A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer.

AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

Characteristic glucuronidation pattern of physiologic concentration of morphine in rat brain.

Formation of conjugated metabolites from morphine at a very low level in brain was studied in vitro in rats. Incubation of a low concentration of 3H-morphine with brain homogenate followed by two successive high-performance liquid chromatographic analyses showed that endogenous morphine is converted by brain enzymes to its 3- and 6-glucuronides (M-3-G and M-6-G), and codeine glucuronide (Cod-G). However, the formation of morphine-6-sulfate was likely to be low if it was produced at all. All of the cerebral hemisphere, brain stem and cerebellum were capable of producing M-3-G, M-6-G and Cod-G, although there were differences in selectivity. The capacity of the brain for glucuronide formation was far less than that of the liver, but UDP-glucuronosyltransferase in brain was much more selective in forming M-6-G and Cod-G than liver enzymes.

13-Week oral repeated administration toxicity study of bovine lactoferrin in rats.

Bovine lactoferrin (LF), which is an iron-binding glycoprotein in milk, was administered orally to groups of 12 males and 12 female rats at dose levels of 200, 600 and 2000mg/kg/day once daily for 13 weeks and its toxicity on repeated administration was examined. Throughout the administration period, there were no deaths caused by administration of the test compound, nor were there any adverse effects noted in the general condition of the animals. The study findings concerning body weight and food consumption, ophthalmology, urinalysis including water consumption, haematology, blood chemistry, necropsy, organ weights and histopathology revealed that there were no apparent changes due to administration of LF. Therefore, the level of LF at which no adverse effect was observed was considered to be 2000mg/kg/day for both sexes.

[Nasal decongestion evaluated by acoustic rhinometry].

Acoustic rhinometry measures the cross-sectional area of the nasal cavity based on changes in acoustic impedance. The volume of the nasal cavity can be calculated by mathematical integration of the cross-sectional areas. One of the advantages of this procedure is that repeated measurements can be quickly performed non-invasively. In this study, we analyzed the mechanisms of nasal mucosal decongestion after applying vasoactive agents. The experiments were performed in normal adult volunteers (17 males, 3 females) who gave their informed consent to participate in this study. Three vasoactive agents (0.1% epinephrine, 0.5% phenylephrine hydrochloride, 0.5% oxymetazoline hydrochloride), two alpha-receptor antagonists (0.2% phenoxybenzamine, 0.4% yohimbine) and a local anesthetic (4% lidocaine) were used. In order to apply the agents precisely and safely, we attached a 6mm diameter disc moistened with 0.1 ml of solution to the anterior portion of the inferior turbinate unilaterally for fifty seconds. After removing the disc, acoustic measurements were performed for an hour. To analyze data we divided the nasal cavity into three portions, i.e., anterior, middle and posterior. Volume changes in each portion are expressed as percentages. Immediately after applying phenylephrine and oxymetazoline, ipsilateral volume in the anterior portion began to increase, and then extended posteriorly. The level of decongestion remained unchanged for an hour. Contralateral volume decreased in all portions. When epinephrine was applied, mucosal decongestion occurred first followed by congestion in all portions of the ipsilateral side after 20 minutes. Mucosal congestion occurred in all portions of the contralateral side. After applying phenoxybenzamine or yohimbine for ten minutes, we administered vasoactive agents topically. Pretreatment with alpha-1 antagonist almost totally suppressed the mucosal decongestion caused by phenylephrine and oxymetazoline. Contralateral congestion was decreased by antagonizing the suppression of ipsilateral decongestion. After application of lidocaine for ten minutes, phenylephrine still caused ipsilateral decongestion only in the anterior portion, but decongestion of the middle and posterior portion and congestion on the contralateral side totally disappeared. These findings suggest the following conclusions: 1) decongestion evoked by adrenergic agents is probably caused by direct activation of alpha-1 receptors, 2) decongestion of the middle and posterior portions is evoked by drug particles conveyed by ciliary movement, and 3) the contralateral response is probably related to the activation of sensory nerves on the ipsilateral side.

[Electron microscopic cytochemical study on lectin binding sites in the epiphyseal cartilage-plate of rabbit tibia].

Lectin is a common name given to a certain group of hemagglutinating proteins found primarily in plant seeds, which bind specifically to the branching sugar molecules of glycoproteins and glycolipids of the surface of the cells. The author selected 3 kinds of lectin among others. Those were concanavalin A (Con A) which specifically binds to the alpha-D-mannose, wheat germ agglutinin (WGA) which binds to N-acetyl glucosamine, and peanut agglutinin (PNA) which binds to beta-D-galactosamine. The localization of these lectins was examined in order to obtain any information on the process of the proteoglycan synthesis during the cellular differentiation in the epiphyseal cartilage-plate of the rabbit. The binding sites of Con A were determined by conjugating horse radish peroxidase as a marker in case of optical microscopic observations. For the purpose of electron microscopic observations, lectins were marked with gold colloidal particles. Most Con A was found in the rough surfaced endoplasmic reticulum, while a part of them was bound to the cis side of the Golgi apparatus. In the cellular column of the cartilage, Con A was increasingly abundant from the younger proliferating stage, through the maturing stage to the stage of hypertrophy, and diminished abruptly at the stage of provisional calcification. These observations were coincided with the degree of development of the endoplasmic reticulum during the maturation of cartilage cells. These findings suggest that alpha-D-mannose is indispensable to the initial stage of proteoglycan synthesis. WGA was observed from the cis side to the intermediate layer of Golgi apparatus, but not at the trans side of the Golgi apparatus, nor in the endoplasmic reticulum. These findings suggest that N-acetyl-glucosamine is an essential substance to the middle stage of proteoglycan synthesis. PNA was found within the nucleus and at the cis side of Golgi apparatus, but not in the endoplasmic reticulum nor in the secretion granules. This observation corroborates that beta-D-galactosamine is also essential to the middle stage of proteoglycan synthesis.

Wavelength Effect on the Action of a N-Phenylimide S-23142 and a Diphenylether Acifluorfen-Ethyl in Cotyledons of Cucumber (Cucumis sativus L.) Seedlings.

Specific wavelengths of light required for expression of phytotoxic activity of S-23142 (N-[4-chloro-2-fluoro-5-propargyloxy]phenyl-3,4,5,6-tetra- hydrophthalimide) and acifluorfen-ethyl (ethyl-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitro benzoic acid) were determined in cotyledons of cucumber seedlings using the Okazaki Large Spectrograph. Leakage of amino acids from the cotyledons was measured as an indication of the phytotoxic activity. The wavelength effects showed common major peaks of activity at 550 and 650 nanometers and a minor peak at 450 nanometers for both herbicides, indicating a common primary photoreaction. Concomitant application of DCMU (3-[3,4-dichlorophenyl]-1,1-dimethylurea) with S-23142 had little influence on the effective wavelengths for S-23142 activity. Light of 450 and 650 nanometers was relatively less effective in achlorophyllous tissue grown in far red light than in green tissue. These results strongly suggest that the phytotoxic action of S-23142 and diphenylethers involves multiple photoreactions and that one of the photoreceptor pigments may be chlorophyll or its related pigment, although photosynthesis is not involved.

Alcohol intake and hypertension among urban and rural Japanese populations.

A significant positive relationship was found between alcohol intake and blood pressure for men 40-69 years old living in urban Osaka (492 men) and in rural Akita (395 men), Japan, surveyed from 1975 to 1977. Both mean blood pressure and the prevalence of hypertension were related to alcohol intake in a graded fashion. Stepwise multiple regression also showed that both systolic and diastolic pressure were associated with alcohol intake independent of ponderosity index, serum cholesterol, triglycerides, hemoglobin, uric acid, smoking, and age. This cross-sectional study indicates a continuous--and not a threshold--relationship between alcohol and blood pressure, with the effect of even moderate consumption, e.g. 28-55 g per day (equivalent to about 2-4 U.S. drinks per day).

Serum total cholesterol, triglyceride level, and dietary intake in Japanese students aged 15 years.

The authors surveyed serum cholesterol and triglyceride levels in 238 male and 217 female students aged 15 years in Osaka, Japan, in 1977, as well as dietary intake, using a 24-hour record in 81 male and 61 female students. Serum cholesterol and triglyceride levels of Japanese students were 163.6 mg/dl and 81.7 mg/dl, respectively, for males, and 182.2 mg/dl and 78.9 mg/dl for females. For female students, those who participated in a school sports club regularly during the previous three years had cholesterol levels 10 mg/dl lower than the subjects who had not participated in a sports club; these active students also had smaller skinfold thickness, although there was no difference in other anthropometric measurements. Although the dietary intake of Japanese students was found to be westernized, compared with that of Japanese adults, Japanese students reported low fat intake (25-30% of energy), high polyunsaturated/saturated fatty acid ratio (1.1-1.2), and high carbohydrate intake (55-61% of energy), differing considerably from US students.