Buspirone effects in an animal conflict procedure: comparison with diazepam and phenobarbital

Buspirone has been introduced as a novel non-benzodiazepine anti-anxiety agent. The Conditioned Suppression of Drinking (CSD) paradigm is an "animal model" for anxiety which provides information on both the relative potency and relative efficacy of anti-conflict agents. The present study compared the anti-conflict effects of buspirone to those of more "classical" anti-anxiety agents, diazepam and phenobarbital. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA), electrification being signalled by a tone. Within 2-3 weeks control CSD responding had stabilized (approximately 15-20 shocks/session and 10-15 ml water/session); drug tests were conducted at weekly intervals. Diazepam and phenobarbital markedly (400-500%) increased the number of shocks received at doses which did not depress background responding (i.e., water intake). A number of agents, most notably morphine and ethanol, did not reliably affect punished responding in the CSD. Administered IP, low doses (0.25-1 mg/kg) of buspirone increased punished responding only slightly (less than 100% increase); higher doses (2, 4 mg/kg) depressed background responding. Administered SC, buspirone (0.125-1.0 mg/kg) had more potent effects on both punished and unpunished responding; again, anti-conflict efficacy was only marginal. These results suggest that buspirone might be less effective than the benzodiazepines in the management of anxiety.     

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S (±)-ketamine and of each enantiomer, S(+)-ketamine and R(–)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid E_max pharmacodynamic model, yielding estimates of both maximal effect (E_max) and sensitivity (IC₅₀) to the racemic and enantiomeric forms of ketamine. R(–)-ketamine was not as effective as R,S(±)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean±SD) of the median frequency (E_max)for R(–)-ketamine was 4.4±0.5 Hz and was significantly different fromR,S (±)-ketamine (7.6 ±1.7 Hz) and S(+)-ketamine (8.3±1.9Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC₅₀) was 1.8±0.5g/mL for R(–)-ketamine; 2.0±0.5 g/mL for R,S(±)-ketamine; and 0.8±0.4 g/mL for S(+)-ketamine. Because the maximal effect (E_max) of the R(–)-ketamine was different from that of S(+)-ketamine and R,S(±)-ketamine, it was not possible to directly compare the potency (i.e., IC₅₀) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.This work was supported in part by a Starter Grant from the American Society of Anesthesiologists, the Biomedical Research Support Grant NIH 2S07RR5353-20, 1981, (P.F.W.); and NIH and NIA Research Grants NS-17956 and AG03104 (D.R.S., A.J.T., L.B.S). The research fellowship of Dr. Schüttler was made possible by a NATO Foundation Grant (300-402-511-3), awarded by the German Academic Exchange Service. This study is part of Dr. Schüttler's Habilitation Thesis for the Faculty of Medicine at the University of Bonn, West Germany. Dr. Verotta is a fellow of the program of advanced training established by EEC and Regione Lombardia on leave of absence from Mario Negri Institute of Pharmacological Research, Milan, Italy.     

The Prevalence of Type A Personality in the Children of Alcoholics

Three studies are reported which investigate the prevalency of an excess risk of type A personality in the children of alcoholics (COAs). Reports in the clinical literature suggest there is an excess risk of type A in COAs, but this has never been empirically demonstrated. The Matthews Youth Test for Health (MYTH) was administered to nonalcoholic mothers of 46 COAs and 65 matched controls to measure children's type A competitiveness and impatience-aggression. Results were significant only for greater impatience-aggression in COAs. In a second study, 104 COAs and controls matched for age, sex, race, and father's occupational status were rated by military fathers of intact families using MYTH. The results of the first study were not replicated for COAs, and there was no correlation between a father's Jenkins Activity Scale (JAS) score and his child's type A personality. A third study of 70 matched COAs and controls used the Hunter-Wolf A-B Rating scale, a self-rating scale for children and found no significant differences in children's type A personalities based on membership in an alcoholic family, sex, or birth order. It was concluded that the discrepancy between clinical reports and the present data may have been due to misperceptions about successful, hardworking COAs who, particularly in contrast to their more notorious siblings, may be viewed as "workaholics" and improperly labeled as type A personalities.     

Self-reported illness and general practice consultations in Asian-born and British-born residents of West London

Summary Using data collected in a large scale community survey, some aspects of illness behaviour were compared in Asian-born and British-born residents of West London. Asian-born men were found to be far more likely to consult a general practitioner than British men, although the former group reported less long-standing illness and emotional distress than the latter. Self-assessed health among Asian men was significantly worse than among native men, and it was this health measure which was found to have the greatest effect on general practice consultations when a linear model was constructed. Differences in illness behaviour between Asian-born an indigenous women were not significant.     

gamma-Aminobutyric acid (GABA)- and barbiturate-mediated 36Cl- uptake in rat brain synaptoneurosomes: evidence for rapid desensitization of the GABA receptor-coupled chloride ion channel

"Desensitization" of the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied using an in vitro method for measuring chloride (Cl-) permeability in brain vesicles (synaptoneurosomes). Muscimol, a GABA agonist, stimulated 36Cl- uptake in rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (EC50 7.3 +/- 0.5 microM), whereas pentobarbital stimulated 36Cl- uptake in a biphasic manner, indicated by a bell-shaped concentration-response relationship, with a maximal response at 500 microM (EC50 271 +/- 17 microM). Higher concentrations of pentobarbital led to progressively smaller stimulation of 36Cl- uptake and blocked muscimol-stimulated 36Cl- uptake. Lower concentrations of pentobarbital (100-200 microM), when added with muscimol, produced an additive effect in stimulating 36Cl- uptake, whereas even lower (subthreshold) concentrations of pentobarbital (50 microM) potentiated muscimol-stimulated 36Cl- uptake. Following continuous exposure of synaptoneurosomes (up to 20 min) to muscimol (50 microM) or pentobarbital (500 microM), the 36Cl- uptake response diminished to a new steady state level with a t1/2 of approximately 6 sec and 30 sec, respectively. The decrement in response to these agonists was dependent on both concentration and length of exposure. No decrement was observed in the ability of subthreshold concentrations of pentobarbital to enhance muscimol-stimulated 36Cl- uptake following prolonged (20 min) incubation. "Heterologous desensitization" between muscimol and pentobarbital was observed in experiments where either muscimol or pentobarbital was added to the vesicles following pretreatment with the other. These findings suggest that "desensitization" of the GABA receptor/Cl- ion channel may involve both the GABA and barbiturate recognition sites or a common effector component such as the ionophore itself.     

Raising the ambient potassium ion concentration enhances carbachol stimulated phosphoinositide hydrolysis in rat brain hippocampal and cerebral cortical miniprisms

Summary The influence of the ambient potassium ion concentration ([K⁺]_ upon agonist stimulated hydrolysis of phosphoinositides (PI) has been studied in isolated miniprisms of rat hippocampus and cerebral cortex. When the external [K⁺] was raised from 6 to 18 mmol/l, there was little or no increase in the hydrolysis of PI in the absence of agonist, however, carbachol (100 mol/l) stimulated hydrolysis was greatly enhanced in both brain regions studied. Thus, carbachol stimulated the hydrolysis of PI to 146% and 386% of control levels at potassium concentrations of 5.8 and 18.2 mmol/l, respectively, in the rat hippocampus. A similar enhancement of muscarine (100 mol/l) stimulation was observed in cortical miniprisms with 18 mmol/l [K⁺]. A further enhancement was seen at higher ambient [K⁺], although basal hydrolysis of PI was then also increased. The carbachol-stimulated hydrolysis of PI found at both 6 and raised [K⁺] was prevented by atropine (1 and 10 mol/l) and tetraethylammonium (20 mmol/l), but not by 10 mmol/l Mg²⁺. Pirenzepine (50 nmol/l) also reduced this response. The ions Cs⁺ and Rb⁺ (but not Li⁺ or Tris⁺) produced a similar enhancement of the carbachol stimulation to that found with K⁺. At a buffer [K⁺] of 6 mmol/l, noradrenaline (100 mol/l) produced a 2-fold increase in the hydrolysis of PI whereas 5-hydroxytryptamine (100 mol/l) and histamine (500 mol/l) had little or no effect. However, histamine and 5-hydroxytryptamine did stimulate the hydrolysis of PI when [K⁺] was increased. Miniprism ATP content was not changed by a rise in [K⁺] to 18 mmol/l. The significance of these results is discussed in terms of the postsynaptic cellular events following cholinergic stimulation.     

Effects of cadmium exposure on zinc and copper distribution in neonatal rats

Tissue zinc and copper concentrations undergo marked changes in the neonatal rat during the first several weeks of life and it was of considerable interest to study the effect of cadmium exposure on these ontogenic changes. Long evans rats received either 2 or 10 mol cadmium chloride per kg SC at 9 days of age and were sacrificed at 20 or 36 days of age. Tissue copper and zinc concentrations in cadmium-treated rats were compared to those of age-matched controls for statistically significant changes. The tissue affected, the element altered and the direction of change in concentration, increased (+) or decreased (-), are summarized for the two dosing groups (age at dosing, age at sacrifice in days): 2 mol/kg (9, 20): kidney Zn (+), blood Zn (-), cerebral Cu (-), cerebellar Cu (+); 2 mol/kg (9, 36): blood Zn (-); 10 mol/kg (9, 20); liver, kidney, cerebral and cerebellar and blood Zn (-), cerebellar Cu (+); 10 mol/kg (9, 36]: liver and heart Zn (+), blood Zn (-); liver and heart Zn (+), blood Zn (-); kidney, cerebral, cerebellar and heart Cu (+). Changes in tissue zinc or copper concentrations produced by cadmium treatment could not be accounted for by the direct replacement of these elements by cadmium and may be due to alterations in transport of these elements. These results indicate that early life exposure to low levels of camium can have large and persistent effects on the distribution of the essential metals, copper and zinc.     

CB 1954 revisited

Summary Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 g/ml in mice, while 25 mg/kg gave peak palsma concentrations of 27 g/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t_1/2 values were 1.4–2 h in mice and 2.5–4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%–90%, while brain: plasma ratios were lower, at 37%–50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%–29%, of which 16%–25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t_1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new mixed-function sensitizers.     

Autocrine growth of human blymphocytes: Maintained response to autostimulatory factors is the special feature of immortalization by Epstein-Barr virus—A hypothesis

The autocrine growth profile of human B lymphocytes transformed with Epstein-Barr virus (EBV) was found to comprise three distinct components: a B-cell growth factor (BCGF); an interleukin-1 (IL-1)-like activity; an activity requiring cell-to-cell contact for its action. Observations on the inhibition of the EBV-carrying Daudi lymphoma line by α-interferon indicated that loss of response to these autostimulatory factors was underlying growth cessation. Furthermore, a putative for BCGF was found to be down-regulated on B cells stimulated with non-transforming mitogens but constitutively expressed following EBV-transformation. Taken together with recent evidence that normal B cells produce autostimulatory factors, these findings suggest that the special feature of autocrine growth by EBV-immortalized cells is a maintenance of what should normally be a transient phenotype, possibly through deregulation of receptor expression. This hypothesis is discussed.     

Perioperative transfusions associated with colorectal cancer surgery : Clinical judgment versus the hematocrit

We prospectively studied 123 patients with colorectal cancer in order to identify determinants of perioperative blood transfusions and unnecessary transfusions. Transfusions were considered unnecessary if the preoperative hematocrit reading exceeded 36% or the discharge hematocrit level exceeded 33%. Age, sex, admission hematocrit reading, operative procedure, specimen length, duration of surgery, estimated blood loss, tumor size, tumor differentiation, nodal status, Dukes' staging, and attending surgeon were evaluated in relation to perioperative blood transfusion using stepwise logistic regression. Fifty-one (41%) of the 123 patients in the study were transfused and 35 patients (28%) received at least 1 unnecessary unit of blood. Advanced age, low admission hematocrit reading, high estimated operative blood loss, prolonged procedures, and lengthy specimens were significantly related to the administration of blood. Excessive intraoperative transfusions and the practice of administering blood in pairs of units accounted for the unnecessary transfusions. This study indicates that factors that influence clinical judgment and thereby the decision to transfuse a patient are not accurate indicators of when blood should be given. Greater use of pre-transfusion hematocrit testing, especially in the operating room and before transfusing a second unit of blood, will dramatically reduce blood usage in elective colorectal cancer surgery.

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Resumen Hemos estudiado en forma prospectiva 123 pacientes con cáncer colorrectal con el objeto de identificar factores determinantes de transfusiones sanguíneas perioperatorias y de transfusiones innecesarias. Se consideró que las transfusiones eran innecesarias si el hematocrito preoperatorio excedía 36% o si el hematocrito de egreso excedía 33%. La edad y sexo, el hematocrito de admisión, el tipo de procedimiento operatorio, la longitud del especimen resecado, la duración de la operación, la magnitud estimada de la pérdida de sangre, el tamaño del tumor, el grado de la diferenciación del tumor, el estado de los ganglios, la clasificación Dukes del tumor y el cirujano, fueron valorados en relación con el volumen de transfusión perioperatoria utilizando el método de regresión logística escalonada. Cincuenta y uno (41%) de los 123 pacientes fueron transfundidos y 35 (28%) recibieron por lo menos una unidad de sangre innecesaria. La edad avanzada, un hematocrito bajo en el momento de la admisión, la escimación de una alta pérdida de sangre, los procedimientos prolongados y los especimenes de gran longitud aparecieron como factores significativamente relacionados con la administracion de sangre. Las transfusiones intraoperatorias excesivas y la práctica de administrar sangre en pares de unidades fueron responsables de las transfusiones innecesarias. Este estudio indica que los factores que influencian el juicio clínico, y por consiguiente la decisión de transfundir a un paciente, no son indicadores precisos de cuando se debe administrar sangre. Una mayor utilización del hematocrito pretransfusión, especialmente dentro de la sala de operaciones y antes de transfundir una segunda unidad de sangre, logrará disminuir en forma dramática el uso de sangre en cirugía electiva para cáncer colorrectal.

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Résumé Les auteurs se sont livrés à une étude prospective de 123 malades atteints de cancer colorectal dans le but d'identifier les facteurs qui ont été à l'origine de transfusions pré-, per-, et postopératoires et de transfusions inutiles. Les transfusions ont été considérées comme inutiles lorsque l'hématocrite préopératoire dépassait 36 pour cent ou qu'il excédait 33 pour cent au moment de la sortie de l'opéré. Pour apprécier la valeur de la transfusion périopératorie ont été pris en compte les divers facteurs suivants : l'âge, le sexe, le taux de l'hématocrite à l'admission, le type de l'intervention, la longueur du spécimen, la durée de l'opération, la quantité de sang perdu, la taille de la tumeur, le degré de différenciation du cancer, l'état des ganglions, le stade évolutif (classification de Dukes), la qualification du chirurgien. Cinquante et un des malades (41%) furent transfusés et 35 parmi eux (28%) reçurent inutilement au moins une unité de sang. L'ae avancé de l'opéré, le taux bas de l'hématocrite à l'admission, la perte importante de sang au cours de l'intervention, la longue durée de l'opération, l'importance de la pièce opératoire réséquée furent en rapport de manière significative avec l'administration de sang. Les transfusions inutiles furent le fait de l'administration excessive de sang au cours de l'opération ou de l'emploi d'unités doubles de sang. Cette étude indique que les facteurs cliniques ne constituent pas des éléments de valeur pour déterminer l'indication de la transfusion de sang. C'est le taux de l'hématocrite avant et au cours de l'intervention qu'il faut prendre en compte. L'observation de cette règle est appelée à réduire considérablement l'emploi du sang au cours de la chirurgie colorectale élective.

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Supported by the Frieda and George Zinberg Foundation and NCI-NIH grant 1 RO1-CA-35558-01.