Effects of peripheral administration of a Neuromedin U receptor 2-selective agonist on food intake and body weight in obese mice.

BACKGROUND: Neuromedin U (NMU) is a neuropeptide with various physiological functions, including regulation of smooth-muscle contraction, blood pressure, stress responses and feeding behaviors. NMU activates two distinct receptors, NMUR1 and NMUR2, which are predominantly expressed in peripheral tissues and the central nervous system (CNS), respectively. It is reported that the NMU signaling system regulates food intake (FI) and body weight (BW) via NMUR2, suggesting that an NMUR2 agonist exhibiting anorectic effects would be a potential therapy for obesity. METHODS: Antiobesity effects of NMUR2 activation were assessed using a recently developed, novel NMUR2-selective agonist, NMU-7005 (a polyethylene glycolated octapeptide). Here we assessed cumulative FI and BW loss after peripheral administration of NMU-7005 in NMUR2 knockout and diet-induced obese mice. To gain mechanistic insights, we performed immunohistochemical analysis of c-Fos-like protein expression in the brain. RESULTS: We found that NMU-7005 was a NMUR2-selective agonist with little activity toward NMUR1. The anorectic effect of NMU-7005 was completely abrogated in NMUR2 knockout mice. Repeated subcutaneous administration of NMU-7005 showed a potent antiobesity effect with FI inhibition (P<0.025) in diet-induced obese mice. NMU-7005 in combination with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide showed an additive antiobesity effect, suggesting that NMUR2-mediated anorectic action is different from that of GLP-1R agonists. NMU-7005 also elicited a minimal conditioned taste-aversive effect, while the effect of liraglutide was significant. As c-Fos expression was upregulated in the hypothalamus and the medulla oblongata in NMU-7005-administered mice, the pharmacological effects of NMU-7005 appeared to be mediated via activation of the CNS. CONCLUSION: Our results demonstrated that a novel NMUR2-selective agonist, NMU-7005, is a beneficial tool for the elucidation of NMUR2-mediated physiological functions, which is a promising therapeutic strategy for treating obesity.

Peierls mechanism of the metal-insulator transition in ferromagnetic hollandite K2Cr8O16.

Synchrotron x-ray diffraction experiment shows that the metal-insulator transition occurring in a ferromagnetic state of a hollandite K(2)Cr(8)O(16) is accompanied by a structural distortion from the tetragonal I4/m to monoclinic P112(1)/a phase with a √2×√2×1 supercell. Detailed electronic structure calculations demonstrate that the metal-insulator transition is caused by a Peierls instability in the quasi-one-dimensional column structure made of four coupled Cr-O chains running in the c direction, leading to the formation of tetramers of Cr ions below the transition temperature. This provides a rare example of the Peierls transition of fully spin-polarized electron systems.

[The evaluation of pamidronate therapy for bone metastases from breast cancer].

We devised a method to evaluate comprehensively the therapy to alleviate the pain of bone metastases from breast cancer according to the three items of bone pain and effects of analgesia and radiology. In 12 patients, we evaluated the therapeutic effect of pamidronate as an alleviative treatment for the pain of bone metastases from breast cancer. Bone pain was evaluated on a 6-grade scale, as was use of analgesics. Improvement in bone pain, in addition to improvement in use of analgesia, was evaluated as markedly improved, improved, unchanged, aggravated, no pain or undeterminable. Radiological improvement in bone lesions was evaluated as markedly improved, improved, unchanged, aggravated or undeterminable. An overall evaluation was made by combining the above two. In this evaluation method, pamidronate therapy resulted in an evaluation of markedly improved in 2 patients, improved in 5, unchanged in 4 and aggravated in 1, demonstrating that the therapy was very useful as an alleviative treatment for the pain of bone metastases from breast cancer. The evaluation method, in which pain, a subjective complaint, is combined with use of analgesics, an objective factor, and to which radiological evaluation is added for further objectively, may in the future to be applicable for evaluation of various alleviative treatments of pain of bone metastases.

[Chemotherapy with mitoxantrone for the treatment of recurrent breast cancer].

Two cases of recurrent breast cancer are reported in which chemotherapy with mitoxantrone proved remarkably effective. Case 1 was a 61-year-old postmenopausal female. At 32 postoperative months, multiple metastases of lung and bone were found. Following unsuccessful treatment with anthracyclin and an antiestrogenic agent, we used MVP modified therapy (mitoxantrone (MIT) 16 mg and vincristine (VCR) 1.6 mg once per 4 weeks and medroxyprogesterone acetate (MPA) 1,200 mg/day) and 5'-deoxy-5-fluorouridine (5'-DFUR) 800 mg/daily. After 12 cycles were performed, the patient showed a partial response (PR) (nearly complete response (CR)) on a chest X-ray and bone scintigram. Case 2 was a 49-year-old premenopausal female. At 42 postoperative months, a local recurrence was found and resection was performed. However, after endocrine therapy with goserelin acetate (ZOL) and chemotherapy with CAF (cyclophosphamide, adriamycin and 5-FU) and UFT, local recurrence and pleural effusion were found 6 months after surgical operation. We then used MVP modified chemotherapy and endocrine therapy with ZOL. The patient showed a PR at 9 cycles after therapy. MVP modified chemotherapy is considered an effective treatment for recurrent breast cancer, especially for adriamycin or epirubicin resistant breast cancer.

A Case of Breast Cancer Metastatic to the Head of the Pancrea.

A case of breast cancer that metastasized to the head of the pancreas 6 yearsand 8 months after mastectomy is reported. The pancreas head metastasis was associated with general fatigue and obstructive jaundice. The serum levels of CEA, CA15-3 and NCC-ST-439, tumor markers of breast cancer, were within normal limits, but CA15-3 was immunohistochemically demonstrated in the resected metastatic lesion, in a manner similar to lobular carcinoma of the breast.

[Telomerase activity in colorectal cancer--a semi-quantitative procedure].

Telomerase maintains telomere at the end of chromosome and stabilizes chromosome. It is thought to have important roles in cancer progression and cell immortality. We evaluated the role of telomerase expression in colorectal carcinogenesis. Materials included 13 colonic adenomas, 9 early colorectal cancers, 32 advanced colorectal cancers, 5 metastatic tumors, and 30 non-cancerous colon mucosas. The telomerase activity was analyzed using TRAP-eze (Oncor Inc.) for a semi-quantitative method. The positive rate of telomerase activity was 13.3% in non-cancerous colonic mucosa, 15.4% in colonic adenomas, 77.8% in early colorectal cancers, 93.8% in advanced colorectal cancers, and 100% in metastatic tumors; the mean value was 18.0, 29.9, 65.8, 97.0 and 161.3. The correlation between telomerase activity and tumor size, histologic type, or depth of invasion was noted. Sensitivity, specificity and accuracy were on the order of 89%, 98% and 93% at the cut-off level as two times the mean value of non-cancerous mucosa. Telomerase had an important role in carcinogenesis, and progression of colorectal cancer, and it was suggested to be useful for a tumor marker.

Clinicopathological Features of Hereditary Breast Cancer.

The possible role of germline mutations of BRCA1 and BRCA2 as causative agents of familial breast cancer was assessed. Their possible involvement in the carcinogenesis of hereditary breast cancer was investigated using 63 clinically suspect families. Twenty-one lineages (33.3%) had mutations in one of the two BRCA genes. This relatively low incidence suggested that germline mutations in unknown genes are involved in the carcinogenesis of hereditary breast cancer in the Japanese population. However, the clinicopathological features characteristic of hereditary breast cancer, such as early disease onset, a high incidence of bilateral breast cancer, and a high incidence of multiple primary carcinomas in other organs were confirmed in the present study.

A Case of Breast Cancer Metastatic to the Pituitary Gland.

A case of breast cancer that developed pituitary metastasis 22 years after mastectomy is reported. The pituitary metastasis was associated with hypopituitarism, impairment of the visual field and later diabetes insipidus. The serum levels of CA15-3 and NCC-ST-439, tumor markers of breast cancer, were increased, and CA15-3 (DF3) and NCC-ST-439 were demonstrated in the resected pituitary metastatic lesion immunohistochemically.

Non-Hodgkin's lymphoma of the gastric stump developing 9 years after a distal gastrectomy for a peptic ulcer: a case report and review of the literature.

We report herein the case of a 65-year-old man who developed non-Hodgkin's lymphoma of the gastric stump 9 years after undergoing a distal gastrectomy for a gastric ulcer. The patient presented with epigastric discomfort, and an upper gastrointestinal series and gastroscopy revealed a lymphoma lesion located close to the site of his gastroduodenal anastomosis. A total gastrectomy was performed, followed by combination chemotherapy, comprised of vincristine, Endoxan, prednisone and Adriamycin (VEPA). Histologically, the resected specimen was diagnosed as non-Hodgkin's lymphoma. The patient has remained well without any signs of recurrence for 18 months since his operation. Although there have been a number of reports of adenocarcinoma developing in the gastric stump following surgery for peptic ulcers, the development of malignant lymphoma under such conditions is rare. Following the presentation of this case, we review the available literature and discuss the possibility of malignant lymphoma developing in the gastric stump.

[A case of brain metastasis from breast cancer responding to chemoendocrine therapy].

Brain metastasis is one of the most critical metastatic lesion on the treatment of breast cancer. We reported a case with brain metastasis from breast cancer responding to chemoendocrine therapy. The patient was 71 years old female complaining gait disturbance. Solitary brain metastasis and multiple bone metastases of breast cancer were diagnosed by CT scan and bone scintigram. Standard radical mastectomy was done. Estrogen receptor was proved to be positive in both of the tumor and metastatic lymph node. Tamoxifen and UFT were administered as chemoendocrine therapy. Complete response of brain metastasis was recognized in CT scan and gait disturbance was complete recovered two months after the treatment. She is now living well.

Squamous cell carcinoma of the thyroid--a report of three cases.

Three cases of squamous cell carcinoma of the thyroid are reported herein. In all cases, the carcinoma occurred in old age and was characterized by a rapidly growing tumor, usually associated with dyspnea and dysphagia. The prognosis of all 3 cases was poor, with a mean survival of only 6.3 months. Although squamous metaplasia is an accepted etiology of this disease, clinical investigation of the cases presented here does not favor it in consideration of the clinical features of papillary carcinoma of the thyroid with squamous metaplasia. The histological findings of our cases revealed areas of cystic formation, suggesting that some of these carcinomas may be derived from remnants of embryonic origin.

[Pharmacological effects of CM6912 and its main metabolites].

Pharmacodynamic effects of ethyl 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4- benzodiazepine-3-carboxylate (CM6912), a new benzodiazepine derivative, and its main metabolites (CM6913 = M1, CM7116 = M2) on the peripheral systems were investigated in several species of animals. In pentobarbital-anesthetized rabbits, CM6912 and M2 (1 or 5 mg/kg, i.v.) had little effect on blood pressure, heart rate and ECG, but it slightly reduced the respiration rate. M1 decreased the heart rate without affecting respiration, blood pressure and ECG. In conscious rabbits, CM6912 and M2 (1 mg/kg, i.v.) did not affect respiration, blood pressure, heart rate and ECG, but M1 (1 mg/kg, i.v.) increased the heart rate. CM6912 (5 or 30 mg/kg), when administered orally, also increased heart rate. In pentobarbital-anesthetized dogs, CM6912 and its metabolites (5 mg/kg, i.v.) decreased respiration and heart rate without affecting blood pressure and ECG. CM 6912 (5 mg/kg, i.v.) did not affect cardiovascular responses to the carotid occlusion, vagus stimulation, and pre- and post-ganglionic stimulation of cardiac ganglion in anesthetized dogs. CM6912 and its metabolites affected neither the spontaneous contraction nor the heart rate of isolated rabbit atria. These compounds also had no action on isolated aortic strips from rabbits. CM6912 and its metabolites did not affect the muscle tone of isolated guinea pig intestine, and it had no effects on the contractile responses to acetylcholine, histamine, serotonin and barium chloride. In isolated rabbit intestine, CM6912 and M2 slightly reduced the amplitude of contraction, while M1 had no effect. CM6912 and its metabolites did not affect the spontaneous motility of isolated non-pregnant and pregnant rat uteri as well as in situ non-pregnant rat uterus and isolated guinea pig vas deferens, including the contractile response to adrenaline. CM6912 and M2 relaxed isolated guinea pig trachea strips only at high concentrations. CM6912 and its metabolites did not affect the contractile responses of isolated rat diaphragm to electrical stimulation of the phrenic nerve. CM6912 (2 or 10 mg/kg, p.o.) did not affect the rat renal and hepatic functions. CM6912 influenced neither blood coagulation in rabbits nor blood hemolysis in rats. CM6912 and its metabolites did not affect the pupil size and its light reflex, and they did not produce a local anesthesia and edema. The present results suggest that CM6912 and its main metabolites exert only slight effects on the peripheral systems in animals.

[Pharmacological studies on a new cephamycin, MT-141. (2) Its effect on preparations of neuromuscular junction, smooth muscle organs and gastro-intestinal system].

The results for pharmacological experiments of MT-141 were as follows; Twitch tension of gastrocnemius muscle evoked by the stimulation of sciatic nerve was slightly reduced with 400 mg/kg MT-141 i.v. and upper doses. As the change was very small, however, it seems that MT-141 has no neuromuscular junction blocking action. Although MT-141 did not show any effects on most of isolated smooth muscle organs, only isolated tracheal muscle was somewhat relaxed with 10(-3) g/ml MT-141. The spontaneous motility of smooth muscle in situ was temporarily increased with 800 mg/kg MT-141 i.v. and upper doses. Two hundred mg/kg MT-141 showed no effect on the value of blood sugar and functions of kidney and liver. Any hemolysis did not appear even in the highest dose of 200 mg/kg MT-141 used in this experiment. From the present results and previous report (Krebe, M. et al., Jap. J. Antibiotics, in press), it seems that MT-141 is promised to be a highly safe and useful antibiotic agent in clinical use.

[Pharmacological studies on new cephamycin, MT-141. (1) Its effect on central nervous system, respiration and cardiovascular system].

The results on pharmacological effects of MT-141 were as follows. MT-141 did not exert effect on central nervous system in mice and rabbits but potentiated the anesthetic effect of thiopental at doses above 800 mg/kg i.v. MT-141 slightly raised a level of blood pressure in dogs and also caused a slight increase in the blood flow and heart rate when intravenously given more than 400 mg/kg. This compound did not affect the spontaneous contraction of isolated guinea pig atria and the blood vessels in perfused rabbit ears. MT-141 did not significantly affect the spontaneous contraction and coronary flow in isolated hearts of guinea pig. The body temperature was raised slightly by an injection of more than 400 mg/kg of MT-141. These results suggest that MT-141 does not possess specific effect on central nervous system but at a high dose slightly affects the autonomic nervous system such as blood pressure, body temperature, heart rate and blood flow in experimental animals.

[General pharmacological studies on a new macrolide antibiotic, miokamycin (MOM). 1. Effects on the central nervous system (author's transl)].

Behavioral and electroencephalographic (EEG) effects on a new macrolide antibiotic miokamycin (MOM), 9,3"-diacetylmidecamycin, were investigated in mice, rats and rabbits after oral administration. MOM caused a decrease in the spontaneous motor activity, a slight increase in the effect of megibal seizure at a dose of 1,000 mg (Potency)/kg, and an increase in the number of deaths on the maximal electroshock seizure after administration of doses more than 100 mg (Potency)/kg. Even at a dose of 1,000 mg (Potency)/kg, however, MOM showed no effects on general behavior, rectal temperature, traction test, inclined screen test, rotarod performance, thiopental-induced sleep, pentetrazol seizure, fighting behavior induced by electric stimulation and conditioned avoidance response. EEG effects in unanesthetized rabbits with permanent electrode implants were studied. MOM showed no effects on spontaneous EEG, arousal response to mesencephalic reticular stimulation, photic driving response, evoked cortical response by ventralis posterolateralis stimulation and afterdischarge elicited by hippocampal stimulation at a dose of 1,000 mg (Potency)/kg. Consequently, it can be concluded that MOM has no specific pharmacological effects on the central nervous system. Behavior effects of MOM metabolisms, Mb-1, Mb-2, Mb-6 an Mb-12, were almost the same as those of MOM in the mode of action.

[General pharmacological studies on fosfomycin sodium (author's transl)].

The pharmacological effects of fosfomycin sodium, a new antibiotic agent, were studied on central nervous system, neuromuscular junction, isolated smooth muscles, blood coagulation, red blood cell resistance, body temperature, permeability of skin vessels and IgG and IgE antibody formation in laboratory animals. Fosfomycin sodium inhibited activities on the isolated smooth muscles, elevated body temperature, and increased permeability of skin vessels. Any of these actions, however, was noticeable only when it was administered in higher doses. Except for these above effects, fosfomycin sodium did not show any actions. Consequently, it can be concluded that fosfomycin sodium has no specific pharmacological actions.