Azole resistance in Malassezia pachydermatis has been reported in isolates from canine skin worldwide. Decreased susceptibility of M. pachydermatis to azoles has been hypothesized to potentially result from mutations in the ERG11 gene, which encodes lanosterol 14α-demethylase. To sequence the mutation hotspots of ERG11 in the isolates, we prepared primers (MPERG11hot2S and MPERG11hot2R) based on the conserved sequences of M. pachydermatis ERG11. DNA samples from azole-resistant and -susceptible strains were amplified by PCR using the primer pair. PCR amplicons were sequenced and analyzed for single-nucleotide polymorphisms (SNPs) in the target gene. Seven of the tested azole-resistant strains (16 strains) harbored ERG11 SNPs at nucleotide 904 (G→A) or 905 (C→T), resulting in the replacement of Ala 302 with Thr or Val (Ala302Thr or Val). None of the tested azole-susceptible strains had a mutation at either of those residues. Our PCR method detected SNPs at the nucleotide-905 (C→T) hotspot mutation site in M. pachydermatis ERG11. Moreover, we discovered an additional hot spot site at nucleotide 904 (G→A).

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Previous studies suggest that nonhuman animals form concepts that integrate information from multiple sensory modalities such as vision and audition. For instance, Adachi, Kuwahata, and Fujita (2007) demonstrated that form auditory-visual cross-modal representation of their owner. However, whether such multi-modal concepts would expand to more abstract, or collective, ones remains unknown. To answer the question, we tested whether were sensitive to congruence of human genders suggested by the voice and the face of an unfamiliar person. We showed to the a photograph of a male or female human face on the monitor after playing a voice of a person either matching or mismatching in gender. looked at the photograph for longer duration when the auditory stimuli were incongruent than when they were congruent; that is, expectancy violation was suggested. This result suggests that spontaneously associate auditory and visual information to form a cross-modal concept of human gender. This is the first report showing that cross-modal representation in nonhuman animals expands to an abstract social category.

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2頭のゴールデン・レトリーバーが全身の被毛減量と尾の脱毛を主訴に来院した。犬種と特徴的な臨床所見の他に, 雄の症例ではT₄値と治療試験から, 雌の症例ではT₄fT₄c-TSHの各検査値からともに甲状腺機能低下症と診断した。2症例ともレボチロキシンナトリウムの投与により症状は著しく改善された。

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Indomethacin (IMC) suspended in soybean oil was microencapsulated in a gelatinacacia system by a modified phase separation method from aqueous solution. The microcapsules were hardened with formaldehyde without the use of sodium hydroxide. Average particle diameter of the microcapsules was 111μm, and the content of IMC in the microcapsules was more than 80% of the initial amount of IMC. The in vitro dissolution of IMC from the microcapsules was slower than that of intact IMC, and this indicated that the walls of the microcapsules affected the drug dissolution. The bioavailabilities in beagle of the IMC microcapsules and of a soybean oil suspension of IMC administered in capsules were larger than that of intact IMC.

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Dissolution profiles of sulfamonomethoxine (SMM)/18-crown-6 (1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane) complex, SMM anhydrate and SMM hydrate were investigated by dispersed amount method and stationary disk method, and also in vivo absorption study of these compounds in was carried out in comparison with the data of the dissolution behaviors. According to the dispersed amount method, the concentration of SMM rose quickly and then decreased gradually when the complex was dispersed. On the other hand, a characteristic convex dissolution curve was observed in the case of the anhydrate. This result indicated that the dissolution rate of complex was extremely large, but its decomplexation accompanying the change to the hydrate form in water was also rapid compared with that of the anhydrate. The rate constant of phase change for the complex to the hydrate form, which was calculated by stationary disk method, was extremely large compared with that for the anhydrate. It was observed that the plasma levels of SMM increased extremely by the administration of the anhydrate form. An increase of plasma levels was also observed in the case of the complex.

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An apparent oral toxicity of 18-crown-6 (1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane) and sulfamonomethoxine (SMM)/18-crown-6 complex in was investigated following the bioavailability study of SMM/18-crown-6 complex which the authors reported already. When 18-crown-6 or SMM/18-crown-6 complex was administered orally to healthy beagle , the following symptoms appeared : a tremulous movement, a salivation and a paralysis of hind legs at 2-12 hr after administration. These symptoms disappeared at 24 hr after administration.

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are known to be extremely sensitive to human behavior. They use human gestures such as pointing as a cue better than great apes. A question here is whether this wonderful human companion simply reads apparent "behavior" of us, or, like humans, more deeply some sort of indirect information the behavior implies. In three separate tests, including pointing games with a non-trustworthy person, inference of the door function from human behavior toward it, and third-party affective evaluation of human interactions, we show that often utilize more than superficial actions they observe. are at least somewhat "cognitivists" rather than pure "behaviorists" that learn everything by simple association with observable stimuli.

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We have already recognized that Zn-DTPA (diethylenetriaminepentaacetic acid) is less toxic than Ca-DTPA when they are administered orally to rats. In this study, in order to estimate exactly the safety of Zn-DTPA by the oral administration in humans, by evaluating the degrees of damages in the different animal species between beagle and rats, we examined the toxicity of Zn-DTPA in beagle according to the same methods as the rat, and then the results were compared with those in the rat. Zn-DTPA was administered daily to beagle for 1 month, with the doses of 30, 150, 300μmol/kg body weight. The decreases of body weight, hemorrhage and congestion, and vascular expansion of the lamina propria mucosa and under the serious membrane of the small intestine, and the slight damages of kidney were observed. These changes were similar to those in rats at the same dose.
As a result, it is recognized that there are almost no differences on the Zn-DTPA toxicity between and rats, therefore the safety of orally administered Zn-DTPA in humans might be estimated from the results obtained in the animal experiments without considering the remarkable species differences.

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Recently, detection of canine primary adrenal mass has increased owing to progress in diagnostic imaging. Adrenocortical adenoma, adrenocortical carcinoma, and pheochromocytoma are representative primary adrenal masses; the latter two may invade intravascularly and metastasize to other organs. We encountered a dog exhibiting progressive hindlimb paraplegia. Multimodal imaging including computed tomography (CT) and magnetic resonance imaging (MRI) revealed that the cause of the paraplegia was infiltration of a left adrenal pheochromocytoma into the spinal canal. In addition, MRI detected small liver metastatic lesions that were not detected by CT.

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Optimal bone filling materials that act as a scaffold for the repair of bone defects should possess, histocompatibility, and afford conduction of new bone formation without toxicity or allergic factors. In addition, the materials should ultimatedly be resolved and replaced by new bone. In this study, to develop new bone filling materials that promote bone formation and bone growth, we implanted coral in bone defects and observed the newly-formed bone by confocal laser scanning microscopy (CLSM).
In 3 adult male beagles, bone defects were made in the right and left femora and tibiae under general anesthesia. These defects were either filled with coral blocks or left without any filling material. After 4 weeks, calcein was administered. One week later, the animals were euthanized under general anesthesia, and the femora and tibiae were removed and fixed in formalin. The specimens were divided into two portions: one is for CLSM observation and the other for histopathological observation.
The formation of bone and bone marrow was seen in holes without filling, but only slight bone growth, i.e., increase in bone mass was seen. In the holes with coral filling materials, they were resorbed by giant cells. Furthermore, new bone and bone growth were noted, while lymphocyte infiltration was slight in all holes. Since resorption of the coral inserted into the bone defect was observed, we concluded that coral could be useful for bone regeneration.

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A 6-month repeated dose toxicity study with 1-month recovery test of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, was conducted in beagle . The of both sexes were administered ONO-5046·Na intravenously at a daily dose of 0(vehicle control), 7.5, 15 or 30 mg/kg. In the 15 mg/kg and above groups, transient ataxic gait was observed. It is considered that this symptom could be attributed to the pharmacological effect of ONO-5046·Na. Macro-and micro-scopic hemorrhage at the injection site was observed in the ONO-5046·Na treated groups. However, it is considered that these findings could be attributed to the long-term repeated dosing procedure, and were not toxic changes. There were no treatment-related changes in body weight, food consumption, opthalmology, urinalysis, hematology, blood chemistry, electrocardiography and organ weights. These results indicate that the NOAEL of ONO-5046·Na in is 30 mg/kg/day for both sexes in this study.

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4-week repeated dose toxicity study with 4-week recovery test of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, was conducted in beagle . The of both sexes were administered ONO-5046·Na intravenously at a daily dose of 0(vehicle control), 7.5, 15 or 30 mg/kg. In the 15 mg/kg female group and the 30 mg/kg male and female groups, transient hypoactivity and ataxic gait were observed. It is considered that these symptoms were attributed to the pharmacological effect of ONO-5046·Na. Also, in the 30 mg/kg male and female groups, erythrocyte, hematocrit and hemoglobin were decreased.In the 30 mg/kg male group, lung weight was increased. However, histopathological examination revealed there were no changes in any organs including the lungs. There were no treatment-related changes in body weights, food consumption, opthalmology, occult blood in feces, urinalysis, blood chemistry, electrocardiography, blood pressure, temperature, pulse rate, hepatic and renal function or necropsy. These results indicate that the NOAEL of ONO-5046·Na in is 15 mg/kg/day for both sexes in this study.

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Single-dose toxicity studies of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel neutrophil elastase inhibitor, were conducted in Sprague-Dawley(SD)rats and beagle . The rats of both sexes were administered ONO-5046·Na intravenously at a single dose of 150, 300 or 450 mg/kg. The male were also given ONO-5046·Na at a single dose of 75 or 150 mg/kg. In the rat study, hypoactivity, bradypnea and paleness of limbs and pinna were observed at doses of 300mg/kg and above. In particular, one of six female rats in the 450 mg/kg group showed clonic convulsion and died. In surviving animals, those signs disappeared within 3 hr after administration. No effect on body weight gain was seen in either group. Necropsy findings showed a slight foamy fluid in the bronchus, hemorrhage at the right knee joint muscle, tendon and lung in a dead animal. In the dog study, no effects on clinical signs, body weight, food consumption and blood biochemistry were seen in any animals of the 75 and 150 mg/kg groups. It is concluded that the approximate lethal doses are 450 mg/kg in rats and 150 mg/kg and above in .

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NS-21を0, 3, 17.5および100mg/kgの投与用量でイヌに12力月間反復経口投与し, さらに同投与群について2力月間の回復試験を実施して, 以下の成績を得た。1. 一般臨床検査では, 死亡は全ての投与群でみられず, 散瞳, 嘔吐, 体重の減少ないしは増加抑制が17.5mg/kg以上の投与群で, 流涎および摂餌量の減少が100mg/kg投与群で認められた。眼科学的検査では一般状態でもみられた散瞳が17.5 mg/kg以上の投与群で認められた。摂水量の推移および心電図検査においては特に記すべき変化は認められなかった。2. 尿検査では, 特に記すべき変化は認められなかった。3. 血液学的検査では, 特に記すべき変化は認められなかった。4. 血液化学的検査では, GPTおよびALPの上昇が17.5mg/kg以上の投与群で, GOTの上昇, TGの増加, TPの減少が100mg/kg投与群で認められた。5. 病理学的検査では, 肝細胞肥大が100mg/kg投与群で認められ, 電顕的には肝細胞における滑面小胞体の増生およびライソゾームの増加が17.5 mg/kg以上の投与群でみられ, 小胞体由来の同心円状層状構造物が100mg/kg投与群で認められた他, 肝内胆汁うっ滞が17.5mg/kg以上の投与群で認められた。6. 血漿中のNS-21およびその活性代謝物であるRCC-36の濃度は用量依存的に増加し, 投与期間による差はみられなかった。7. 回復期間終了時には, 上述した変化はいずれも良好な回復性ないしは回復傾向が確認された。以上の結果, 本試験における無毒性量は3mg/kgであると推察された。

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NS-21を0, 5, 25および125mg/kgの投与用量でイヌに13週間反復経口投与し, さらに同投与群について5週間の回復試験を実施して, 以下の成績を得た。1. 一般臨床検査では, 死亡は全ての投与群でみられず, 散瞳, 体重の減少ないしは増加抑制が25mg/kg以上の投与群で, 嘔吐, 流涎および摂餌量の減少が125mg/kg投与群で認められた。眼科学的検査では一般状態でもみられた散瞳が125mg/kg投与群で認められた。心電図検査においては特に記すべき変化は認められなかった。2. 尿検査では, 特に記すべき変化は認められなかった。3. 血液学的検査では, 血小板数の増加が125mg/kg投与群で認められた。4. 血液化学的検査では, GPTおよびALPの上昇およびalbuminの減少が25mg/kg以上の投与群でみられ, TGの増加が125mg/kg投与群で認められた。5. 病理学的検査では, 肝細胞肥大が125mg/kg投与群で認められ, 電顕的には肝細胞における滑面小胆体の増生, 小胆体由来の同心円状層状構造物が25mg/kg以上の投与群で認められた他, 肝内胆汁うっ滞および腸間膜リンパ節における巨核球の出現が25mg/kg以上の投与群で認められた。6. 回復期間終了時には, 上述した変化はいずれも良好な回復性ないしは回復傾向が確認された。以上の結果, 本試験における無毒性量は5mg/kgであると推察された。興奮に基づく頻尿や尿失禁等の症状を改善すると考えられている。今回, 著者らはNS-21の安全性評価の一環として, イヌの13週間反復経口投与毒性試験ならびに5週間回復試験を実施したので, その成績を報告する。

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NS-21のマウス, ラットおよびイヌにおける単回投与毒性試験を実施し, 以下の成績を得た。LD₅₀値は, 経口投与ではマウスの雄で852mg/kg, 雌で1167mg/kg, ラットの雄で2839mg/kg, 雌で1739mg/k9, 腹腔内投与ではマウスの雄で324mg/kg, 雌で390mg/kg, ラットの雄で423mg/kg, 雌で359mg/kgであった。皮下投与ではマウス, ラットともに死亡は認められず雌雄で5000mg/kg以上であった。イヌの経口投与では5000mg/kg投与でも死亡は認められなかったが, 嘔吐がみられたことから最小致死量は求められなかった。一般状態では, いずれの動物, 投与経路においても散瞳が観察された。マウス, ラットの経口および腹腔内投与では, 自発運動の減少, 腹臥位ないしは横臥位, 呼吸数減少, 体温低下, 歩行失調, 攣縮および間代性症撃が認められ, さらにラットの経口投与で流延が, 経口および腹腔内投与では流涙がみられた。マウス, ラットの皮下投与では投与部位皮膚の痂皮形成が観察された。イヌでは散瞳の他, 嘔吐, 結膜ならびに口腔粘膜の充血, 腹臥位, 振戦および間代性痙攣がみられた。体重の増加抑制ないしは減少が, マウス, ラットの各投与経路で認められた。イヌでは体重および摂餌量の減少が認められた。剖検では, 肺の充血がマウス, ラットの経口および腹腔内投与の死亡例で認められた。小腸の拡張が, マウス, ラットの経口投与の死亡例およびラットの腹腔内投与の生存例で認められた。マウス, ラットとも腹腔内投与で, 腹腔内諸臓器の癒着が認められた。イヌでは重量の減少を伴った胸腺の萎縮が認められた。

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Prulifloxacinの反復投与毒性を検討するために,0,30,150および750mg/kgの投与量で,イヌを用いた4週間経口投与毒性試験および4週間回復試験を実施し,以下の結果を得た。1. 150 mg/kg以上の投与群で白色物含有便の排泄が認められ,750 mg/kg投与群では流涎,腹臥,横臥,座位,歩行困難および自発運動の低下がみるれた。体重,摂餌量および摂水量の減少が750 mg/kg投与群で認められた。死亡は全ての群で認められなかった。2. 眼科学的検査,心電図検査ならびに尿検査では,被験物質投与の影響は認められなかった。3. 血液学的検査では,750 mg/kg投与群でWBCの減少が認められた。4. 血液化学的検査では,750 mg/kg投与群でGPTおよびα₂-グロブリン比率の上昇が認められた。5. 病理学的検査では,150 mg/kg以上の投与群で上腕骨と大腿骨の関節軟骨に基質の粗鬆化,空隙および糜爛が,関節滑膜に炎症性細胞浸潤がみられ,750 mg/kg投与群では関節滑膜に限局性の出血が認められた。腎臓では,750 mg/kg投与群で尿細管上皮の再生,炎症性細胞浸潤,間質の線維化および尿細管腔内に結晶物が観察された。6. 回復試験では,上腕骨と大腿骨の関節軟骨の変化ならびに腎臓の変化が依然として観察された。その他の投与期間終了時にみられた変化については良好な回復性が確認された。7. 被験物質活性本体の血漿中および尿中濃度は投与量に依存して増加を示し,その増加度に性差は認められなかった。また反復投与に伴う血漿中濃度の変化も認められなかった。以上のごとく,30 mg/kg投与群では変化は何も認められず,今回の試験で得られた無毒性量は30 mg/kgであった。

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PrulifloxacinおよびNM394のマウス,ラットおよびイヌにおける単回投与毒性試験を実施し,以下の成績を得た。LD₅₀値は,prulifloxacinのマウス経口および皮下投与で雌雄ともに5000 mg/kg以上,腹腔内投与で雄1757 mg/kg,雌1652 mg/kg,ラット経口および皮下投与で雌雄ともに5000 mg/kg以上,腹腔内投与で雄915 mg/kg,雌1076 mg/kg, NM394のラット静脈内投与で雄226 mg/kg,雌238 mg/kgであった。また,prulifloxacinのイヌ経口投与では致死量は雌雄ともに5000 mg/kg以上と推定された。一般状態観察では主な症状として,マウスで鎮静,呼吸数減少,異常歩行,立毛,閉眼,振戦,皮下投与部位の痂皮形成等が認められ,ラットで自発運動の低下,呼吸数減少,流涙,体温の低下,立毛,異常歩行,間代性痙攣,呼吸困難,皮下投与部位の痂皮形成,静脈内投与部位の充血,腫脹,壊死,痂皮形成等が認められた。また,イヌでは嘔吐,皮膚の発赤(耳介内面,腹部),軟便の排泄が認められた。体重推移ではマウス腹腔内投与およびラットの各投与経路で減少あるいは増加抑制が認められた。病理解剖学的所見として,マウスで肝臓および脾臓の退色,肝臓の肥厚,腹腔内諸臓器の癒着,ラットで胸水の貯留,肺の充血・水腫,腹腔内諸臓器の癒着,腎臓における微細な黄白色点状巣,腎臓の腫大,精巣萎縮等が認められた。

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