucosa, and in one male of the 30 mg/kg/day group, which was euthanatized in a moribund state. 4. Blood biochemistry revealed increased GPT activity in males given 15 and 30 mg/kg/day and females given 60 mg/kg/day, which was accompanied by sporadic increases in GOT, A1P and/or gamma-GTP activities. Males given 30 mg/kg/day or more showed decreased total protein. 5. Hepatic function testing (ICG test) showed no statistically significant changes. One female given 60 mg/kg/day showed increased accumulating concentration of ICG. 6. There were no toxicological changes in urinalysis, fecal occult blood, renal function (PSP clearance), ophthalmological and electro-cardiographic examinations. 7. In pathological examination, inflammatory cell infiltration and microgranuloma formation in liver were noted periportally or perivenularly in both sexes given 15 mg/kg/day or more (except for 30 mg/kg/day males). In the some cases, atrophy, degeneration and necrosis of hepatocytes and/or fibrosis around inflammatory cells and microgranuloma were observed. In the spleen, one male given 15 mg/kg/day and one female given 60 mg/kg/day showed increased plasma cells in the red pulp. In the case sacrificed in a moribund condition, findings in the liver and spleen similar to those in surviving cases were detected, but were more severe, and the liver showed diffuse fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)

A fifty-two-week chronic toxicity study of halopredone acetate (THS-201) in dogs.

In order to evaluate the long-term-safety of halopredone acetate (THS-201: 17 alpha, 21-diacetoxy-2-bromo-6 beta, 9 alpha-difluoro-11 beta-hydroxy-1, 4-pregnadiene-3, 20-dione), a 52-week chronic toxicity study was performed on the basis of its local accumulation in dogs. In doses of 0.1, 0.5 and 2.5 mg/kg, THS-201 was injected into the right knee joint in both sexes of dogs every 2 weeks for 39 weeks and withdrawn for 13 weeks. In this study, the below slight local changes were observed in both sexes of dogs treated with 2.5 mg/kg/2 weeks of THS-201: focal loss of hair of the injection site, lesser stain in cartilage matrix of articular cartilage and meniscus in light microscopic examinations, and irregular thickness and elongation of collagen fibers, roughness of fibrous density and decrement of proteoglycans in electron microscopic examinations. In conclusion, systemic adverse effects were not observed in any dogs treated with THS-201.

[Single dose toxicity studies of suplatast tosilate (IPD-1151T)].

Single dose toxicity studies of suplatast tosilate (IPD-1151T) were carried out in mice, rats and dogs of both sexes. The results were as follows: 1. The LD50 values of IPD-1151T were as follows: Mice, 12,500 (both sexes) mg/kg or more in oral route (maximum dose for technical manner); Mice 81 (male) and 96 (female) mg/kg in intravenous route; Rats, 10,000 (both sexes) mg/kg or more in oral route (maximum dose for technical manner); Rats, 96 (male) and 93 (female) mg/kg in intravenous route; Dogs, 2,124 (male) and 2,660 (female) mg/kg in oral route. On the LD50 values, no sexual difference was apparent in all species, but the species difference was noted between the rodent and dog. LD50 values of dog were lower level than those of rodent. 2. As toxic signs, mucous diarrhea with specific smell was noted in orally administered rodent. In addition, rats showed soiled fur in the perianal. In intravenous route, the rodent showed dyspnea, tonic convulsion and lateral position and deaths occurred within 10 min in mice and within 30 min in rats after administration. Dog showed toxic signs similar to those in rodents and deaths occurred within 3 hours. 3. In pathological examinations, dead mice and dogs administered orally showed lung congestion, liver fading or slight hemorrhage in the endo-and/or exocardium. Dead rodent administered intravenously showed only slight hemorrhage and congestion in the lung. Alive mice, rats and dogs showed no remarkable changes. 4. The main cause of deaths seemed to be respiratory disturbance in all species.

[A thirteen-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T) in dogs].

A 13-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 50, 150, 450 and 1350 mg/kg/day using male and female beagle dogs. The results were as follows: 1. In general conditions, soft feces and diarrhea with specific smell were dose-dependently observed in males and females given 450 mg/kg/day or more. Both sexes given 1350 mg/kg/day, revealed reeling with dropped head, abnormal gait, dysstasia, lying at lateral or prone position, sedation, and tremor, and one male and one female in this group died after showing respiratory depression, collapse and cyanosis. 2. There were no significant or remarkable changes in body weight, food consumption, water consumption, ophthalmology, electrocardiogram, urinalysis, hematology, biochemistry, fecal occult blood test, and absolute and relative organ weights. 3. Pathological examination in dead animals revealed hemorrhagic change in the heart and slight vacuolar changes in hepatocytes. In survived animals, there were no pathological changes attributable to the IPD-1151T. 4. In electron microscopic examination, there were no abnormalities in the liver and kidney attributable to the IPD-1151T. 5. After 5-week recovery period, above-mentioned changes disappeared. 6. From the above results, the non-effective dose level and the toxic dose level were estimated to be 150 mg/kg/day and 1350 mg/kg/day, respectively, and no sex differences were found.

[Five-week subacute intravenous toxicity study of cefodizime sodium in dogs].

A subacute toxicity study of cefodizime sodium (THR-221), a new cephem antibiotics, was carried out using male and female beagle dogs. THR-221 was intravenously administered to the dog at dose levels of 500, 1000 and 2000 mg/kg/day for 5 weeks, followed by 4 weeks recovery period. Cefotetan (CTT) as a reference drug was administered in the same manner at a dose level of 2000 mg/kg/day. The summarized results obtained are as follows: 1. Vomiting and salivation were observed in dogs given 1000 and 2000 mg/kg/day of THR-221. However, it caused no deaths or significant effects on body weight and food consumption in all groups treated with THR-221. 2. No toxicological changes associated with the administration of THR-221 were found in urinary and hematological examinations. 3. In serum biochemical examinations, increase or tendencies of increase of albumin and A/G ratio, probably due to the antibacterial action of THR-221, were detected at all dose levels of THR-221. 4. There were no dose-related changes in hepatic and renal function, fecal occult blood, ophthalmological, electrocardiographic and auditory examinations, absolute and relative organ weights. 5. Histopathological examinations revealed fibrosis or granulation in perivascular area of injection sites, particularly in males given 2000 mg/kg/day of THR-221. 6. After 4 weeks of recovery period, above-mentioned changes were generally disappeared and it was suggested that these were reversible ones. 7. In groups treated with CTT (2000 mg/kg/day), damages were recognized mainly in erythron values, liver and kidney, as compared with the same dose of THR-221. Therefore the toxicity of THR-221 was less than that of CTT. 8. From these results, the non toxic effective dose level and the toxic dose level of THR-221 were estimated to be 500 mg/kg/day and more than 2000 mg/kg/day respectively, for male and female dogs.

[Acute toxicity studies of propiverine hydrochloride].

Acute toxicity studies of propiverine hydrochloride (P-4) were carried out in mice, rats and dogs of both sexes. 1. The LD50 values of P-4 were as follows: Mice; 410 (male) and 323 (female) mg/kg in oral route, 223 (male) and 283 (female) mg/kg in subcutaneous route and 36 (male and female) mg/kg in intravenous route, Rats; 1000 (male) and 1092 (female) mg/kg in oral route, 1632 (male) and 1411 (female) mg/kg in subcutaneous route, and 22 (male) and 25 (female) mg/kg in intravenous route. On the LD50 values, no sexual difference was apparent but the species difference between mice and rats observed to be present in oral and subcutaneous routes. The approximate lethal doses of P-4 in dogs were 987-1137 mg/kg for male and 865-894 mg/kg for female in oral route, and the values were almost same as those in rats of oral route. 2. Major toxic signs such as clonic convulsion, bradypnoea, dyspnoea, decreased spontaneous activity and hematuria were observed in mice and rats. Furthermore mydriasis in rats, and transitory salivation and/or vocalization in mice and rats were observed. In some rats, sedation, salivation, soil at hypogastrium, rale and emaciation were detected from the next day of oral administration. In dogs, toxic signs such as vomiting, tremor, tonic and/or clonic convulsion, mydriasis and gasping were observed. 3. Pathological changes observed in dead animals were congestion of lungs, liver and kidneys in all routes, congestion and hemorrhage in digestive tracts in oral route, inflammatory changes at the injection site in subcutaneous route. In addition, retention of hematuria in urinary bladder in rats of oral and subcutaneous routes, the hemorrhagic changes of heart, atonia of urinary bladder and retention of urine in dogs were observed. 4. The main cause of death seemed to be respiratory disturbance in all species and the weakness in a few rats of oral route.

[Three-month subacute oral toxicity study of mofezolac (N-22) in dogs].

Mofezolac (N-22) is a new developed analgesic and anti-inflammatory agent. A subacute oral toxicity test of N-22 was carried out at dose-levels of 0, 2, 6 and 20 mg/kg/day using male and female beagle dogs. Treatment for 3 months was followed by 1 month recovery period except in the case of both sexes receiving 20 mg/kg/day. The results obtained from the present study were as follows. 1. Observation of general conditions revealed vomiting, sporadic bloody feces, anemia, recumbency and hyposthenia in both sexes receiving 20 mg/kg/day. Anemia or erosion of tongue was observed in each female receiving 6 mg/kg/day. 2. Respectively 3 dogs of both sexes receiving 20 mg/kg/day died during dosing period. In these animals, perforating ulcers were observed in the pars pylorica ventriculi or duodenum, and loss of blood, peritonitis and aggravation of general exhaustion were considered as causes of death. 3. Body weight tended to decrease in both sexes receiving 20 mg/kg/day, and food and water consumption levels decreased in males receiving 2 mg/kg/day or above and females receiving 2 mg/kg/day. 4. Urinalysis demonstrated an increasing tendency for specific gravity of urine and a decreasing tendency for urine volume in males receiving 2 mg/kg/day or above. 5. Hematological examination showed decreases in red blood cell count and Hb concentration in males receiving 2 mg/kg/day or above, and in Ht values in males receiving 6 mg/kg/day or above. 6. Serum biochemical examination revealed decreases in total protein and albumin in both sexes receiving 20 mg/kg/day. 7. There were no remarkable changes in hepatic and renal function, ophthalmological findings or electrocardiogram. 8. In the organ weights, significant decrease in thymus weights was observed in the dead animals receiving 20 mg/kg/day. 9. Pathologically, the dead animals receiving 20 mg/kg/day were found to exhibit peritonitis with perforating ulcers in the pars pylorica ventriculi or duodenum. In the surviving animals of this group, scar ulcers in the pars pylorica ventriculi and small intestine were evident on necropsy, and histopathology revealed neutrophils infiltration and thrombosis in blood vessels in the thickened submucosal stomach tissues. Moreover, localized hepatocyte necrosis and intrasinusoidal cellular infiltration in liver, as well as interstitial cellular infiltration, degeneration and dilatation of the renal tubules in the kidney were observed. In females receiving 6 mg/kg/day, the changes in kidney were similar to those in surviving animals receiving 20 mg/kg/day, and male of the group showed atrophy of thymus.(ABSTRACT TRUNCATED AT 400 WORDS)

[A six-month intravenous repeated dose toxicity study of tazobactam/piperacillin and tazobactam in dogs].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. A six-month intravenous repeated dose toxicity study of TAZ/PIPC and TAZ including a one-month recovery period were carried out using male and female dogs. The doses were 200, 400 and 800 mg/kg/day for TAZ/PIPC, and 40, 80 and 160 mg/kg/day for TAZ. The results were as follows. 1. No test article-related deaths occurred during the study period. No effects on clinical findings, body weight and food consumption were evident. 2. No test article-related changes were noted in hematological, serum biochemical and urinalysis evaluations, and opthalmological and electrocardiographic examinations. 3. There were no test article-related changes in macroscopic findings or organ weight. 4. The histopathological examination revealed deposition of marked PAS-positive aggregates in liver cells of dogs given 400 mg/kg/day or more of TAZ/PIPC and 80 mg/kg/day or more of TAZ. Electron micrographs of hepatocytes revealed glycogen granules to be accumulated in the cytoplasm, and an increase of smooth endoplasmic reticulum. 5. After a one-month recovery period, the histopathological changes had generally disappeared, suggesting that they were reversible. 6. From the histopathological changes of liver, the no-toxic dose levels for TAZ/PIPC and TAZ were 200 mg/kg/day and 40 mg/kg/day, respectively.

[Acute toxicity study of cefodizime sodium].

Acute toxicity of cefodizime sodium (THR-221) was examined in mice of both sexes, rats of both sexes (including 5-day-old young), and male dogs. The LD50 values of THR-221 (mg/kg) were as follows: (1) mice: intravenous, 7200 for males and 5000 for females; intraperitoneal, 10500 for males and 11000 for females; subcutaneous, 17500 for males and 16500 for females; and oral, 28000 for males and 29000 for females. (2) rats (adult): intravenous, 7000 for males and 8200 for females; intraperitoneal, 9500 for males and 8800 for females; subcutaneous, 17000 for males and 15500 for females; oral, more than 20000 for both sexes; and intramuscular, more than 3200 for both sexes. (3) 5-day-old rats: subcutaneous, 5278 for males and 5314 for females. (4) male dogs: intravenous, more than 5000. Major changes in general conditions observed in mice and rats were decreased spontaneous activity, lying prone, respiratory changes, staggering gait, clonic or clonic-tonic convulsions, and cyanosis, and in the animals dosed orally, diarrhea or salivation was also noted. The changes in 5-day-old rats were respiratory changes, agony, loss of reflex to an external stimulus, and congestion at the injection site, and those in dogs were vomiting, dryness of the nose, and soft or mucous stools. Autopsies on the mice and rats which died revealed hemorrhage on the brain surface. In addition, the following were seen: intraperitoneal retention of fluid and dark red spots on the abdominal wall (i.p.), subcutaneous retention of fluid or jellylike material and hemorrhage at the injection site (s.c.), and retention of fluid and dark red spots on the mucosa in the digestive tract (mice p.o.). In 5-day-old rats which died, the subcutaneous tissue at the injection site showed hemorrhage macroscopically and inflammatory changes microscopically. Hematological and blood chemical tests performed in dogs showed an increase in white blood cells and changes suggesting anemia, increases in GOT, LDH and ALP activities, and slight changes in urea nitrogen and inorganic phosphorus. In one animal given a low dose of 2500 mg/kg, an increase in GPT activity was also seen. However, these changes were all transient. Microscopic findings in dogs were slight inflammatory changes in the subcutaneous tissue around the injection site.