The effect of pulvinar-lateral posterior complex stimulation on multiunit activity at the cingulate cortex in the cat.
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Animals↗
Biomedical subjects
C Frenkel
Publications and source records attributed to C Frenkel.
[The molecular action profile of intravenous anesthetics].
A close look at the molecular interactions of intravenous anaesthetics reveals a complex and non-uniform picture. A multitude of membrane structures are affected by the individual anaesthetic compounds, although with specific differential profiles of molecular action for the different groups of anaesthetic substances. This is consistent with the hypothesis of a multi-mechanistic mode of action, where anaesthesia results from the superposition and integration of several anaesthetic actions on the molecular level. This overall concept is illustrated by using the well characterised voltage-activated human brain sodium channel protein and its interactions with various intravenous anaesthetics as an example for other membrane proteins. Using the novel lipid bilayer "voltage-clamp" technique, single sodium channels were incorporated into artificial lipid bilayers and their single channel properties studied. Compared to controls, all studied anaesthetics (propofol, pentobarbital, ketamine, midazolam) interacted in a dose-dependent manner with two key sodium channel functions: 1. reduction of the voltage-independent fractional channel open-time and 2. interaction with the voltage-dependent steady-state activation process. Only propofol and pentobarbital demonstrated these effects at clinically relevant concentrations; hence, the sodium channel might serve as a molecular site of action for these substances only. Differences between clinical anaesthetics and their clinical actions may thus correlate with differential molecular sites and modes of action.
Anesthesia, Intravenous↗
Molecular actions of racemic ketamine on human CNS sodium channels.
In search of a molecular site and mechanism of action for anaesthetics, we have examined the effects of racemic ketamine on single human CNS sodium channels with the new planar lipid bilayer technique. In the dose range studied (0.05-9.2 mmol litre-1) ketamine depressed in a dose-dependent manner two major functions of the sodium channel, by reducing the fractional open time in a voltage-independent manner (ED50 1.1 mmol litre-1; maximal conductance block 71%) and by interfering with the voltage-dependent, steady-state activation. These actions occurred at concentrations which were greater than those used clinically in general anaesthesia (up to 0.02 mmol litre-1), therefore they reflect local rather than general anaesthetic effects which may be related to the hydrophobic properties of ketamine. In comparison with two other i.v. anaesthetic agents, pentobarbitone and propofol, racemic ketamine behaves differently at both the molecular and the clinical level.
Anesthesia↗
[The incidence of post spinal headache in a group of young patients].
Post-dural puncture headache (PDPH) is a significant and well-known complication of procedures that perforate the dura mater, e.g., clinical spinal anaesthesia (SpA). The exact mechanisms leading to PDPH are still not completely understood, although several factors, particularly the patient's age, modulate the incidence. In young patients (20-30 years) previous studies reported high occurrences of PDPH in 6%-16% of cases [5, 8], decreasing the value and acceptance of SpA in this patient group. This study was undertaken to reevaluate under reproducible study conditions the incidence of PDPH and other side effects due to SpA in a larger and more homogeneous patient group. METHODS. Two hundred and two male patients between 19 and 30 years of age were included in this study. The standard anaesthetic technique consisted of oral premedication (1 mg flunitrazepam), preanaesthetic intravenous hydration with at least 0.5 l Ringer's lactate, monitoring of vital signs, and a standard lumbar puncture (lateral position, L2/3 or L3/4 interspace, 25-gauge spinal needle, parallel bevel direction). Anaesthesia was achieved using 12.5 mg hyperbaric 0.5% bupivacaine. Anaesthetic level, onset, and duration (pinprick method) and intraoperative events were recorded. Patients were randomly immobilised for either 6 or 24 h postoperatively. Patients were visited on the 2nd, 4th, and 7th postoperative day to ascertain the occurrence of PDPH and further anaesthesia-related complications. RESULTS. The 202 patients studied had homogeneous demographic characteristics (Table 1). During surgery (average duration: 36 min +/- 18; 10-100 min) with satisfactory anaesthetic levels 1 patient demonstrated a high spinal block (T1). Intraoperatively, a significant decrease in blood pressure was noted in 5 patients (2.5%) and bradycardia in 24 (11.9%). Ten minutes after local anaesthetic instillation the sensory block reached an average level of T10 and had ascended to T8 after 25 minutes (start of surgery). During the three postanaesthetic visits PHPD was present in 7 cases (3.5%); 3 other patients had non-PDPH "tension" headaches (1.5%). All PDPHs occurred on the first 2 postoperative days with a maximum duration of 4 days (1 patient). Treatment consisted of bed rest, hydration, and/or oral analgesics. No patient developed any neurologic sequelae. Moderate back pain (12.4%) and urinary retention (2.5%) were the other postoperative complications. The duration of prophylactic postoperative immobilisation had no obvious impact on PDPH occurrence. Our patients' acceptance of SpA was very high; 98.5% of them would favour SpA for future surgery. DISCUSSION. In contrast to previous studies reporting a high incidence of PDPH (6%-16%) in young adults, we found, in a stringent investigation of a large number of comparable patients in a defined age group, a PDPH rate of 3.5% and a few other minor side effects together with good anaesthetic quality, intraoperative stability, and excellent patient acceptance. Although future studies are needed to further minimise SpA complications, we found SpA a safe anaesthetic technique in our well-defined patient group.
Adult↗
Human brain sodium channels as one of the molecular target sites for the new intravenous anaesthetic propofol (2,6-diisopropylphenol).
Single sodium channels from human brain cortex tissue were incorporated into voltage-clamped planar lipid bilayers in the presence of batrachotoxin and studied with various doses of the new anaesthetic compound propofol (2,6-diisopropylphenol). Propofol was found to depress two major sodium channel functions, leading to a reduction of the time-averaged fractional channel open-time (half-maximal blocking concentration, ED50, 20 microM; maximal block 28%) and an interaction with the steady-state activation. These effects occurred at clinically relevant serum concentrations, suggesting the human brain sodium channel as one of the molecular target sites of action for propofol.
Binding Sites↗
Acetaldehyde stimulation of net gluconeogenic carbon movement from applied malic Acid in tomato fruit pericarp tissue.
Applied acetaldehyde is known to lead to sugar accumulation in fruit including tomatoes (Lycopersicon esculentum) (O Paz, HW Janes, BA Prevost, C Frenkel [1982] J Food Sci 47: 270-274) presumably due to stimulation of gluconeogenesis. This conjecture was examined using tomato fruit pericarp discs as a test system and applied i-[U-(14)C]malic acid as the source for gluconeogenic carbon mobilization. The label from malate was recovered in respiratory CO(2), in other organic acids, in ethanol insoluble material, and an appreciable amount in the ethanol soluble sugar fraction. In Rutgers tomatoes, the label recovery in the sugar fraction and an attendant label reduction in the organic acids fraction intensified with fruit ripening. In both Rutgers and in the nonripening tomato rin, these processes were markedly stimulated by 4000 ppm acetaldehyde. The onset of label apportioning from malic acids to sugars coincided with decreased levels of fructose-2,6-biphosphate, the gluconeogenesis inhibitor. In acetaldehyde-treated tissues, with enhanced label mobilization, this decline reached one-half to one third of the initial fructose-2,6-biphosphate levels. Application of 30 micromolar fructose-2,6-biphosphate or 2,5-anhydro-d-mannitol in turn led to a precipitous reduction in the label flow to sugars presumably due to inhibition of fructose-1,6-biphosphatase by the compounds. We conclude that malic and perhaps other organic acids are carbon sources for gluconeogenesis occurring normally in ripening tomatoes. The process is stimulated by acetaldehyde apparently by attenuating the fructose-2,6-biphosphate levels. The mode of the acetaldehyde regulation of fructose-2,6-biphosphate metabolism awaits clarification.
Journal Article↗
Molecular models of anesthetic action on sodium channels, including those from human brain.
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Anesthetics↗
Molecular actions of pentobarbital isomers on sodium channels from human brain cortex.
New planar lipid bilayer technology enabled the pharmacologic study of single sodium channels from human brain, overcoming the limitations of tissue availability and the rapid loss of protein function in conventional experimental preparations. Synaptosomal vesicles prepared from human brain cortical tissue were fused with planar lipid bilayers. In the presence of batrachotoxin, sodium channels were incorporated into lipid bilayers and their single-channel properties studied. Pentobarbital was found to depress two major functions of the sodium channel, leading to a voltage-independent reduction of the fractional channel open-time (ED50 0.61-0.75 mM) and an interaction with the voltage-dependent steady-state activation. The steady-state activation curve was shifted to more negative potentials and had a reduced slope, i.e., negative membrane potentials became less effective at closing sodium channels. The results were consistent with a pentobarbital-induced increase in protein flexibility. The actions of the two optical stereoisomers of pentobarbital showed no significant differences, indicating that other ion channels must also be involved in the clinical actions of barbiturates. The pentobarbital effects on sodium channels occurred at concentrations thought to be relevant in general anesthesia and within the clinical range. This suggests that sodium channels could contribute to overall anesthetic depression, supporting our hypothesis that anesthesia results from the superposition and integration of several anesthetic actions at the molecular level.
Cerebral Cortex↗
Pentobarbital suppresses human brain sodium channels.
Ion channels, key components in neuronal signal transmission and processing, are likely to be important molecular sites of anesthetic action. Sodium channels from human brain tissue were incorporated into planar lipid bilayers in the presence of batrachotoxin and exposed to the anesthetic pentobarbital. This barbiturate, in a dose-dependent manner and at clinically relevant concentrations, reduced fractional channel open time independent of membrane potential, and interfered with the steady-state activation process.
Cerebral Cortex↗
Veratridine modification of the purified sodium channel alpha-polypeptide from eel electroplax.
In the interest of continuing structure-function studies, highly purified sodium channel preparations from the eel electroplax were incorporated into planar lipid bilayers in the presence of veratridine. This lipoglycoprotein originates from muscle-derived tissue and consists of a single polypeptide. In this study it is shown to have properties analogous to sodium channels from another muscle tissue (Garber, S. S., and C. Miller. 1987. Journal of General Physiology. 89:459-480), which have an additional protein subunit. However, significant qualitative and quantitative differences were noted. Comparison of veratridine-modified with batrachotoxin-modified eel sodium channels revealed common properties. Tetrodotoxin blocked the channels in a voltage-dependent manner indistinguishable from that found for batrachotoxin-modified channels. Veratridine-modified channels exhibited a range of single-channel conductance and subconductance states. The selectivity of the veratridine-modified sodium channels for sodium vs. potassium ranged from 6-8 in reversal potential measurements, while conductance ratios ranged from 12-15. This is similar to BTX-modified eel channels, though the latter show a predominant single-channel conductance twice as large. In contrast to batrachotoxin-modified channels, the fractional open times of these channels had a shallow voltage dependence which, however, was similar to that of the slow interaction between veratridine and sodium channels in voltage-clamped biological membranes. Implications for sodium channel structure are discussed.
Animals↗
[Serum and cerebrospinal fluid kinetics of ceftazidime].
Ceftazidime serum concentrations and cerebrospinal fluid (CSF) penetration across non-inflamed meninges were evaluated in 10 patients after intravenous application of 2 g ceftazidime over a period of 30 min. After a continuous increase during infusion the highest level of ceftazidime in serum with 172.27 micrograms/ml (+/- 60.43 micrograms/ml) was ascertained at the end of the infusion. The further development demonstrated a continuous decrease of serum concentrations. Concentrations in serum followed a two-compartment open kinetic model. Mean distribution volume was 17.6 l, the total clearance was 142.97 ml/min, half-life was 1.8 h and the determined area under the curve was 139.89 micrograms x min/ml. Penetration of ceftazidime into CSF could only be pointed out in 5 patients. The highest level with 5.11 micrograms/ml (+/- 1.2 micrograms/ml) was observed 32 min after starting the infusion. A steady state with CSF-concentrations over 2 micrograms/ml could be ascertained during the following 4 hours in these patients. Obviously high statistic significance (p less than or equal to 0.01) was present when penetration into CSF was correlated to body surface area (BSA) using the exact Fisher test with Yates correction. Penetration of ceftazidime into CSF across non-inflamed meninges with therapeutic concentrations over a period of 4 hours could only be achieved when BSA was less than 1.95 m2. Further investigations in more patients are necessary to evaluate if BSA is the only parameter which affects distribution of ceftazidime into CSF.
Adult↗
Human brain sodium channels in bilayers.
Sodium channels from human cortex were fused into planar lipid bilayers in the presence of batrachotoxin, and their single channel properties examined. Single channel slope conductance averaged 26 ps; tetrodotoxin block of the channels was voltage dependent with a K1/2 at 0 mV of 51 nM. The channel was asymmetrically selective for sodium over potassium. The permeability ratio (PNa/PK) equalled 3.3 when potassium was present only on the intracellular side of the channel, but it was 5.7 with potassium on the extracellular side. The average channel activation gating midpoint was -91 mV. These results indicate that sodium channels from human brain can be successfully studied both electrophysiologically and pharmacologically with the planar bilayer system.
Batrachotoxins↗
[Pathogen spectrum in suppurative meningitis with special reference to a patient sample].
In a five years period (1982 till 1986) the spectrum of pathogenic bacteria and fungi in acute meningitis was analysed. The appearance, spreading and suspected spectrum of pathogens have to be followed by special aspects considering effective therapeutic proceedings. 361 out of 392 positive cerebrospinal fluids (92.1%) were derived from only 3 (neurosurgical, neurological and pediatric department) out of 14 possible departments. Whereas in the pediatric department the classical pathogens of acute meningitis predominated, the patients in the neurosurgical department mainly showed nosocomial infections. There has to be considered the accidental infection, especially in the severely ill patients of the neurosurgical intensive care unit, which favours highly resistant pathogens. Furthermore, to initiate an infection, the pathogenicity of nosocomial microorganisms is not required to be high. The correlation of clinical signs and the proof of pathogens showed that often so called contaminants could be of higher value to be the infectious agent as assumed. Nevertheless, there seemed to be a regression of acute meningitis due to better diagnostic and therapeutic proceedings.
Adolescent↗
Inhibition of pear fruit ripening by mannose.
Softening of the flesh and the rise in ethylene evolution and respiration associated with ripening in pear (Pyrus communis L.) fruit was delayed when mannose was vacuum infiltrated into intact fruit. The extent of delay could be modified by altering the concentration or the volume of mannose applied to the fruit. Inhibition of ripening was associated with phosphorylation of mannose to mannose 6-phosphate (M6P), and accumulation of M6P was associated with lowered levels of inorganic phosphate (Pi), glucose 6-phosphate (G6P), and ATP in the fruit tissue. Subsequently, however, as the M6P was metabolized, the levels of Pi, G6P, and ATP increased and ripening processes were concomitantly released from inhibition. Hence, the degree of inhibition by mannose or the release from inhibition was related to the level of M6P in the fruit and its rate of metabolism. The data provide correlative evidence to support a view that one inhibitory effect of mannose is depletion of Pi in the cell as a result of phosphorylation of mannose to M6P. Inhibition of ripening by mannose was not alleviated by co-application of glucose as a competitive substrate for the hexokinase(s), or by Pi, presumably the depleted metabolite. Also, incubation of tissue disks with M6P resulted in inhibition of ethylene production and respiration. The structural analogs of mannose, glucosamine, and 2-deoxyglucose, which have been shown to mimic mannose action in several plant tissues, did not cause inhibition of ripening of pear fruit comparable with that associated with mannose. Both analogs stimulated respiration, and glucosamine caused only a small inhibition of softening and ethylene evolution. Another mannose analog, alpha-methylmannoside, did inhibit fruit ripening though to a lesser extent than mannose. Its influence was also associated with accumulation of M6P and a decrease of Pi levels. We conclude that the mannose effect may, in part, be due to M6P toxicity, as well as by depletion of Pi.
Journal Article↗
Pharmacokinetic aspects of cerebrospinal fluid penetration of fosfomycin.
Even today antibiotic therapy of postoperative or posttraumatic meningitis remains a problem. In patients in a neurosurgical intensive care unit, nosocomial microorganisms with high resistance are mainly found. There are no antibiotics available which have simultaneously a good efficacy on the higher resistant nosocomial microorganisms and a good penetration through the blood-brain or blood-cerebrospinal fluid barrier. We analysed the cerebrospinal fluid (CSF) penetration of fosfomycin carrying out the investigations in patients in whom a CSF drainage was required for a neurosurgical indication. The blood-brain barrier was considered to be largely intact (total CSF protein and cell counts with in the normal range). Five or 10 g fosfomycin were administered to adults in 30 min infusions. After administration of 5 g, the CSF concentration formed a plateau between 8.6 and 9.9 micrograms/ml 3 to 6 h after the infusion. Increasing the dose infused (10 g) markedly shortened the latency period between reaching a sufficient concentration of fosfomycin in the CSF. With repeated doses of fosfomycin (3 X 5 g/day) the concentration in the CSF did not fall below the therapeutic level. Even in the presence of an intact blood-brain barrier, fosfomycin in our investigation showed a satisfactory penetration into the CSF. This is attributable to the favourable physicochemical state of fosfomycin (relative molecular mass 182).
Adolescent↗
Role of oxidative metabolism in the onset of senescence in plant storage.
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Free Radicals↗
Effect of Ethylene and Oxygen on the Development of Cyanide-resistant Respiration in Whole Plant Mitochondria.
Mitochondria from whole potatoes (Solanum tuberosum) ordinarily fail to oxidize respiratory substrates and to consume molecular O(2) in the presence of cyanide. Mitochondrial preparations obtained from tubers previously held for 24 hours in ethylene (10 microliters per liter) in air are only partially inhibited by cyanide. Application of ethylene in 100% O(2) led to an additional increase in the resistance of the mitochondrial respiration to cyanide. The resistance to cyanide was accompanied by a decrease in the respiratory control but no change in oxidative phosphorylation as shown by the measurement of ATP synthesis.The development of resistance to cyanide following the application of ethylene appears to require whole tubers and may represent an inductive process.
Journal Article↗
Factors Influencing the Development of Cyanide-resistant Respiration in Potato Tissue.
Ethylene, cyanide gas, and volatalized ethanol, acetaldehyde, and acetic acid were applied in a continuous flow to whole potato tubers. Freshly cut slices were obtained periodically during the treatment, and showed a progressive development of a cyanide-resistant respiration. The application of the employed volatiles in 100% O(2) accelerated the onset and the magnitude of the cyanide-resistant respiration.These results show that, similar to ethylene and cyanide, the application of ethanol, acetaldehyde, or acetic acid can also lead to the development of cyanide-resistant respiration in whole potato tubers, and that this type of respiration is retained in freshly cut slices.
Journal Article↗