ABSTRACT
A molecular survey was conducted to understand recent distribution of pathogens associated with canine infectious respiratory disease (CIRD) in Japan. Nasal and/or pharyngeal swabs were collected from asymptomatic dogs and those with CIRD, living in private house or in kennels. PCR-based examination was conducted for detecting nine pathogens. Among private household dogs, 50.8% with CIRD, 11.1% with respiratory disease other than CIRD, and 4.3% asymptomatic were positive for more than one pathogen, whereas in kennel-housed dogs, 42.9% with CIRD and 27.3% asymptomatic were positive. Bordetella bronchiseptica was most frequently detected, followed by canine herpesvirus 1, canine parainfluenza virus, canine pneumovirus, Mycoplasma cynos, and canine adenovirus type 2. In kennel environment, asymptomatic dogs might act as reservoirs carrying the respiratory pathogens.
Subject(s)
Dog Diseases/diagnosis , Molecular Diagnostic Techniques/veterinary , Respiratory Tract Infections/veterinary , Animals , Bordetella bronchiseptica , Dog Diseases/microbiology , Dog Diseases/virology , Dogs , Female , Japan , Male , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/virologyABSTRACT
To improve the metabolic stability of 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, we designed and synthesized new taxane analogues. Most of the synthetic compounds maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes. And some compounds exhibited potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration similarly to 3.
Subject(s)
Antineoplastic Agents/chemistry , Taxoids/chemistry , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Humans , Melanoma, Experimental/drug therapy , Melanoma, Experimental/metabolism , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Taxoids/metabolism , Taxoids/therapeutic useABSTRACT
It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.
Subject(s)
Taxoids/chemical synthesis , Acetals/chemical synthesis , Acetals/metabolism , Acetals/pharmacology , Animals , Antineoplastic Agents , Cell Division/drug effects , Drug Design , Drug Stability , Humans , Mice , Microsomes, Liver/metabolism , Structure-Activity Relationship , Taxoids/metabolism , Taxoids/pharmacologyABSTRACT
Antitumor activity of combination chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin was compared to that with CPT-11 and cisplatin. In vitro cytotoxicity of SN-38 (an active metabolite of CPT-11) in combination with nedaplatin or cisplatin was evaluated using three human cervical cancer cell lines (ME-180, CaSki and SiHa). IC50 values of nedaplatin against these three human cervical cancer cell lines were about 2-fold as high as those of cisplatin, indicating somewhat weak cytotoxic effects of nedaplatin. Interactions between two drugs in combination were investigated using a simultaneous-exposure schedule and analyzed by the IC50-based isobologram method. Simultaneous exposure to SN-38 with each platinum preparation showed synergistic and additive effects against ME-180 and SiHa. In vivo antitumor effects of CPT-11 in the combination with each platinum were studied using SiHa xenografts. While CPT-11, nedaplatin and cisplatin alone hardly showed any antitumor effects even at the maximum tolerated dose (MTD) levels, the combination chemotherapy with CPT-11 and nedaplatin or cisplatin resulted in significant antitumor effects even at three-quarter MTD of CPT-11 combined with two-third MTD of platinum. All treatments were tolerable for mice, indicating that the combinations did not cause significant enhancement in toxicity. In clinical application, nedaplatin causes a lower incidence of nephropathy and does not require the replacement of a large volume of fluid, which is needed for cisplatin administration, facilitating treatment at the out-patient clinic. In addition, the incidences of digestive disorder, peripheral neuropathy and auditory disorder are lower. These findings suggest that the combination chemotherapy with CPT-11 and nedaplatin for squamous cell cancer of uterine cervix is very useful in clinical practice. A dose-finding study should be conducted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Neoplasms, Experimental/drug therapy , Uterine Cervical Neoplasms/drug therapy , Animals , Camptothecin/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Cell Division/drug effects , Cisplatin/administration & dosage , Dose-Response Relationship, Drug , Female , Humans , Inhibitory Concentration 50 , Irinotecan , Maximum Tolerated Dose , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasms, Experimental/pathology , Organoplatinum Compounds/administration & dosage , Tumor Cells, Cultured , Uterine Cervical Neoplasms/pathologyABSTRACT
We synthesized novel water-soluble and orally active taxane analogues, 7-deoxy-9beta-dihydro-9,10-O-acetal taxanes. Cytotoxicities of the synthetic compounds were greater than those of paclitaxel and docetaxel, especially against resistant cancer cell lines expressing P-glycoprotein. In addition, some compounds showed potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration.
