Current local anesthetics in segmental nerve blocks

The evolution of central segmental blockades was studied in 133 patients by using epidural and spinal anesthesias. The efficiencies of 2% Ultracaine (Hoechst) and 2% Lidocaine (Egis) solutions used for epidural anesthesia and 5% Ultracaine (Hoechst) and 0.75% Bupivacaine (Astra) hyperbaric solutions were evaluated. Central segmental blockade induced by Ultracaine was found to be similar to Lidocaine and Bupivacaine in clinical parameters. At epidural blockade, the latent period was identical for the two agents and the duration of analgesia caused by Ultracaine was 20 minutes longer than that with Lidocaine, the consumption of the former being 20% less. At spinal anesthesia, there were no great differences in the depth and duration of conduction block, but with 5% Ultracaine, the analgesic zone was large (13.2 +/- 1.0 and 15.1 +/- 0.6 segments, p < 0.05). No differences were found in the magnitude of hemodynamic changes both with various anesthetics and different types of segmental blockades. The findings make it possible to regard Ultracaine as an drug that has some advantage over Lidocaine for prolonged epidural anesthesia and similar to the latter in pharmacological characteristics. Ultracaine may be regarded as alternative to Bupivacaine for spinal anesthesia.     

Response of human uterine arteries to local anesthetics

The in vitro effects of local anesthetics and norepinephrine upon strips of early gestation and term pregnancy uterine arteries were studied in eight cases. In another case, the effect upon uterine veins was studied with a standard organ bath used to record isometric contractions. Histologic preparations were made to verify the type of vessel studied. An artery obtained from an eight-week gestation did not respond to either lidocaine or mepivacaine. All other arterial specimens (radial and helicoidal strips) responded with slow, rising, strong contractions to diluted concentrations of both of these substances. Likewise they responded with rapid contractions when exposed to norepinephrine. Alpha blockers were unable to prevent the contractions triggered by the local anesthetics. The vein specimens did not respond to local anesthetics but contracted when stimulated by norepinephrine. Based on these observations and after brief review of some hypotheses advanced to explain post-paracervical anesthesia fetal bradycardia, it is postulated that this bradycardia is probably due to uterine artery spasm, causing decreased intervillous space blood flow and fetal hypoxia.     

Biological dyes may improve the safety of local anesthetics

One of our patients was a 66-year-old woman with a T2 renal cell carcinoma weighing 3900 g. Two years after radical nephrectomy the woman was alive and well. A survey of Japanese medical literature revealed that patients with renal cell carcinomas weighing more than 2000 g have an unexpectedly favorable prognosis with a 5-year survival rate of 76.9%.     

The action of local anesthetics on myelin structure and nerve conduction in toad sciatic nerve

X-ray scattering and electrophysiological experiments were performed on toad sciatic nerves in the presence of local anesthetics. In vitro experiments were performed on dissected nerves superfused with Ringer's solutions containing procaine, lidocaine, tetracaine, or dibucaine. In vivo experiments were performed on nerves dissected from animals anesthesized by targeted injections of tetracaine-containing solutions. In all cases the anesthetics were found to have the same effects on the x-ray scattering spectra: the intensity ratio of the even-order to the odd-order reflections increases and the lattice parameter increases. These changes are reversible upon removal of the anesthetic. The magnitude of the structural changes varies with the duration of the superfusion and with the nature and concentration of the anesthetic molecule. A striking quantitative correlation was observed between the structural effects and the potency of the anesthetic. Electron density profiles, which hardly showed any structural alteration of the unit membrane, clearly indicated that the anesthetics have the effect of moving the pairs of membranes apart by increasing the thickness of the cytoplasmic space. Electrophysiological measurements performed on the very samples used in the x-ray scattering experiments showed that the amplitude of the compound action potential is affected earlier than the structure of myelin (as revealed by the x-ray scattering experiments), whereas conduction velocity closely follows the structural alterations.     

Pericranial injection of local anesthetics for the management of resistant headaches

This study investigated the effect of early feeding mode on the neurological condition at 42 months. For this purpose, healthy pregnant women were recruited in Groningen and Rotterdam, The Netherlands. Children were healthy and born at term. At 42 months, the children were neurologically examined by means of the Touwen/Hempel technique. In addition to the clinical diagnosis, the neurological findings were interpreted in terms of optimality. Special attention was paid to the quality of movements in terms of fluency. In total, 200 (51%) exclusively breastfed(for > or = 6 weeks) and 194 (49%) formula-fed children were studied. Twelve (3%) 42-month-old children were considered to be neurologically mildly abnormal and 1 child was diagnosed as abnormal. No effect of the type of feeding was found on the clinical diagnosis or the neurological optimality. After adjustments for study centre and social, obstetric, perinatal and neonatal neurological differences, a beneficial effect of breastfeeding on the fluency of movements was found (odds ratio for non-optimal fluency 0.56; 95% confidence interval 0.37-0.85). The prolongation of full breastfeeding beyond 6 weeks did not influence the quality of movements. In conclusion, among Dutch preschool children, there was a small advantageous effect of full breastfeeding during the first 6 weeks of life on the fluency of movements.     

Memory-impairing effects of local anesthetics in an elevated plus-maze test in mice

Detailed deletion mapping of chromosome 6q has shown that the highest percentage of loss of heterozygosity (LOH) is located at 6q25-q27 and suggested that an ovarian cancer associated tumor suppressor gene may reside in this region. To further define the smallest region of common loss, we used 12 tandem repeat markers spanning a region no more than 18 cM, located between 6q25.1 and 6q26, to examine allelic loss in 54 fresh and paraffin embedded invasive ovarian epithelial tumor tissues. Loss of heterozygosity was observed more frequently at the loci defined by marker D6S473 (14 of 32 informative cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). Detailed mapping of chromosome 6q25-q26 in these tumor samples identified a 4 cM minimal region of LOH between markers D6S473 and D6S448 (6q25.1-q25.2). Loss of heterozygosity at D6S473 correlated significantly both with serous versus non-serous ovarian tumors (P=0.040) and with high grade versus low grade specimens (P=0.023). The results suggest that a 4 cM deletion unit located at 6q25.1-q25.2 may contain the putative tumor suppressor gene which may play a role in the development and progression of human invasive epithelial ovarian carcinomas (IEOC).     

The partition coefficient as a predictor of local anesthetic potency for spinal anesthesia: evaluation of five local anesthetics in a mouse model

Local anesthetic partition coefficients correlate with drug potencies in vitro, but in vivo data have not always complimented in vitro results. Despite extensive studies on intrathecal anesthetic action, whether there is correlation between the partition coefficient and local anesthetic potency has not been addressed. Mice (n = 150) were randomly allocated into 15 groups. Intrathecal injections of etidocaine (E), tetracaine (T), bupivacaine (B), lidocaine (L), or procaine (P) were administered and analgetic effect was measured using tail-flick (TF) test. Concentration-response regressions were constructed for each drug; EC50 values were calculated and compared at 95% confidence intervals. The EC50 values between E (0.017%), T (0.019%), and B (0.012%) were not significantly variant. The EC50 of L (0.098%) and P (0.229%) were significantly different from each other and from E, T, and B. The EC50 values were converted to ED50 in nmols. Relative anesthetic potency, defined as the inverse value of ED50 of drug was 23:16:15:2.4:1 for B, E, T, L, and P, respectively. ED50 showed high correlation (R = 0.978) with partition coefficients of local anesthetics. This study implies that the partition coefficient is a predictor of intrathecal local anesthetic potency. We suggest that the mouse model is reliable for evaluation of intrathecal local anesthetic action.     

Effect of intrathecally administered local anesthetics on protein phosphorylation in the spinal cord

To elucidate the biochemical mechanisms of spinal anesthesia, we studied the effects of procaine and tetracaine on protein phosphorylation in the mouse spinal cord. Mice were injected intrathecally with either procaine, tetracaine (67 mM/approximately 2%, 10 microL, N = 5/drug), or saline (N = 4/group). Five minutes after injection, animals were killed with a guillotine, and the spinal cord was removed. The caudal 3-cm cord segment was homogenized and centrifuged, and an aliquot of the supernatant was used for phosphorylation assays. Calcium-dependent phosphorylation was initiated by incubating the samples in buffer containing [gamma-32P]ATP at 37 degrees for 30 min. The proteins were electrophoresed using slab gel and two-dimensional electrophoresis, and phosphorylated proteins were visualized by autoradiography. The data demonstrated that spinal anesthesia changes the phosphorylation state of five endogenous substrate proteins with apparent molecular masses of 130 (protein-a), 105 (protein-b), 55 (protein-c), 47 (protein-d), and 33 (protein-e) kDa. In two-dimensional electrophoresis, protein-a resolved into two proteins (a1 and a2). Analysis of variance of the densitometric data suggested a significant effect for the treatment (F(2,16) 735, P < 0.00005). Post hoc comparisons with the saline-treated controls, using the Newman-Keuls test, indicated that local anesthetics significantly affected phosphoproteins (P < 0.05) except for protein-al in the tetracaine-treated group. Further characterization of these phosphoproteins should aid in determining their role in the signal transduction cascade affected by spinal anesthesia.     

Bound volatile general anesthetics alter both local protein dynamics and global protein stability

BACKGROUND: Recent studies have demonstrated that volatile general anesthetic agents such as halothane and isoflurane may bind to discrete sites on protein targets. In the case of bovine serum albumin, the sites of halothane and chloroform binding have been identified as being located in the IB and IIA subdomains. This structural information provides a foundation for more detailed studies into the potential mechanisms of anesthetic action. METHODS: The effect of halothane and isoflurane and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane on the mobility of the indole ring in the tryptophan residues of albumin was investigated using measurements of fluorescence anisotropy. Myoglobin served as a negative control. In addition, the effect of bound anesthetic agents on global protein stability was determined by thermal denaturation experiments using near-ultraviolet circular dichroism spectroscopy. RESULTS: The fluorescence anisotropy measurements showed that halothane and isoflurane decreased the mobility of the indole rings in a concentration-dependent manner. The calculated dissociation constants were 1.6+/-0.4 and 1.3+/-0.3 mM for isoflurane and halothane, respectively. In contrast, both agents failed to increase the fluorescence anisotropy of the tryptophan residues in myoglobin, compatible with lack of binding. The nonimmobilizer 1,2-dichlorohexafluorocyclobutane caused no change in the fluorescence anisotropy of albumin. Binding of the anesthetic agents stabilized the native folded form of albumin to thermal denaturation. Analysis of the thermal denaturation data yielded dissociation constant values of 0.98+/-0.10 mM for isoflurane and 1.0+/-0.1 mM for halothane. CONCLUSIONS: Attenuation of local side-chain dynamics and stabilization of folded protein conformations may represent fundamental modes of action of volatile general anesthetic agents. Because protein activity is crucially dependent on inherent flexibility, anesthetic-induced stabilization of certain protein conformations may explain how these important clinical agents change protein function.     

The pharmacology of memory

Neurotransmitters play a critical role in the brain circuits involved in various aspects of memory. The importance of acetylcholine is illustrated by the psychopathology of Alzheimer's disease. Cholinergic replacement therapy is now available for treating the cognitive decline associated with this form of degenerative disease. Dopamine in the prefrontal cortex also contributes to information storage, particularly working memory. In both cases efforts have been made to identify the receptor subtype involved and such information is essential if pharmacologically specific drugs are to be developed for cognitive enhancement.     

The characteristics of the action of Carpule-delivered local anesthetics and their combinations with vasoconstrictors (a preliminary report)]

Analysis of the authors' findings and published reports on the effects of local anesthetics will help a dentist properly choose adequate anesthesia for each patient with due consideration for the type of intervention and anesthesia. Study of the carpulated local amide anesthetics lidocaine, mepivacaine, and articaine helped detect the relationship between the efficacy of analgesia and its effect on the cardiovascular system, on the one hand, and the drug used, presence of a vasoconstrictor, and type of anesthesia, on the other.     

Pharmacology of local anesthetics and clinical aspects of segmental blocking. II. Spinal anesthesia

Clinical picture of development of segmental blocking after subarachnoidal injection of hyperbaric solutions of 0.75% bupivacaine, 5% ultracaine, and isobaric 0.5% bupivacaine is studied. A total of 152 patients operated on the lower part of the body and the lower limbs were examined under conditions of single, prolonged subarachnoidal, and combined spinal epidural anesthesia. Ultracaine and bupivacaine in different concentrations with different barism provided anesthesia equivalent by the efficacy, depth, and dissemination of sensory block. Segmental blocking with 5% ultracaine was characterized by the shortest latent period (3.14 +/- 0.16 min, p < 0.05) but was no shorter (124.1 +/- 3.37 min) than operative analgesia with 0.75% hyperbaric bupivacaine (120.0 +/- 5.10 min). Isobaric bupivacaine provided the longest effective analgesia (215.0 +/- 45.0 min, p < 0.05). Microcatheter technique improved the safety and control of subarachnoidal anesthesia in comparison with a single injection, and combined spinal epidural anesthesia shortened the latent period of segmental blocking and ensured intraoperative anesthesia and postoperative analgesia at the expense of the epidural component.     

Skin testing after anaphylactoid reactions to dental local anesthetics. A comparison with controls

Reactions to scratch and intradermal challenge with a variety of local anesthetics were examined in 90 patients and compared with 45 controls. The frequency of a positive scratch test was 13 of 90 in the patient group and 12 of 45 in the control group. Thus scratch testing did not appear to discriminate between test and control groups. Significantly greater numbers of patients (22 of 90) gave a positive intradermal response than controls (4 of 45) (chi-squared test p < 0.05). Nine patients showed reactions to more than one agent. The majority of reactions in both patients and controls were in atopic subjects (chi-squared test p < 0.05). In 87 of the 90 patients with suspected anaphylactoid reactions to local anesthetic agents, negative skin reactions to at least one of the agents allowed intrabuccal challenge and subsequent recommendation of an agent for future use. Skin testing, though not providing formal proof of allergy, provides a useful test to indicate local anesthetics that may be used for future procedures.     

The effect of CO2 on the blocking of excitation conduction by local anesthetics in feline A-delta and C fibers]

The data obtained showed that the CO2 potentiated the conduction blockade of the saphenous nerve with tertiary amine trimecaine in anesthetised cats. The data suggests that acidification of cytoplasm with increased CO2 increases the concentration of active cationic protonated forms of a local anesthetic agent.