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).     

Spatio-temporal progression of the AEP P300 component using the cortical imaging technique

Summary The cortical imaging technique (CIT), a mathematical method for simulating the potential fields on the surface of the brain, was used to analyze the spatio-temporal progression of the AEP P300 component (as well as the preceding and subsequent N2a and N3 components) from thirty normal adult subjects recorded in a standard oddball paradigm. Comparisons were made between the progressions of the endogenous event-related cognitive potentials and the exogenous stimulus-dependent potentials (Nl component). Cortical imaging results suggest that different and multiple generator sites are involved in the production of exogenous and endogenous evoked responses. We particularly note the asymmetric development of the P300 component and the apparent anterior generator sites for the N2a component. This last result is interesting because the N2a precedes the P300 component and supports an earlier frontal contribution.     

Double β-lactam regimen compared to an aminoglycoside/β-lactam regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients

In a prospective, randomized trial, 205 febrile episodes in granulocytopenic cancer patients were treated with ceftazidime with or without tobramycin (C±T), both agents being administered only if the initial granulocyte count was below 200/l, or ceftazidime plus piperacillin (C+P). The overall response rate was 71% (39 of 60 for C±T and 45 of 58 for C+P). Logistic regression analyses documented no evidence of a significant difference between the two regimens in overall treatment effect after accounting for the linear effects of potentially important variables, such as infection type and granulocyte count. Although the response rates for the subgroup of patients with bacteremias was better with the C+P regimen (P=0.06), there was no difference in response for patients with bacteremia and profound (<100/gml) sustained granulocytopenia. The double -lactam combination demonstrated in vitro synergism in 73%; antagonism was not seen. Both regimens produced execllent serum bactericidal levels (C±T geometric mean peak 1:170; C+P peak 1:137) against gram-negative but not gram-positive pathogens (1:4; 1:7 respectively) that had caused bacteremia. Emergence of resistance and significant coagulopathy and/or bleeding did not occur during therapy. Antibiotic-related nephrotoxicity was noted in 7 of 95 trials in the C+P and in 6 of 89 trials in the C±T group (P=0.19). The incidence of secondary infections in patients with profound (<100/l) sustained granulocytopenia was lower in the C±T group (P=0.04). Alimentary canal anaerobic flora preservation with C±T, and suppression with C+P, was demonstrated. These results suggest that these regimens are of similar effectiveness and neigher is associated with major toxicity.     

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.     

Blood lead levels in sheep exposed to automotive emissions

Summary The lead content of whole blood of 62 sheep grazed continuously for 6 months near a major highway was compared with 38 sheep from a nearby uncontaminated area. Mean values of 0.90 and 0.20 g/ml were obtained. Four sheep from the contaminated area were placed in an uncontaminated paddock and the lead content of the blood decreased rapidly during the first 10 days and thereafter more slowly. After 185 days, blood lead levels had still not quite reached normal levels.Animals from an uncontaminated area showed an immediate rise in the blood lead levels when placed near a major highway. Sheep placed in a concrete pen away from motor vehicle exhaust emissions showed a rise in lead levels when fed with, forage cut from the verges of a busy highway. Sheep placed near a highway and fed with forage from an uncontaminated area showed an increase of lead levels in the blood, comparable to that of the previous experiment. It was concluded that lead uptake by ingestion of polluted forage and by inhalation of airborne particulates are both mechanisms responsible for enhanced lead levels in ovine blood.     

Face lifting with suspensory restoration of the fibromuscular tissues of the face and neck

A series of before and after slides are shown of patients who have had the author's wall type restoration of the fibro-fatty musculo-fascial restoration of the face and neck in conjunction with face lifting. Several sutures (2–0 white Dacron usually 8 to 10 in all) are placed together so as to tighten the fibro-fatty musclo-fascial layer of the neck and face to as nearly as possible that which it had in youth. These are not the typical plication sutures but are sturdy suture material and are tied tightly. Furthermore, the tension on the tissues is distributed evenly by a whole series of sutures which additionally gives a smoother wall type reconstruction.The technique decreases the dead space in the cervico-facial dissection by at least 50 per cent and avoids suture ridging. Since using this technique and subsequent to the submission of this paper, there have been no hematomata in over 150 consecutive face lifts.     

Patterns of response and relapse in chemotherapy of extensive squamous carcinoma of the lung

Summary In a large study of combination chemotherapy for patients with extensive squamous carcinoma of the lung, 44 of 247 patients (18%) achieved>50% regression of tumor mass. The likelihood of response was significantly (and independently) higher for females and for fully ambulatory patients. Bone and liver were the most commonly involved metastatic sites, with documented involvement pretreatment in 32 and 16% of patients, respectively. Recurrence in the ipsilateral hemithorax after radiation therapy was the only clinical evidence of disease in 24% of the patients. There were no significant differences in response rate by individual metastatic sites, or for single compared to multiple sites. The median time to response was 4 weeks, with response noted by 8 weeks in 74%.Clinically evident relapse has occurred in 39. Among these, the primary site was the only clinical site of failure in 14, of whom 7 never received radiation therapy. The brain was the only site of initial failure in 6, only 1 of whom had preexisting evidence of brain involvement. Failure in a single area of previously evident disease or the brain accounted for 74% of recurrences in the responding group. These observations suggest that sequential, planned radiation therapy to sites of previous clinical involvement, together with prophylactic whole-brain radiation, may be of benefit in the drug-responsive subpopulation of patients with extensive disease.     

Guidelines for use access to compuuterized medical records

Computerization of the medical record allows the unique capability to provide differential access to various components of the record by users outsid of the immediate provider/patient health care setting Guidelines for designers, programmers, and users of computerizeid medical records have been defined in order to clarify which data elements or categories are appropriate for communication to various parties involved in utilizing patients information.     

The effects of Δ9-tetrahydrocannabinol alone and in combination with cannabidiol on fixed-interval performance in rhesus monkeys

It has been reported that cannabidiol (CBD) antagonizes the effects of ⁹-tetrahydrocannabinol (THC) on operant behavior in rats and pigeons. We have replicated this finding with rhesus monkeys. Four rhesus monkeys were trained to lever press on a fixedinterval 5-min schedule of food presentation with a 1-min limited hold and 1-min time out between successive intervals. The effects of 0.3 and 1.0 mg/kg THC alone were determined three times during the experiment; before the CBD-THC interaction, after the CBD-THC interaction and once with the CBD vehicle. A dose of 30 mg/kg CBD, which alone resulted in a 24% reduction in responding, completely antagonized the response rate reduction produced by 0.3 mg/kg THC. The effects of THC revealed a rate-dependent effect that did not conform to the log-linear rate-dependency plots described for most other drugs.This research was reported at the FASEB Meeting in Atlantic City, NJ in 1978 [Fed. Proc. 37: 739 (Abs.) 1978]