Pharmacodynamic dose-response and safety study of cisatracurium (51W89) in adult surgical patients during N2O-O2-opioid anesthesia.

After administration of doses ranging from 0.025 to 0.25 mg/kg, the neuromuscular blocking effect of cisatracurium was assessed in 119 adult surgical patients receiving N2O-opioid-midazolam-thiopental anesthesia. The calculated 95% effective dose (ED95) for inhibition of adductor pollicis twitch evoked at 0.1 Hz was 0.053 mg/kg. With 0.10 mg/kg injected over 5-10 and 20-30 s, median onset times (range) were 5.8 (3.0-7.7) and 4.8 (1.2-10.2) min, respectively, and median times to 5% and 95% recovery (range) were 27 (19-46) and 48 (25-68) min, respectively. For doses of 0.10, 0.20, and 0.25 mg/kg, median 5%-95% and 25%-75% recovery indexes ranged from 48 to 90 min and 8 to 9 min, respectively. After administration of neostigmine (0.06 mg/kg) at 10%-15% or 16%-30% recovery, the median times to 95% recovery (range) were 6 (2-22) and 4 (2-5) min, respectively. There were no changes in heart rate, blood pressure, or plasma histamine concentrations during the first 5 min after administration of cisatracurium at doses up to 5 x ED95 injected over 5-10 s. No cutaneous flushing or bronchospasm was noted. In summary, cisatracurium is a potent neuromuscular blocking drug with an intermediate duration of action, characterized by excellent cardiovascular stability, with no apparent histamine release.

Cardiac and regional hemodynamic interactions between halothane and nitric oxide synthase activity in dogs.

BACKGROUND: In vitro, halothane appears to affect the role played by nitric oxide in the regulation of vascular tone and cardiac function. In vivo, the results of the interactions between halothane and the nitric oxide pathway remain controversial. The authors investigated the effects of halothane on the cardiac and regional hemodynamic properties of N-methyl-L-arginine (NMA), a specific nitric oxide synthase inhibitor, in dogs. METHODS: Twenty-five dogs were chronically instrumented. Aortic pressure, the first derivative of left ventricular pressure, cardiac output, heart rate, and carotid, coronary, mesenteric, hepatic, portal and renal blood flows were continuously recorded. N-methyl-L-arginine was infused intravenously at 20 mg/kg over 1 min in awake dogs (n = 11) and in 1.2% halothane-anesthetized dogs (n = 10). As a control group, the remaining four dogs were studied awake and during 1.2% halothane for 2 h in the absence of NMA. RESULTS: In awake dogs, NMA produced a sustained pressor response (34%) and systemic vasoconstriction (40%) associated with a decrease in cardiac output (16%). Regional circulation changes included an immediate and transient increase in carotid (43%) and coronary (237%) blood flows and a subsequent decrease in carotid blood flow (25%). Hepatic and mesenteric blood flows also decreased, by 43% and 16%, respectively. Except for the coronary circulation, regional vascular resistance increased significantly. Halothane did not affect the pressor response to NMA but did blunt the cardiac output changes. Consequently, the systemic vasoconstriction after nitric oxide synthase inhibition was of shorter duration and of lesser magnitude during halothane anesthesia. Halothane also blunted the carotid, mesenteric, and renal vasoconstriction induced by NMA. Finally, in 1.2% halothane-anesthetized dogs, NMA induced a coronary vasoconstriction. CONCLUSIONS: Halothane minimally interferes with the systemic and regional hemodynamic consequences of nitric oxide synthase blockade. The nature and magnitude of the interaction depend on the territory in which they occur.

HLA class I and neuroendocrine antigen expression in multidrug resistant small cell lung carcinoma cell lines.

Antigenic marker expression was studied in a series of eight small cell lung carcinoma (SCLC) cell lines, according to their histological subtype, classic or variant. These lines were obtained from human tumors xenografted into nude mice, originally derived from heterotransplanted tumor biopsy samples. We looked at an altered expression of HLA class I antigens, a battery of neuroendocrine antigens and the P-glycoprotein (Pgp) responsible for MDR1 encoded multidrug resistance, as markers of tumor malignancy. Three cell lines out of four of the classic subtype and two cell lines out of four of the variant subtype showed a lack or a low expression of HLA class I antigen. Recombinant interferon gamma (rIFN-gamma) treatment (100 U/ml, for 48 h) increased HLA class I expression of the cell lines differently, but did not induce an imbalance between HLA-A and HLA-B molecules as described in other tumor models. Neuroendocrine antigens were tested in six out of these eight lines, using a family of monoclonal antibodies developed against the cell membrane antigens of low passage cell lines derived from pleural effusions (de Leij et al, Cancer Res 45: 2192-2200, 1985). Globally, these antigens were more highly expressed in classic subtypes of SCLC. Neuroendocrine antigens corresponding to MOC-21 and MOC-32 monoclonal antibodies were weakly expressed in variant forms. Pgp expression was detectable with the JSB1 monoclonal antibody on the three variant SCLCs out of the six lines. Comparing two cell lines originated from the same patient before and after therapy, we showed that neuroendocrine reactivity to MOC-21 and MOC-32 was lost simultaneously with a gain of Pgp expression, and with a classic to variant histological transition. With regard to the clinical evolution, HLA class I expression and stimulation by rIFN-gamma was not related to malignancy. It appears that for variant forms, a low expression of neuroendocrine antigens detected by MOC-21 and MOC-32 monoclonal antibodies and a high level of Pgp predict for a poor prognosis.

Phase I/II study of paclitaxel plus cisplatin as first-line chemotherapy for advanced non-small cell lung cancer: preliminary results.

From March 1993 to May 1994, 32 chemotherapy-naive patients with advanced non-small cell lung cancer entered a phase I/II study to determine the maximum tolerated dose and the activity of the paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/cisplatin combination. The 21 men and 11 women had a median age of 59 years (range, 25 to 72 years) and a median performance status of 1 (range, 0 to 2). Histologic types were adenocarcinoma (13 cases), squamous cell carcinoma (10), and large cell carcinoma (nine). Nine patients had stage IIIB disease and 23 had stage IV disease. The first four dose levels of paclitaxel were 135, 175, 200, and 225 mg/m2 given with a fixed cisplatin dose of 100 mg/m2; at level 5, paclitaxel 225 mg/m2 was again given, and the cisplatin dose was increased to 120 mg/m2. Cycles were given every 3 weeks. Paclitaxel was administered as a 3-hour infusion followed by cisplatin, with standard premedication and hyperhydration. The maximum tolerated dose for the first cycle was not reached. Grades 3 and 4 neutropenia occurred in 24% and 16% of cycles (two cases with fever), respectively. Grades 2 and 3 peripheral axonal neurotoxicity occurred in two and 16 patients, respectively; the neurotoxicity appeared to be dose dependent and cumulative after a median total paclitaxel dose of 1,300 mg/m2. Of the 29 patients evaluable for efficacy, 11 (38%) had a partial response; efficacy was superior at paclitaxel doses of at least 200 mg/m2, with eight (47%) of 17 evaluable patients responding at these levels. In conclusion, at these doses of paclitaxel and cisplatin, the dose-limiting neurologic toxicity is dose dependent and cumulative after a total paclitaxel dose of approximately 1,300 mg/m2. This combination is highly active, with a total objective response rate of 38% and an objective response rate of 47% at paclitaxel doses of 200 mg/m2 or higher. Further evaluation is warranted.

Rocuronium (Org 9426) for caesarean section.

This was a prospective, non-randomized, multicentre study of rocuronium (Org 9426) in 40 elective Caesarean section patients at full term without fetal distress. Anaesthesia was induced with thiopentone 4-6 mg kg-1 i.v. and rocuronium 0.6 mg kg-1 and maintained with isoflurane and nitrous oxide in oxygen. Monitors included ECG, arterial pressure, pulse oximeter and train-of-four (TOF) produced by ulnar nerve stimulation. In all patients, full neuromuscular block at the hand indicating the maximum effect of rocuronium (T1 = 0) occurred at a mean time of 98.1 (SE 9.4) s. However, after 79.3 (2.9) s, excellent to good intubating conditions were achieved in 90% of patients. Injection to delivery time was 12.7 (0.9) min and the surgical procedure lasted 53.1 (3.5) min. After administration of rocuronium, T2 appeared after 32.7 (1.8) min (indicating duration of effect). At the end of the surgical procedure in 39 patients, glycopyrronium 0.2 mg and neostigmine 1 mg were given every 5 min to antagonize residual neuromuscular effect. The mean dose of neostigmine required was 1.54 (0.1) mg. Rocuronium had no clinically significant effect on maternal heart rate or arterial pressure. After administration of thiopentone and rocuronium in two patients, temporary erythema occurred, one along the site of injection and the other on the chest wall. Rocuronium had no untoward effects on the neonates, evaluated by 1- and 5-min Apgar scores, time to sustained respiration, total and muscular neuroadaptive capacity scores, acid-base status and blood-gas tensions in umbilical arterial and venous blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of NG-methyl-L-arginine in chronically instrumented conscious dogs.

The cardiovascular effects of nitric oxide blockade were examined in five conscious chronically instrumented dogs. The hypothesis tested was that nitric oxide release plays a role in vascular tone and regional organ blood flow under physiological conditions. Aortic pressures; the first derivative of the left ventricular pressure; cardiac output (CO); heart rate; and carotid, coronary, renal, hepatic, and portal blood flows were recorded before and after bolus injection of 5, 10, and 20 mg/kg of NG-methyl-L-arginine (L-NMA). In response to L-NMA, mean arterial pressure increased by 7, 20, and 35%, respectively, in a dose-dependent manner, whereas CO decreased. CO reduction was sustained at the highest dose, whereas peripheral blood flows were not altered. These data suggest that blocking basal nitric oxide synthesis by administering L-NMA leads to a modest dose-dependent pressor response despite a marked and sustained reduction in CO recorded at the highest dose of L-NMA. Moreover, within our dose range, although the nitric oxide synthase inhibition provides a significant pressor response, it does not alter the resting carotid, coronary, renal, hepatic, and portal blood flows.

Heterogeneous expression of oncogenes in small-cell lung-cancer xenografts.

The analysis of oncogene expression may provide insights into the pathogenesis of small cell lung cancer (SCLC) and may help to predict clinical behavior. The expression of 8 oncogenes (c-myc, N-myc, L-myc, Ha-ras, Ki-ras, N-ras, erbB-2, v-sis) was evaluated in small cell lung cancer (SCLC) xenografts of tumor samples, recentlly transplanted, taken from 17 different patients. Eight of these 17 SCLC lines expressed the L-myc oncogene and 2 SCLC lines expressed the c-myc oncogene. One SCLC line (SCLC-63M) simultaneously expressed the L-myc and c-myc oncogenes. All SCLC lines examined had almost similar high RNA levels of the Ki-ras oncogene, while the expression of Ha- and N-ras oncogenes was not always observed. The N-myc and v-sis oncogenes were expressed in only one tumor and at a very weak level, and no transcript of the erbB-2 oncogene was observed in any of our 17 SCLC lines. These results indicate that oncogene expression in SCLC lines is heterogeneous, with the exception of the Ki-ras oncogene which is constantly overexpressed.

[Management of pulmonary metastases from osteosarcomas]. / Le traitement des métastases pulmonaires des ostéosarcomes.

The management of pulmonary metastases from osteosarcomas rests at present on thoracic surgery combined with chemotherapy. Until the beginning of the seventies chemotherapy proved very disappointing. With adriamycin, methotrexate in high doses followed by folinic acid and, more recently, platinum cis-dichlorodiamine, remissions, which are usually partial, are obtained in a significant proportion of patients (at least 30%). The addition of less active agents such as vincristine, cyclophosphamide, actinomycin D and bleomycin is helpful. Among 31 patients with pulmonary metastases from treated osteosarcomas seen at the Gustave Roussy Institute, 18 underwent thoracic surgery as the first treatment; in 10, surgery was followed by chemotherapy with adriamycin, vincristine, methotrexate in high doses + folinic acid + cyclophosphamide. Five patients are in complete remission 27, 30, 49, 50 and 77 months after the surgical procedure. 12 patients were initially treated with a similar chemotherapeutic regimen; a subsequent thoracic surgical procedure was undertaken in two patients who died 18 and 30 months after the pulmonary metastases had appeared. In one patient, the metastases were treated by irradiation. These results are compared to previous reports in the medical literature.