Sevoflurane in combination with propofol, not thiopental, induces a more robust neuroapoptosis than sevoflurane alone in the neonatal mouse brain.

PURPOSE: Sevoflurane is the most widely used volatile anesthetic of general anesthesia. In children and neonates, it is commonly used alone or in combination with thiopental or propofol. A few recent studies reported that sevoflurane induced neuronal death in the developing rodent brain. We measured the neurotoxicity of these anesthetics at clinical doses, alone and in combination, in the developing mouse brain. METHODS: Seven-day-old C57BL/6 mice were randomly assigned to 6 treatment groups. Three groups were exposed to 3% sevoflurane for 6 h after injection of saline, thiopental (5 mg/kg), or propofol (10 mg/kg), whereas three groups were exposed to room air for 6 h after injection of equal doses of saline, thiopental, or propofol. Apoptosis in the hippocampal CA1 region (CA1) and retrosplenial cortex (RC) was assessed using caspase-3 immunostaining. RESULTS: Sevoflurane alone caused significantly higher apoptosis in the CA1 compared with saline plus air (P = 0.04). Sevoflurane in combination with propofol resulted in significantly greater numbers of apoptotic neurons than sevoflurane alone in both the CA1 and the RC (P = 0.04). However, there was no significant difference in apoptotic neuron density in both the regions between the groups treated with sevoflurane alone and in combination with thiopental (P = 0.683). CONCLUSION: Sevoflurane alone can induce neuronal apoptosis, and this effect is enhanced by propofol. Thiopental did not exacerbate the neurotoxicity of sevoflurane. There is the possibility that the combination of sevoflurane and propofol is a more harmful anesthetic technique than sevoflurane alone in pediatric patients.

Comparison of thiopental, urethane, and pentobarbital in the study of experimental cardiology in rats in vivo.

BACKGROUND: Despite earlier research studying the influence of anesthetics in arrhythmia models, a lot of controversy remains. The aim was to compare the influence of three anesthetics (60 mg/kg thiopental, 1200 mg/kg urethane, 60 mg/kg pentobarbital intraperitoneally) on ventricular arrhythmias and to combine it with measured hemodynamic parameters to find the most suitable agent for such experiments. METHOD: In the model of ischemia- and reperfusion-induced arrhythmias in Sprague-Dawley rats, after left anterior descending coronary artery occlusion (7 minutes) and reperfusion (15 minutes), the following parameters have been measured or calculated: mortality index; ventricular fibrillation and tachycardia incidence and duration; systolic, diastolic, and mean arterial blood pressure; heart rate; myocardial index of oxygen consumption; and plasma creatine kinase concentration. RESULTS: Evident depressive action of urethane on heart rate, blood pressures, and myocardial index of oxygen consumption should be reason enough to exclude it from use in such studies. Pentobarbital had no effect on arrhythmias, whereas thiopental was antiarrhythmic. CONCLUSIONS: Pentobarbital is the most suitable anesthetic offering stable hemodynamic values during arrhythmia studies. These hemodynamic values, which were similar to physiological values in awake rats, the long arrhythmia duration during reperfusion and approximately 50% mortality index are crucial parameters for evaluating antiarrhythmic drugs.

Succinate and artificial maintenance of normal body temperature synergistically correct lethal disorders in thiopental coma rat.

Under modeling of thiopental coma influence of sodium succinate and (or) external warming for the support of normal body temperature (isothermal regimen) on the gas exchange, blood gas content, acid-base status and survival rate was studied in rats. In the absence of therapy hypothermia was developed (-9.4 degrees C), O(2) consumption decreased by a factor 5, oxygenation of arterial blood (pO(2)) did not change while that of venous blood increased, where with arteriovenous oxygen tension gradient decreased by half. Blood tension of carbon dioxide (pCO(2)) increased twice, respiratory and metabolic acidosis was developed. Survival rate under absence of a therapy was 42%, with isolated use of isothermal regimen or succinate therapy alike-50%; with their use in combination drastically increased up to 92%. Succinate increased arteriovenous gradient of pO(2), decreased deficit of buffer bases, increased bicarbonate concentration. At isothermal regimen accumulation of CO(2) in the blood was diminished, its excretion was increased, pH of blood approached normal values. Combined use of both therapy agents increased O(2) consumption and potentiated their positive influence on acid-base status. The implication is that hypothermia restrains effect of succinate in barbiturate coma; prevention of hypothermia in combination with succinate administration is highly effective method of experimental therapy of barbiturate intoxication.

Fulminant hyperammonaemia induced by thiopental coma in rats.

Fulminant hyperammonaemia as a threshold effect of coma-inducing dose of sodium thiopental has been revealed in rats. Blood ammonia content increased progressively after the introduction of 1.0 LD(50) (but not 0.8 LD(50)) of sodium thiopental three times in 3h and five times in 18h. The urinary ammonia excretion was not impaired while the volatilization of ammoniac from the body of ST-treated rats was higher, giving evidence of the augmentation of ammonia production. Blood urea increased by one third despite of insignificant alterations of haematocrit and blood creatinine. Ammonia hyperproduction in the digestive tract could result from gastrointestinal stasis, which has been verified by roentgenography and confirmed by correlation of hyperammonaemia with the stool retardation. In thiopental coma rats the slope of a dose-dependent increase of the blood ammonia and the blood urea after the intraperitoneal injection of ammonium acetate did not exceed that in intact animals. So the ammonia hyperproduction in the digestive tract could be the main contributing cause of fulminant hyperammonaemia in rats with thiopental coma and thus be involved into pathogenesis of the coma.

Natural and derivative brevetoxins: historical background, multiplicity, and effects.

Symptoms consistent with inhalation toxicity have long been associated with Florida red tides, and various causal agents have been proposed. Research since 1981 has centered on a group of naturally occurring trans-fused cyclic polyether compounds called brevetoxins that are produced by a marine dinoflagellate known as Karenia brevis. Numerous individual brevetoxins have been identified from cultures as well as from natural bloom events. A spectrum of brevetoxin derivatives produced by chemical modification of the natural toxins has been prepared to examine the effects of functional group modification on physiologic activity. Certain structural features of natural and synthetic derivatives of brevetoxin appear to ascribe specific physiologic consequences to each toxin. Differential physiologic effects have been documented with many of the natural toxins and derivatives, reinforcing the hypothesis that metabolism or modification of toxin structures modulates both the specific toxicity (lethality on a per milligram basis) and potentially the molecular mechanism(s) of action. A series of naturally occurring fused-ring polyether compounds with fewer rings than brevetoxin, known as brevenals, exhibit antagonistic properties and counteract the effects of the brevetoxins in neuronal and pulmonary model systems. Taken together, the inhalation toxicity of Florida red tides would appear to depend on the amount of each toxin present, as well as on the spectrum of molecular activities elicited by each toxin. Toxicity in a bloom is diminished by the amount brevenal present.

Only extra-high dose of ketamine affects l-glutamate-induced intracellular Ca(2+) elevation and neurotoxicity.

The neurotoxic effects of anesthetics on the developing brain are a concern. Although most of the anesthetics are GABAA agonists or NMDA antagonists, the differences in these effects on prospective glutamate-neurotoxicity in the brain is not fully understood. We examined the degree of L-glutamate-induced intracellular calcium ([Ca(2+)]i) elevation and neurotoxicity in neurons exposed to anesthetics. Primary cortical neurons from E17 rats were preincubated with 1-100 µM of ketamine or thiopental sodium (TPS) for the first 72 h of culturing. Two weeks later, the neurons were exposed to L-glutamate. The extent of glutamate toxicity was evaluated using Ca(2+)-imaging and morphological experiments. Preincubation with 100 µM ketamine but not with other concentrations of ketamine and TPS for the first 72 h in culture significantly enhanced L-glutamate-induced [Ca(2+)]i elevation 2 weeks later. Morphology experiments showed that vulnerability to L-glutamate-mediated neurotoxicity was only altered in neurons preincubated with 100 µM ketamine but not with TPS. Although preincubation with high concentration of ketamine showed enhancement of L-glutamate-induced [Ca(2+)]i elevation 2 weeks later, long-term exposure to TPS or ketamine at clinical doses during developmental periods may not result in a dose-related potentiation of exogenous glutamate-induced neurotoxicity, once the intravenous anesthetics are discontinued.

Abnormal embryogenesis induced by thiopental.

The effects of thiopental on chick embryos were analyzed in the present study. Thiopental was dissolved in saline and injected into embryonating chicken eggs at doses ranging from 0.2 to 4.0 mg per egg. The injections were made into the air sacs of eggs after two to four days of incubation. Control eggs were injected with an equivalent volume of saline (0.1 ml per egg). In all 1080 chicken eggs were used for this study. All embryos were examined on day 7. The LD50 for eggs injected on days 2, 3 and 4 was 2.1, 1.9, and 4.1 mg per egg, respectively. The principal malformations observed were exencephaly, anencephaly, twisted limbs, twisted neck, microphthalmia, everted viscera, and hemorrhage above the left eye and in both cerebral hemispheres. The results of the present study indicate that thiopental has a tendency to cause malformations in the chick embryos tested.

Pharmacological comparison of R(+), S(-) and racemic thiopentone in mice.

The i.p. LD50's of the enantiomorphs of thiopentone have the following increasing order of lethality R(+), racemate and S(-). Whereas the racemate and the S(-) compound have similar therapeutic indices, the R(+) compound has the highest value. The S(-) isomer is the most potent anesthetic agent, followed by the R(+) and the racemate. In the ability to block pentylenetetrazol- and strychnine-induced seizures, the compounds are ranked in the following order of decreased potency: S(-), racemate and R(+). The differences in potency between antipodes have been related to absolute steric configuration of the molecules. Differences in potency of the stereoisomers have been discussed in relationship to known metabolic conversions of thiopentone and its rapid penetration into body fat depots.

Focal cerebral ischemia during anesthesia with etomidate, isoflurane, or thiopental: a comparison of the extent of cerebral injury.

An investigation was performed to compare the cerebral protective properties of etomidate, isoflurane, and thiopental. In separate groups of spontaneously hypertensive rats, etomidate, isoflurane, or thiopental was administered to achieve and maintain burst-suppression of the electroencephalogram (3-5 bursts/min) for the duration of the experiment. A fourth group received 1.2 minimal alveolar concentration halothane. All groups underwent 3 hours of middle cerebral artery occlusion and then 2 hours of reperfusion. Thereafter, the animals were killed and the volume of injured brain was determined by staining with 2,3,5-triphenyltetrazolium. Physiological parameters did not differ among the four groups during the investigation, with the exception that hemolysis occurred in the etomidate group (free hemoglobin levels, approximately 0.4 g.dl-1). The volume of injured brain in the thiopental group (56 +/- 10 mm3) was significantly smaller than that in the halothane control group (99 +/- 13 mm3). The volumes of injured brain in the etomidate and isoflurane groups (145 +/- 11 mm3 and 139 +/- 14 mm3, respectively) were significantly larger than those in the control and thiopental groups. We speculate that the apparently detrimental effect of etomidate may be the result of the binding of nitric oxide of cerebral endothelial origin by the iron component of free hemoglobin. Intracranial pressure was not recorded, and in the isoflurane group, there may have been adverse effects on cerebral perfusion pressure associated with vasodilation caused by high concentrations of isoflurane. The results are consistent with a protective effect by barbiturates.

Pharmacokinetics and anesthetic potency of a thiopental isomer.

In developing a high-performance liquid chromatographic assay for thiopental [5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid], a thiopental isomer [5-ethyl-5-(1-ethylpropyl)-2-thiobarbituric acid] was found. This isomer occurs (6-7%) in supposedly pure thiopental and in the commercially available thiopental sodium administered to patients for induction of anesthesia. A similar type of isomer also occurs in pentobarbital, the oxybarbiturate analogue of thiopental. Because the disposition and anesthetic potency of the isomer is unknown, its pharmacokinetic properties were determined in humans and its anesthetic potency in mice. In five surgical patients, the terminal elimination half-life, clearance, and volume of distribution at steady state of the isomer were not statistically different from those of thiopental. In mice, the isomer proved to be as effective as thiopental for induction of anesthesia. The LD50 and sleep time at one-half the LD50 did not statistically differ between the two compounds in mice. The close structural similarity of thiopental and the isomer results in similar pharmacokinetic and anesthetic properties. It does not appear critical that the isomer be separated from thiopental in subsequent pharmacological research.

[Detoxifying action of various plasma substitute solutions in acute intestinal obstruction (experimental study)]. / Dezintoksikatsionnoe deistvie nekotorykh plazmozameshchaiushchikh rastvorov pri ostroi kishechnoi neprokhodimosti (Eksperimental'noe issledovanie).

Animal experiments have established that infusions of plasma substituting solution from milk serum in combination with sodium succinate produce detoxifying effect in ileus. The use of the solution allows one to correct water electrolyte metabolism and to enhance detoxifying processes.

Cytotoxicity and type of cell death induced by midazolam in human oral normal and tumor cells.

BACKGROUND: Intravenous anesthetics have been used during the treatment of various malignant tumors, however, their effects on oral tissues is not well-understood. In the present study, the cytotoxicity of five intravenous anesthetics towards oral tumor and normal cells was compared. MATERIALS AND METHODS: Tumor specificity index was determined by the ratio of the mean 50% cytotoxic concentration for normal cells to that for tumor cells. Apoptosis induction was monitored by internucleosomal DNA fragmentation and caspase-3, -8, and -9 activation. Fine cell structure was observed under transmission electron microscopy. RESULTS: Benzodiazepines (midazolam and diazepam) exhibited higher cytotoxicity than barbiturates (thiopental and thiamylal), whereas propofol had the intermediate range of cytotoxicity. Midazolam showed the highest cytotoxicity. HL-60 cells were the most sensitive to midazolam, followed by epidermal keratinocytes, oral squamous cell carcinoma (OSCC), glioblastoma and then oral normal cells. Midazolam did not induce the production of apoptosis markers such as internucleosomal DNA fragmentation and activation of caspase-3, -8 and -9, but did induce the appearance of many vacuoles, mitochondrial swelling and cell membrane rupture in OSCC cell lines (HSC-2 and HSC-4) cells. The cytotoxicity of midazolam was not reduced by pre-treatment with autophagy inhibitors (3-methyladenine and bafilomycin A1). CONCLUSION: These results suggest that midazolam may induce necrotic cell death, rather than apoptosis or autophagy, in OSCC cell lines.

Psychopharmacological properties of an aqueous extract of Tetracarpidium conophorum Hutch. & Dalziel in mice.

The extract of the nut of Tetracarpidium conophorum (TC), commonly known as African walnut, is widely used to relieve pain, increase sperm count, enhance sexual performance in males and as a nerve tonic in ethnomedicine. This study describes the psychopharmacological properties of the aqueous extract of the nut of TC in mice. The spectrum of activities studied were the effects of TC on the duration of immobility in the forced swim test of the behavioural despair model of depression; prolongation of the duration of sleep produced by thiopentone; amphetamine-induced stereotyped behaviour; and on pain episodes produced by acetic acid and by formalin. Orally administered TC (50-200 mg/kg) produced a significant and dose-related decrease in the duration of immobility in the forced swim test in mice. TC also exhibited analgesic property, as shown by its ability to reduce the frequency of abdominal constrictions induced by acetic acid and to inhibit the nociceptive responses produced by formalin. However, at the tested oral doses of 50-200 mg/kg, TC did not prolong the duration of sleep produced by thiopentone nor alter the pattern of the stereotyped behaviour induced by amphetamine. This investigation provides evidence that may support the ethnomedicinal applications of the extract of the nut of TC in the treatment of pain. The study also revealed that TC seems to demonstrate antidepressant-like activity, as evidenced by its ability to shorten the period of immobility in the forced swim test; however, further studies are necessary to clearly define the role of TC in depression.

Hydrogenative desulphurization of thienopyrrolizinones: an easy and selective access to (Z)-phenethylidenepyrrolizinones with in vitro cytotoxic activity.

Attempts in view to dearomatize some previously reported tripentones with potent antineoplastic activities led in thiophene series to an unexpected hydrogenative desulphurization reaction. The resulting (Z)-phenethylidenepyrrolizinones were tested in vitro over human epidermoid carcinoma KB cell line. The results of this biological evaluation indicated that the tricyclic core of our model can be cleaved with a partial respect of the activity.