Underlying immunopathology as a cause of adverse responses to two intravenous anaesthetic agents.

A patient who had shown some evidence of immunological sensitivity underwent several operations under general anaesthesia for otitis media without ill effect. On his second exposure to Althesin, however, he suffered a severe reaction. Facial angioneurotic oedema was accompanied by peripheral vasodilatation and sweating, and C3 conversion was observed in his plasma. Subsequent anaesthetics produced no reactions until four years later, when thiopentone and suxamethonium were given. This reaction was much milder, but C3 conversion again occurred. Although the clinical signs indicated an anaphylactoid reaction, the laboratory findings suggested that this patient had an underlying immunopathological condition involving complement activation, which could be triggered by any intravenous agent that activated complement. The judgment that a reaction to a particular drug is anaphylactic cannot be made on the basis of clinical signs alone. Simple laboratory analysis will show whether the reaction is due to an underlying immunopathological condition that may be triggered by any of several drugs.     

Measurement of Recovery from Outpatient General Anaesthesia with a Simple Ocular Test

Measurements of extraocular muscle balance with a Maddox wing can be a useful clinical test of the rate of recovery from general anaesthesia. In 65 dental outpatients recovery was found to be most rapid in those patients given only nitrous oxide, oxygen, and halothane, whereas the previous administration of methohexitone, propanidid, or thiopentone for induction was associated with slower recovery. Recovery rates after methohexitone and propanidid were similar and rapid enough to confirm their choice for intravenous induction of anaesthesia in outpatients, but delayed recovery after thiopentone showed that this agent is best avoided in these circumstances.     

The effects of general anaesthetics on glucose and phosphate transport across the membrane of the human erythrocyte

A study has been carried out into the effects of clinically important general anaesthetics, althesin, thiopentone and propanidid, on the transport of glucose and phosphate across the membrane of the human erythrocyte. In general these three substances all inhibit both transport processes but with characteristic inhibition profiles and varying degrees of efficacy. Glucose transport was more sensitive to the hydrophobic steroids and phosphate transport to propanidid. Some hydrophobic agents, e.g., iodobenzene and its azide, were not inhibitory. Removal of cholesterol to some extent augmented the inhibitory effects of most of these compounds (not propanidid). It is argued that these effects are due to the penetration of the anaesthetics into the lipid bilayer and either subsequent disruption of the lipid annuli surrounding the integral membrane proteins and/or direct anaesthetic-protein interaction.     

Electrocardiography during Manual Dilatation of the Anus

Manual dilatation of the anus was carried out on 50 unpremedicated outpatients under propanidid, nitrous oxide, and halothane anaesthesia with E.C.G.monitoring. About half of the patients received intravenous atropine with the propanidid. The operation induced a variety of changes in heart rate but in the whole experiment only two isolated cardiac arrhythmic complexes were seen—a single defect of conduction and a solitary ventricular extrasystole. Changes in rate were not modified by atropine. It is concluded that manual dilatation of the anus is a safe procedure when carried out under the anaesthetic described and that prior medication with atropine is not necessary. This work supports the view that propanidid protects patients from most abnormalities of heart action which result from intense visceral stimulation.     

Potency of propofol, thiopentone and ketamine at various endpoints in New Zealand White rabbits

Effective plasma concentrations of propofol, thiopentone and ketamine were determined at different endpoints in a study with randomized, crossover design in nine New Zealand White rabbits. A continuous infusion was used (30 ml/h) with concentrations of 10 mg/ml for propofol, 25 mg/ml for thiopentone and 20 mg/ml for ketamine. The endpoints were loss of the righting reflex, loss of purposeful reactions to tail clamping (as an example of a peripheral pain stimulus) or to intranostril insufflation of ammonia vapour (as an example of a central reflex stimulus), and the recovery of these reflexes and reactions. According to the ED50 values the potency ratios of propofol, thiopentone and ketamine were at the loss of righting reflex 1:1.8:1.2, at the loss of reaction to ammonia vapour 1:1.5:1.6, and at the loss of reaction to tail clamping 1:1.5:3.9, respectively. Recovery was significantly faster after propofol than after thiopentone and ketamine. Measuring the effective plasma concentrations of intravenous anaesthetics provides a method of relating dose to effect, but there still remains a variable gap between plasma concentration and effect.     

Possible binding sites and interactions of propanidid and AZD3043 within the γ-aminobutyric acid type A receptor (GABAAR)

Propanidid is an intravenous anesthetic with transient action and rapid recovery features, but it is clinically unacceptable due to its side effects. AZD-3043, an analog of propanidid with the methoxy group substituted by the ethoxy group, has become the focus of recent development efforts. Although propanidid and AZD-3043 are known to act by potentiating the γ-aminobutyric acid type A receptors (GABA_ARs), their action sites and binding modes in the recognition of target proteins still remain unclear. In this study, molecular docking and ONIOM calculations were performed to explore the possible binding sites and binding modes of propanidid and AZD-3043 with the GABA_AR. The predicted active region located in the transmembrane domain (TMD) of GABA_AR was identified as the most favorable binding site for propanidid and AZD-3043, with the highest docking score (?39.69 and ?39.44 kcal/mol, respectively) and the largest binding energy (?88.478 and ?78.439 kcal/mol, respectively). The important role of amino acids Asp245, Asp424, Asp425, Arg428, Phe307, and Ser308 in determining the binding modes of propanidid or AZD-3043 with GABA_AR was revealed. The detailed molecular interactions between propanidid and AZD-3043 and the GABA_AR were revealed for the first time. This could improve our understanding of the action mechanism of general anesthetics and will be helpful for the design of more potential lead-like molecules.     

The effects of althesin on luteinizing hormone release cannot be explained by actions of the GABAA receptor alone

Althesin and pentobarbitone are anaesthetics which act by prolonging the open time of the chloride channels of the GABA(A) receptor. To explain why luteinizing hormone (LH) release is less depressed by Althesin anaesthesia than by pentobarbitone anaesthesia we suggest that either Althesin is a less potent anaesthetic in the preoptic area or that Althesin as well as stimulating GABA(A) receptors has some other action, perhaps stimulation of GABA(B) receptors, which may facilitate LH release. To investigate the relative potency of the anaesthetics in the preoptic area nine cats were anaesthetised, six with Althesin and three with pentobarbitone, mounted in a stereotaxic frame and prepared for extracellular recording and stimulation of spontaneously active units in the preoptic region. When cats anaesthetised with Althesin were compared with cats anaesthetised with pentobarbitone there were significantly fewer of these units for the number of tracks made. These units also had a significantly lower frequency and a distribution significantly skewed toward lower frequencies. Electrical stimulation of the fornix and of sites in the medial basal hypothalamus and medial forebrain bundle inhibited about 50% of the units and the median duration of the inhibitory pause was significantly longer following stimulation at all three sites in cats anaesthetised with Althesin. We conclude that Althesin is a more potent anaesthetic than pentobarbitone in the preoptic region and that its effects on LH release cannot be explained by its effects on the GABA(A) receptor alone.     

Standardization of Anaesthesia for Radiorenography With Primates Under Laboratory Conditions

The influence of thiopentone intravenous infusion or halothane inhalation on the results of radiorenography was evaluated using, in six chacma baboons (Papio ursinus), ^99mTc-diethyltriamine-pentaacetic acid (DTPA) as scanning agent. The renogram parameters, which depend on the condition of the cardiovascular system, differed significantly for the two anaesthetic agents. Since anaesthesia is necessary in baboon studies for the duration of renogram acquisition, it is imperative to standardize an experimental procedure which will leave the cardiovascular system relatively stable. From this investigation it seemed most appropriate to use as an anaesthetic a constant intravenous infusion of thiopentone.     

Comparative evaluation of anesthesia with etomidate and propanidid in patients undergoing electric cardioversion]

Cardioversion is one of the most effective treatment in cardiac arrhythmias. However, this technique is painful it requires proper anaesthesia assuring stable circulatory and respiratory functions. The authors compared two anaesthetics: etomidate and propanidid. No significant difference in their effects on both circulation and respiration has been noted. Some differences between both drugs in the produced adverse reactions were however noted. Etomidate caused pain at the site of injection, propanidid allergic reactions in the form of skin rash.     

The effect of althesin on plasma corticosterone levels

Althesin in doses which produced anesthesia (4 and 6 ml kg-1, i.p.) produced biphasic changes in plasma corticosterone levels. Plasma corticosterone showed an increase (p less than 0.05) due to the stress of injection but returned to basal levels by 30 min. Subsequent to the anesthetic effect (approximately 30 min) corticosterone levels increased markedly (p less than 0.01). Althesin's effectiveness showed time of day effects, i.e., Althesin was more effective in the A.M. Rats given 6 ml kg-1 Althesin showed graded plasma corticosterone responses to stresses of varying intensity. Blood withdrawal and surgical stress evoked significant increases in plasma corticosterone but a 2-min holding stress had no effect on plasma corticosterone levels. Instrumented rats receiving supplemental injections (i.p.) presented patterns of plasma corticosterone which were different from those receiving supplemental infusions (i.a.). Whereas plasma corticosterone levels of rats receiving the continuous infusion of Althesin remained relatively constant, corticosterone levels of those which received supplemental injections tended to increase. Collectively, these data suggest that Althesins usefulness as an experimental anesthetic is limited to those studies which are not compromised by stress-induced pituitary-adrenal activity.     

The gamma-aminobutyrate/benzodiazepine receptor from pig brain. Enhancement of gamma-aminobutyrate-receptor binding by the anaesthetic propanidid.

The binding of [3H]muscimol, a gamma-aminobutyrate (GABA) receptor agonist, to a membrane preparation from pig cerebral cortex was enhanced by the anaesthetic propanidid in a concentration-dependent manner. At 0 degrees C, binding was stimulated to 220% of control values, with 50% stimulation at 60 microM-propanidid. At 37 degrees C, propanidid caused a more powerful stimulation of [3H]muscimol binding (340% of control values). Propanidid (1 mM) exerted little effect on the affinity of muscimol binding (KD approx. 10 nM), but increased the apparent number of high-affinity binding sites in the membrane by 2-fold. Enhancement of [3H]muscimol binding was observed only in the presence of Cl- ions, half-maximal activation being achieved at approx. 40 mM-Cl-. Picrotoxinin inhibited the stimulation of [3H]muscimol binding by propanidid with an IC50 (concentration causing 50% inhibition) value of approx. 25 microM. The enhancement of [3H]muscimol binding by propanidid was not additive with the enhancement produced by secobarbital. Phenobarbital inhibited the effect of propanidid and secobarbital. The GABA receptor was solubilized with Triton X-100 or with Chaps [3-[(3-cholamidopropyl)dimethylammonio]propanesulphonate]. Propanidid and secobarbital did not stimulate the binding of [3H]muscimol after solubilization with Triton X-100. However, the receptor could be solubilized by 5 mM-Chaps with retention of the stimulatory effects of propanidid and secobarbital. Unlike barbiturates, propanidid did not stimulate the binding of [3H]flunitrazepam to membranes. It is suggested that the ability to modulate the [3H]muscimol site of the GABA-receptor complex may be a common and perhaps functional characteristic of general anaesthetics.     

Food hypersensitivity; correlation of intradermal skin tests with clinical allergenicity

A study was made to determine how well the results of skin tests for sensitivity to various foods agreed with observation of clinical reactions to those foods. Test reactions were divided into several categories-negative, and 1, 2, 3 or 4 plus. Then the strong reactions, that is the 3 and 4 plus reactions, the milder reactions and the negative results were studied separately to determine the agreement of results, in each category, with the clinical response. Wide variations were noted. For some foods the agreement was high, for others low. For some foods, the agreement was high in some categories of reaction, low in others. For example, negative results of skin test might match with nonreaction to the food clinically in a high proportion of cases, and 3 or 4 plus reaction to skin test might be in close agreement with the incidence of distress upon ingestion of the food, yet for the same food there might be very poor correlation between mild reaction to skin test and clinical response. This being the case, accuracy of skin tests cannot be determined simply by combining all data on reactions, of whatever degree, and taking the aggregate of agreement in all categories as an index of the validity of the test. Each category of reaction must be considered separately.Combined data and categorized data on accuracy of skin tests for sensitivity to 26 foods were tabulated in the present study.     

The mechanism of reducing thiopentone dose in elderly patients undergoing surgery

The dose of thiopentone required to induce anesthesia in adults decreasing with age is not due to pharmacodynamic change. The change of pharmacokinetic properties of thiopentone with age in undergoing surgery patient's arterial blood was investigated in seven elderly (67-82 yr) and six young (21-33 yr) patients of both sexes. Thiopentone (3 mg kg-1) was administered intravenously and arterial blood samples were obtained immediately after the injection to measure plasma and red blood cell thiopentone concentrations by an HPLC method. Plasma protein binding was studied using ultracentrifuge method. The disappearance of thiopentone from the arterial blood was described by a two-compartment open model. The distribution rate constant (alpha) was significantly larger in the young patients (p less than 0.001). The distribution half-life was longer in the elderly (p less than 0.05). Both the input microscopic rate constant, K21, and the exit microscopic rate constant, K12, with the central compartment were significantly larger in the young patients. (p less than 0.02 and p less than 0.001, respectively). The difference between the exit and input microscopic rate constant, K12-K21, was much larger in the young patients (p less than 0.001). The plasma protein binding was significantly reduced in the elderly (p less than 0.05). The apparent overall volume of distribution, Vd was not significantly different between young and elder patients. However, the volume of distribution of the central compartment was smaller in the young patients (p less than 0.05). This was probably due to the difficulty of estimation of initial thiopentone plasma concentration post-equilibrium in the central compartment after administration of thiopentone.(ABSTRACT TRUNCATED AT 250 WORDS)     

FOOD HYPERSENSITIVITY—Correlation of Intradermal Skin Tests with Clinical Allergenicity

A study was made to determine how well the results of skin tests for sensitivity to various foods agreed with observation of clinical reactions to those foods.Test reactions were divided into several categories—negative, and 1, 2, 3 or 4 plus. Then the strong reactions, that is the 3 and 4 plus reactions, the milder reactions and the negative results were studied separately to determine the agreement of results, in each category, with the clinical response. Wide variations were noted. For some foods the agreement was high, for others low. For some foods, the agreement was high in some categories of reaction, low in others. For example, negative results of skin test might match with nonreaction to the food clinically in a high proportion of cases, and 3 or 4 plus reaction to skin test might be in close agreement with the incidence of distress upon ingestion of the food, yet for the same food there might be very poor correlation between mild reaction to skin test and clinical response. This being the case, accuracy of skin tests cannot be determined simply by combining all data on reactions, of whatever degree, and taking the aggregate of agreement in all categories as an index of the validity of the test. Each category of reaction must be considered separately.Combined data and categorized data on accuracy of skin tests for sensitivity to 26 foods were tabulated in the present study.     

Polymerase chain reaction with lesion scrapping for the diagnosis of human American tegumentary leishmaniasis

The objective of this work was to compare the polymerase chain reaction (PCR) using lesion scrapping with other conventional techniques for the diagnosis of the American tegumentary leishmaniasis (ATL). For this, patients with cutaneous lesions suspected to be ATL were studied. The DNA was amplified with the MP1L/MP3H primers. From the 156 studied patients, 79 (50.6%) presented positive parasite direct search (PD), 81 (51.9%) had positive Montenegro skin test (MST), and 90 (57.7%) presented PD and/or MST positive. The PCR was positive in all of the positive-PD patients (100% sensitivity), in 91.1% of the positive PD and/or MST patients, and in 27.3% of the patients that presented negative PD and positive MST. The PCR positivity was similar to the PD (P = 0.2482) and inferior to the MST (P = 0.0455), and to the PD/MST association (P = 0.0133). The high PCR sensitivity, and positivity in those cases where the PD was negative, highlights the importance of this technique as an auxiliary tool for the diagnosis of ATL.     

REACTIONS TO INSECT ALLERGENS—The Incidence of Response to Testing Among Allergic and Nonallergic Persons

Positive reactions to skin tests with extracts of various insects were found to be significantly higher in 200 patients with allergic disease than in 150 nonallergic controls.Forty-seven per cent of the allergic group had positive reaction to bee, 46 per cent to house fly, 39.5 per cent to moth, 29.5 to ant and 28.5 to aphid. Ant and house fly extract caused the greatest number of severe reactions (4+), with moth second and bee third.Because extracts of nonstinging insects caused reaction almost as often and as strong as stinging insects, it may be inferred that sensitization is due to inhaled insect particles. There appeared to be no necessary connection between a history of having been stung and a strong skin test reaction to bee protein.Testing for insect sensitivity appears a good way to get diagnostic information that can enhance the effectiveness of treatment.     

Production of the Shwartzman Reaction with Microbial L Forms

Study of potential pathogenicity of microbial L forms was done by the localized Shwartzman reaction. Stable L forms of Proteus mirabilis served as skin preparation in rabbits for induction of Shwartzman reaction by subsequent intravenous injection of either P. mirabilis L forms or Escherichia coli endotoxin. The intensity of the reaction was positively correlated to numbers of L forms in the skin. L forms also served as the intravenous challenge. In vivo multiplication of L forms was not a prerequisite for the reaction, as it could be produced with nonviable, osmotically lysed L forms. The reaction produced with L forms in the skin was more intense than that produced with the parent bacterial form. These latter observations, coupled with the demonstration that L forms disappeared from the skin (lysed?) after 4 hr, in contrast to bacteria which were recoverable for 72 hr (duration of study), suggest release of endotoxin by L forms as a pathogenic mechanism.     

Coccidioidomycosis in San Fernando Valley; report of a study carried out in 1951-1952

Four cases of benign pulmonary coccidioidomycosis occurred during May 1951 among some 35 teenage students at a boarding school and farm for boys that occupies 30 acres in the northwestern section of the San Fernando Valley within the City of Los Angeles. Epidemiological and serological study of the patients yielded evidence that exposure had occurred on the farm or nearby. Correlation of results of skin testing for sensitivity to coccidioidin among students over the subsequent months and of serologic studies in cases in which there was positive reaction to skin tests indicated exposure to coccidioides during the time the subjects were in residence at the school. In addition, two boys had conversion from negative to positive reaction to coccidioidin while they were in residence.     

COCCIDIOIDOMYCOSIS IN SAN FERNANDO VALLEY—Report of a Study Carried Out in 1951-1952

Four cases of benign pulmonary coccidioidomycosis occurred during May 1951 among some 35 teenage students at a boarding school and farm for boys that occupies 30 acres in the northwestern section of the San Fernando Valley within the City of Los Angeles.Epidemiological and serological study of the patients yielded evidence that exposure had occurred on the farm or nearby.Correlation of results of skin testing for sensitivity to coccidioidin among students over the subsequent months and of serologic studies in cases in which there was positive reaction to skin tests indicated exposure to coccidioides during the time the subjects were in residence at the school. In addition, two boys had conversion from negative to positive reaction to coccidioidin while they were in residence.     

Acute effects of verapamil on neuromuscular transmission in patients with myasthenia gravis

The effects of intravenous verapamil (18 micrograms, 36 micrograms, 72 micrograms kg-1) on neuromuscular transmission were studied in the integrated electromyographic (IEMG) responses of indirectly stimulated thenar muscles of five myasthenia gravis patients and 12 other patients without neuromuscular diseases anesthetized with thiopentone, pethidine and nitrous oxide in oxygen. In all subjects, verapamil 72 micrograms kg-1 significantly prolonged the P-R interval of the electrocardiogram from 0.122 +/- 0.004 to 0.152 +/- 0.005 sec and decreased the heart rate from 78.7 +/- 9.5 to 69.6 +/- 6.6 beat min-1, but it had no effect on arterial blood pressure. Verapamil 36 micrograms, 72 micrograms kg-1 significantly inhibited the IEMG to 84.50 +/- 3.30% and 79.25 +/- 3.52% of control value, respectively, in the myasthenia gravis patients. However, these doses did not influence the IEMG of normal subjects. The specific site and mechanism of verapamil's neuromuscular blocking action remain unclear. It is concluded that verapamil can produce neuromuscular blocking action in myasthenia gravis patients and that therefore caution is needed in administering verapamil to such patients.