thiopental and Neuroblastoma

We have examined the effects of two intravenous anaesthetic induction agents, propofol and thiopentone, on K+ and carbachol evoked [3H]noradrenaline release from a human neuroblastoma cell line, SH-SY5Y. In this model, we have previously demonstrated that K+ evoked [3H]noradrenaline release was dependent on Ca2+ entry and carbachol evoked release was extracellular Ca(2+)- independent. Propofol inhibited K+ (100 mM)-evoked (IC50 of 42 +/- 11 microM), but not carbachol (1 mM)-evoked, [3H]noradrenaline release. Thiopentone inhibited both K+- and carbachol-evoked release with IC50 values of 116 +/- 15 microM and 169 +/- 39 microM, respectively. These inhibitory effects were not due to changes in the release dynamics, as assessed using perfused cells. Furthermore, thiopentone inhibition of carbachol-evoked release was not due to muscarinic receptor antagonism. Both propofol and thiopentone caused noncompetitive inhibition of K+-stimulated Ca2+ influx, with IC50 values of 127 +/- 7 microM and 121 +/- 10 microM, respectively. These effects were not due to interaction with GABAA receptors, but suggest that both compounds block voltage-sensitive Ca2+ channels. Thiopentone, but not propofol, inhibited carbachol-stimulated increased intracellular Ca2+ concentrations in the presence and absence of extracellular Ca2+. However, thiopentone had no effect on carbachol-stimulated inositol (1,4,5)-triphosphate formation, suggesting that thiopentone may directly inhibit Ca2+ release from intracellular stores.

Topics: Calcium; Carbachol; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Neuroblastoma; Norepinephrine; Potassium; Propofol; Thiopental; Time Factors

1. NIE-115 mouse neuroblastoma cells were studied under voltage clamp in the whole-cell patch-clamp configuration. Peak currents induced by bath application of 5-hydroxytryptamine (5-HT) were inwardly rectifying, reversed at 0.4 +/- 0.2 mV (mean +/- s.e.mean), and were approximately half-inhibited (at 1 microM 5-HT) by 2 nM of the 5-HT3 selective antagonist MDL-72222 (3-tropanyl-3,5-dichlorobenzoate). 2. Peak inward currents activated by a low concentration of 5-HT at a holding potential of -50 mV were potentiated by volatile general anaesthetics. At their human minimum alveolar concentrations (MACs), the degree of potentiation increased in the order isoflurane < halothane < enflurane < methoxyflurane. Potentiation by methoxyflurane was independent of membrane potential in the range -70 mV to +40 mV. The reversal potential was the same in the presence and absence of methoxyflurane. 3. Methoxyflurane shifted the 5-HT dose-response curve to lower 5-HT concentrations, without significantly changing the Hill coefficient or maximum response. The EC50 concentration for 5-HT decreased from 1.86 +/- 0.02 microM to 1.07 +/- 0.11 microM (means +/- s.e.mean) due to the presence of 1 MAC (270 microM) methoxyflurane. 4. In contrast to the volatile anaesthetics, the barbiturate anaesthetic, thiopentone, inhibited the 5-HT3 receptor. Hill analysis of thiopentone dose-response data gave an average IC50 = 117 +/- 8 microM thiopentone and Hill coefficient = 1.6 +/- 0.2 (means +/- s.e.mean). These parameters were not significantly different for data obtained at 5-HT concentrations above and below the control EC50 concentration for 5-HT, consistent with non-competitive inhibition. 5. The n-alcohols occupied an intermediate position between the volatile and barbiturate anaesthetics. The lower alcohols (butanol and hexanol) potentiated 5-HT responses at low alcohol concentrations but inhibited them at high concentrations. In contrast, the higher alcohols (octanol, decanol, dodecanol, tridecanol, tetradecanol and pentadecanol) produced no potentiation, but only inhibition, at all alcohol concentrations. 6. Inhibition of the 5-HT3 receptor by the n-alcohols exhibited a cutoff in potency similar to those previously found for tadpoles, luciferase enzymes and a neuronal nicotinic acetylcholine receptor channel.

Topics: Alcohols; Anesthetics, General; Animals; Methoxyflurane; Mice; Neuroblastoma; Patch-Clamp Techniques; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Thiopental; Tumor Cells, Cultured

Four children ranging in age from 6-30 months were treated with twice-daily (BID) radiation therapy under general anesthesia with a 5-6 hr treatment interval. Anesthesia was accomplished with sodium thiopental administered intravenously (IV) by bolus injection. This as followed by continuous drip infusion of sodium thiopental in a few instances where more prolonged anesthesia was required. Children received an initial formula feeding 6 hr before their first treatment and were subsequently kept NPO (nothing by mouth) until they recovered from their second anesthesia. Recovery from thiopental was rapid and children were ready for a normal feeding within 1-1 1/2 hr of the second treatment. No parenteral feedings were required in any of these patients. Children maintained their weight during courses of radiation therapy which ranged between 19 and 43 elapsed days. There were no radiation-related treatment breaks. One child experienced two hypotensive episodes during anesthesia which responded rapidly to intravenous atropine. No other anesthetic complications occurred. This experience demonstrates that hyperfractionated radiation therapy can be safely delivered in infants requiring general anesthesia for immobilization. We feel that sodium thiopental is the anesthetic of choice in this setting because of the short duration of action and consequently rapid post-anesthesia recovery which makes it possible to achieve adequate nutrition with oral feedings alone.

Topics: Anesthesia, General; Cerebellar Neoplasms; Child, Preschool; Female; Humans; Infant; Male; Medulloblastoma; Neoplasms; Neuroblastoma; Radiotherapy Dosage; Rhabdomyosarcoma; Spinal Cord Neoplasms; Thiopental; Time Factors