Comparative Pharmacology of Cisatracurium (51W89), Atracurium, and Five Isomers in Cats

Background: Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development.

Methods: Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium.

Results: Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95 NMB values varied approximately tenfold (43+/-2 micro gram/kg-488+/-56 micro gram/kg). The "R-series" isomers were more potent than the corresponding "S series" isomers. With the exception of the S,Trans-S', Trans isomer, the NMB effects, i.e., onset times (range 2.6+/-0.2 min to 4.7+/-0.3 min) and total durations (range 9.9+/- 1.4 min to 14+/-0.9 min), of the other five isomers were very similar to that of atracurium. The former isomer had a relatively short duration of action. The 25-75% recovery times after cisatracurium at 1x ED sub 95 (4.4+/-0.4 min), 4x ED95 (4.5+/-0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8+/-0.4 min) indicated a noncumulative effect. The vagal ID50: NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25: NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micro gram/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60x the NMB ED95 (62+/-8 micro gram/kg).     

Molecular diagnosis of exocrine pancreatic cancer using a percutaneous technique

Background: The K-ras oncogene is activated by point mutations at codon 12 in most patients with exocrine pancreatic cancer. Mutant-enriched polymerase chain reaction (PCR) amplification can enhance the detection of mutated K-ras. This technique was applied to patients undergoing percutaneous fine-needle aspiration (FNA) biopsy of suspect pancreatic lesions. Methods: Twenty-five patients underwent percutaneous FNA of the pancreas for cytologic and molecular analysis. After preparing cytologic smears, the 22-gauge needle and syringe used for FNA were rinsed in RPMI-1640. The specimen was centrifuged, and DNA was extracted from the supernatant and subjected to mutant-enriched PCR using appropriate mismatched primers that introduce a BstNI restriction endonuclease cleavage site at codon 12 of wild-type, but not mutant, K-ras. After digestion with BstNI, the DNA was reamplified. To increase assay sensitivity, the final five PCR cycles were completed incorporating 5 μCi of (α-32P)dCTP. The DNA was then redigested and subjected to gel electrophoresis and autoradiography. Results: The median amount of DNA retrieved per specimen was 3.33 μg. Mutant K-ras was detected as a band of 143 bps; residual wild-type DNA was seen as a 114-bp fragment. Twenty-one of 25 specimens demonstrated mutated K-ras DNA. Two patients with nondiagnostic cytology results had mutated K-ras DNA; adenocarcinoma of pancreatic origin was confirmed in both cases after pancreatectomy. Conclusion: The molecular diagnosis of pancreatic cancer through identification of mutations in K-ras can be readily performed on specimens obtained by percutaneous FNA. As aggressive multimodality management of this disease becomes more common, pretreatment analysis of molecular determinants may have greater clinical significance. Presented at the 48th Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

A Field Test of the Sweat Patch

The sweat patch is a new, noninvasive method designed to estimate the ethanol consumption of drinking subjects. It consists of salt-impregnated absorbent pads protected by a plastic chamber with attached water-tight adhesive. The patch reportedly collects transepidermal fluid at a steady rate for up to 10 days. Recent laboratory research has indicated a linear relationship between the concentration of ethanol in transepidermal fluid and mean concentration of ethanol in blood. Levels of ethanol in the sweat patch allowed identification of persons drinking at least 0.5 g of ethanol/kg/day with 100% sensitivity and specificity. The study reported here was conducted to test the field effectiveness of this sweat patch in normal, active research subjects. First, several pretests were conducted to determine the optimal location of the patch on the body and its fluid uptake at various sites. A laboratory experiment using nonalcoholic subjects was conducted to replicate previous work, and methods of measuring ethanol concentration in the patch were refined. A field test of the patch was then carried out. Healthy active volunteers drank a single "moderate" dose of ethanol (0.5 g of ETOH/kg of body weight) and then remained abstinent for the next 3 days. A week later, a "heavy" dose (1.0/kg of body weight) was consumed. Only a trace of ethanol was detected in any of the patches worn in either experiment. The patch did not measure ethanol in the transepidermal fluid under field conditions. Thus, further design modifications and pilot testing are required before the full benefits of this unobtrusive measure of drinking can be realized.     

Reading, Demographic, Social and Psychological Factors Related to Pre-adolescent Smoking and Non-smoking Behaviors and Attitudes

The purpose of this study was to examine reading, demographic, social and psychological factors related to pre-adolescent smoking and non-smoking behaviors and attitudes. The school-home humanistic education program was implemented in a large, urban public school system. It stressed responsible decision-making, increased self-esteem and the inter-relationships among the acquisition of knowledge of the consequences of smoking, personal feelings, family relationships and behavior. The results showed that family involvement was necessary to affect smoking attitudes and behaviors. Of all the variables studied, reading had a most pervasive relationship. Peer influence and self-esteem also were related to smoking knowledge, smoking attitude, future smoking intentions and the "purchase" of cigarettes. Two of several conclusions drawn from the results are: 1. Family involvement is necessary to affect attitudes and behaviors. 2. Health education research that does not investigate the relationship between program outcomes and reading achievement may be misleading.     

Modification of Gastric Banding,Using a Fundal Suture

Many forms of gastric banding have been described and high reoperation rates reported. These can be mainly attributed to excess vomiting associated both with and without stenosis. Reflux oesophagitis and the ‘sump’ effect may be other causes. This paper examines the problems associated with banding leading to revisional surgery and introduces a new technique, ‘fundal supporting suture’, to correct these problems. Preliminary results on 126 bandings without the modification and 22 with the modification are presented.     

Effect of an opiate antagonist (naloxone) on the gastric acid secretory response to sham feeding,pentagastrin, and histamine in man

We studied the effect of the opiate antagonist naloxone on the human gastric acid secretory response to three secretory stimulants: sham feeding, pentagastrin, and histamine. Intravenous naloxone (40 g/kg/hr) significantly inhibited the acid secretory response to sham feeding without affecting the serum gastrin response to sham feeding. Naloxone also significantly reduced pentagastrin- and histamine-stimulated acid secretion. These studies indicate that naloxone reduces acid secretion in response to all stimulants of acid secretion yet tested in humans.This study was supported by grants AM-16816 and AM-17328, from the National Institute of Arthritis, Metabolism and Digestive Diseases.Presented in part at the Plenary Session of the American Gastroenterological Association, Salt Lake City, Utah, May 19, 1980.     

The somatizing patient

The authors discuss the significance of identifying primary care patients with dramatic and persistent unexplained physical (medical) symptoms, especially given the concerns about containing health care costs. Such patients are a cause of frustration to the clinician, because the clinician may experience a sense of failure after using the state of the art and still being eluded by a diagnosis. We focus on the methods for understanding somatic worry or preoccupation, which is the essential process in a variety of somatoform disorders. The second half of the article focuses on evaluation and treatment considerations and includes a discussion of both psychotherapeutic and psychopharmacologic treatment strategies for the somatizing patient.     

三日龄大鼠缺氧缺血性脑损伤对大脑MRI影像和学习记忆能力的远期影响

Objective To investigate the activation of apoptotic genes of the brain with hypoxia- ischemia (HI) in newborn SD rats, and MRI changes and memory and learning ability in adulthood. Methods HI was induced by right carotid artery ligation followed by 2.5 h of hypoxia (6% O2) on 3-day-old SD rats (n=36). Control pups were sham-operated (n = 27). Right brain hemisphere was collected at 12 h and 7 d after HI and subjected to an apoptosis Oligo GEArrayR. MRI and Morris water maze test were performed on both groups at 42 and 44 days old, respectively. Results Comparing to 12 h after HI, up-regulated apoptotic genes included TNF, Caspase and pro-apoptotit genes of Bcl2 families, whereas the anti-apoptotic genes of Bcl2 family were down-regulated at 7 d after HI. The MRI assessment of the rats in HI group demonstrated that the area of the right cerebra l cortex was significantly smaller than the left side and control [periventricular layer: (23.5±3.6) mm2 vs (33.0±4.3) mm2, (34.5±3.9) mm2; hippocampus layer: (18.9±4.4) mm2 vs (29.1±5.0) mm2,(30.8±4.5) mm2, both P<0.01]. During the navigation trial, the HI rats demonstrated longer escape latency (4th day: (52.7±35.9) vs (17.8±8. 9) s, P<0.01). HI rats passed the platform less times than the control ones (T= 292.5, P<0.05) in space probe trial. Conclusions The activation of apoptotic genes induced by HI brain injury remains until 7 days later, involving intrinsic and extrinsic apoptotic pathway. The apoptosis of neural cells may lead to poor development of the cortex and impair the memory and learning ability in the adult rats after neonatal hypoxia- ischemia injury.     

CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines.

BACKGROUND AND PURPOSE: The appropriate application of 3-D CRT and IMRT for HNSCC requires a standardization of the procedures for the delineation of the target volumes. Over the past few years, two proposals--the so-called Brussels guidelines from Grégoire et al., and the so-called Rotterdam guidelines from Nowak et al.--emerged from the literature for the delineation of the neck node levels. Detailed examination of these proposals however revealed some important discrepancies. MATERIALS AND METHODS: Within this framework, the Brussels and Rotterdam groups decided to review their guidelines and derive a common set of recommendations for delineation of neck node levels. This proposal was then discussed with representatives of major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG), which, after some additional refinements, have endorsed them. The objective of the present article is to present the consensus guidelines for the delineation of the node levels in the node-negative neck. RESULTS AND CONCLUSIONS: First a short discussion of the discrepancies between the previous Brussels and the Rotterdam guidelines is presented. The general philosophy of the consensus guidelines and the methodology used to resolve the various discrepancies are then described. The consensus proposal is then presented and representative CTVs that are consistent with these guidelines are illustrated on CT sections. Last, the limitations of the consensus guidelines are discussed and some concerns about the direct applications of these guidelines to the node-positive neck and the post-operative neck are described.