The modulatory effect of (+)-TAN-67 on the antinociceptive effects of the nociceptin/orphanin FQ in mice

To clarify the pharmacological properties of (+)2-Methyl-4aalpha-(3-hydroxyphenyl)-1, 2, 3, 4, 4a, 5, 12, 12aalpha-octahydro-quinolino[2, 3, 3-g]isoquinoline ((+)-TAN-67), the effect of (+)-TAN-67 on the antinociception induced by the intrathecal (i.t.) administration of nociceptin/orphanin FQ was studied in mice using the tail-flick test and the formalin test. I.t. administration of (+)-TAN-67, at doses of 1 to 10 ng, facilitated the tail-flick response in a dose-dependent manner in mice. In addition, i.t. administration of (+)-TAN-67 (1 to 10 ng) in mice produced a marked pain-like aversive responses. I.t. pretreatment with D-Pro(9)-[spiro-gamma-lactam]-Leu(10)-Trp(11)-physalaemin(1-11) (GR82334, 0.1-1.0 nmol), a potent and selective tachykinin NK(1) receptor antagonist, dose-dependently blocked the reduction of the tail-flick response induced by (+)-TAN-67. Furthermore, (+)-TAN-67-induced facilitation of the tail-flick response was abolished in capsaicin-treated mice. On the other hand, (+)-TAN-67-induced flinching responses were dose-dependently and significantly reduced by i.t. pretreatment with GR82334 (0.1-1.0 nmol). The duration of i.t. (+)-TAN-67-induced flinching responses was significantly reduced in capsaicin-treated mice as compared with naive mice. I.t. administration of nociceptin/orphanin FQ (1-10 nmol) dose-dependently increased the tail-flick latency. I.t. administration of nociceptin/orphanin FQ (0.1-1.0 nmol) significantly and dose-dependently reduced the first-phase nociceptive response, but not the second-phase nociceptive response. I.t. pretreatment with (+)-TAN-67 (0.3-3.0 microg) for 30 min dose-dependently attenuated the antinociception induced by i.t. nociceptin (10 nmol) in the tail-flick test. Furthermore, the antinociceptive effect of nociceptin/orphanin FQ (1 nmol, i.t.) on the first-phase response in the formalin test was dose-dependently attenuated by s.c. pretreatment with (+)-TAN-67 (0.3-3.0 microg). (+)-TAN-67 (0.3-3.0 microg, i.t.), by itself, did not facilitate the tail-flick response or produce apparent behavioral changes. It is possible that (+)-TAN-67 has an antagonistic effect on nociceptin/orphanin FQ-induced antinociception.     

An electromyographic method for the assessment of naloxone-induced abstinence in morphine-dependent rats

Summary The electromyographic (EMG) activities of suprahyoideal muscle were recorded to measure naloxone-precipitated abstinence signs in morphine-dependent rats anesthetized with urethane (1 g/kg). Rats were rendered dependent on morphine by implanting 2 morphine pellets (75 mg each) and abstinence signs were induced by intravenous injections of various doses of naloxone at different times after pellet implantation. Three precipitated abstinence signs, a) myoclonic twitch activity (MTA), b) mastication, and c) body shakes were observed on EMG recordings after the injection of naloxone. Of these symptoms, only the MTA induced by naloxone (10 g/kg) occurred 4 h after pellet implantation and its sensitivity to naloxone increased with prolonged pellet implantation. Both mastication and precipitated shakes could be induced at 24 h. However, higher doses of naloxone were required to produce the shakes than is required to induce mastication. There appears to be a positive correlation between the intensity of naloxone-induced MTA and the degree of physical dependence on morphine. Since the MTA and mastication can be induced by low doses of naloxone in morphine-dependent rats, we suggest that these two parameters may be used to detect morphine abstinence signs in this species.Deceased February 13, 1979     

Relationships for recombinant interleukin-2-stimulated mixed lymphocyte tumor extract reaction between peripheral blood lymphocytes and regional node lymphocytes in gastric cancer patients.

To investigate the relationship between "systemic" antitumor immunity and "local" antitumor immunity with respect to the histopathological stage of gastric cancer, interleukin-2 stimulated mixed lymphocyte tumor extract reactions (ILS-MLTR) of peripheral blood lymphocytes (PBL) and regional node lymphocytes (RNL) were evaluated in 59 gastric cancer patients. ILS-MLTRs of both PBL and RNL decreased with the advance of cancer stage, but ILS-MLTRs of PBL were always lower than those of RNL. Positive correlations in MLTR between PBL and RNL were found in patients with depth of invasion to muscularis propria and serosa and peritoneal dissemination. Inverse correlations between PBL and RNL were noted in patients with stage IV and distant nodal involvement. These results suggest that variations in the anticancer immunities might be effectively managed by an immunotherapy which is designed according to the responsiveness in the immune parameter ILS-MLTR.     

Some dietary and fool selection changes or jejunoileal bypass patients.

Twenty-seven persons who had undergone jejunoileal bypass surgery eight months or more previously returned a questionnaire which sought information about: (a) Demographic characteristics and weight loss; (b) pre- and postoperative eating behavior and food selection; (c) dietary instruction; (d) postoperative complications; and (e) postoperative attitudes. Twenty other patients were seen in a surgery clinic and interviewed informally to aid in the evaluation of data. Neither demographic characteristics nor weight loss correlated with other variables, including food selection, behavior, attitudes, or complications. Postoperative complications did relate to the consumption of green vegetables and "snacking." Postoperative changes noted were diminished appetite and less use of alcoholic beverages. Changes in post-operative eating behavior were positively correlated with changes in patients' attitudes of self-confidence and self-esteem. Neither a dietitian nor a nutritionist had been available on a structured consultation basis. During the interviews, subjects did express a desire for dietary discussions with trained professionals. In spite of distress and complications, most subjects were satisfied with the operation and perceived an improvement in their lives.     

Effects of support group intervention in postnatally distressed women. A controlled study in Taiwan

Objective: The symptoms of depression experienced by women during the postnatal period may have profound effects on the lifelong health of both the mother and the child. In this randomized controlled study, we systematically evaluated the effects of weekly supportive group meetings for women with postnatal distress. Methods: Sixty postnatally distressed women were randomly assigned to support (n=30) and control (n=30) groups. Women assigned to the support group participated in four supportive group sessions that comprised discussions concerning transition to motherhood, postnatal stress management, communication skills, and life planning. Results: Subjects who attended the support sessions had significantly decreased scores on the Beck Depression Inventory (BDI) and the Perceived Stress Scale (PSS), and significantly increased scores on the Interpersonal Support Evaluation List (ISEL) as evaluated at the end of the fourth weekly session. In contrast, no significant changes were observed in the control group during this period. Conclusion: This is the first controlled study to provide evidence that participation in support groups for postnatally distressed women provides quantifiable psychosocial benefits.     

Biliary hamartomas associated with biliary stones presenting as multiple microabscesses: case report

A 63-year-old men suffered from fever, jaundice, and right upper quadrant pain for 1 week. Biliary stones with biliary tract infection were diagnosed. He was treated with parenteral antibiotics. However, abdominal ultrasonography showed multiple hyperechoic lesions in both lobes, and infiltrating hepatocellular carcinoma was suspected initially. Numerous hypervascular nodular-enhancing lesions were revealed by computed tomography. Magnetic resonance imaging further disclosed numerous tiny cystic lesions with peripheral enhancement. Exploratory laparotomy was performed for biliary calculi and probable underlying malignancy. Cholecystectomy, choledocholithotomy, and liver wedge biopsy were done. The pathology revealed bile duct hamartomas with microabscess formation. The past literature about biliary hamartomas is reviewed.     

Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer.

PURPOSE: This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-na?ve, epidermal growth factor receptor-positive, stage IV non-small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival. PATIENTS AND METHODS: Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m2 intravenously was administered the first week, followed by weekly doses of 250 mg/m2. Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m2 on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy. RESULTS: The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days. CONCLUSION: The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.