Schistosoma mansoni: effects of anesthetics and antimonial drugs on worm shift in the mouse

Mice experimentally infected with Schistosoma mansoni were injected with sodium thiopental or sodium antimonyl gluconate (Triostib R), or submitted to halothane inhalation, with or without a previous injection of thiopental. Data obtained showed that halothane and thiopental induce worm shift to the liver (99 and 76%, respectively). Sodium gluconate and antimonium (Triostib R) shifted 52% of worms towards the liver. These results seem to indicate that the use of antimonium would be unnecessary, when surgical removal of schistosomules is carried out through the extracorporeal filtration technique, in patients with portal hypertension.

Can the dopaminergic-related effects of general anesthetics be linked to mechanisms involved in drug abuse and addiction?

BACKGROUND: General anesthetics (GA) are well known for the ability to induce a state of reversible loss of consciousness and unresponsiveness to painful stimuli. However, evidence from animal models and clinical studies show that GA exposure may induce behavioral changes beyond acute effects. Most research and concerns are focused on changes in cognition and memory. METHODS: We will look at effects of GA on behavior that is mediated by the dopaminergic system. RESULTS: Pharmacological resemblance of GA with drugs of abuse, and the complexity and importance of dopaminergic systems in both reward seeking and addictive illnesses make us believe that it deserves an overview about what is already known and what matters to us as healthcare workers and specifically as anesthesiologists. CONCLUSION: A review of available evidence strongly suggests that there may be a link between the effects of GA on the brain and substance abuse, partly explained by their influence on the dopaminergic system.

Novel anesthetics and other treatment strategies for refractory status epilepticus

Refractory status epilepticus (RSE)-that is, seizures resistant to at least two antiepileptic drugs (AEDs)-is generally managed with barbiturates, propofol, or midazolam, despite a low level of evidence (Rossetti, 2007). When this approach fails, the need for alternative pharmacologic and nonpharmacologic strategies emerges. These have been investigated even less systematically than the aforementioned compounds, and are often used, sometimes in succession, in cases of extreme refractoriness (Robakis & Hirsch, 2006). Several possibilities are reviewed here. In view of the marked heterogeneity of reported information, etiologies, ages, and comedications, it is extremely difficult to evaluate a given method, not to say to compare different strategies among them. Pharmacologic Approaches Isoflurane and desflurane may complete the armamentarium of anesthetics,' and should be employed in a ''close'' environment, in order to prevent intoxication of treating personnel. c-Aminobutyric acid (GABA)A receptor potentiation represents the putative mechanism of action. In an earlier report, isoflurane was used for up to 55 h in nine patients, controlling seizures in all; mortality was, however, 67% (Kofke et al., 1989). More recently, the use of these inhalational anesthetics was described in seven subjects with RSE, for up to 26 days, with an endtidal concentration of 1.2-5%. All patients required vasopressors, and paralytic ileus occurred in three; outcome was fatal in three patients (43%) (Mirsattari et al., 2004). Ketamine, known as an emergency anesthetic because of its favorable hemodynamic profile, is an N-methyl-daspartate (NMDA) antagonist; the interest for its use in RSE derives from animal works showing loss of GABAA efficacy and maintained NMDA sensitivity in prolonged status epilepticus (Mazarati & Wasterlain, 1999). However, to avoid possible neurotoxicity, it appears safer to combine ketamine with GABAergic compounds (Jevtovic-Todorovic et al., 2001; Ubogu et al., 2003), also because of a likely synergistic effect (Martin & Kapur, 2008). There are few reported cases in humans, describing progressive dosages up to 7.5 mg/kg/h for several days (Sheth & Gidal, 1998; Quigg et al., 2002; Pruss & Holtkamp, 2008), with moderate outcomes. Paraldehyde acts through a yet-unidentified mechanism, and appears to be relatively safe in terms of cardiovascular tolerability (Ramsay, 1989; Thulasimani & Ramaswamy, 2002), but because of the risk of crystal formation and its reactivity with plastic, it should be used only as fresh prepared solution in glass devices (Beyenburg et al., 2000). There are virtually no recent reports regarding its use in adults RSE, whereas rectal paraldehyde in children with status epilepticus resistant to benzodiazepines seems less efficacious than intravenous phenytoin (Chin et al., 2008). Etomidate is another anesthetic agent for which the exact mechanism of action is also unknown, which is also relatively favorable regarding cardiovascular side effects, and may be used for rapid sedation. Its use in RSE was reported in eight subjects (Yeoman et al., 1989). After a bolus of 0.3 mg/kg, a drip of up to 7.2 mg/kg/h for up to 12 days was administered, with hypotension occurring in five patients; two patients died. A reversible inhibition of cortisol synthesis represents an important concern, limiting its widespread use and implying a careful hormonal substitution during treatment (Beyenburg et al., 2000). Several nonsedating approaches have been reported. The use of lidocaine in RSE, a class Ib antiarrhythmic agent modulating sodium channels, was reviewed in 1997 (Walker & Slovis, 1997). Initial boluses up to 5 mg/kg and perfusions of up to 6 mg/kg/h have been mentioned; somewhat surprisingly, at times lidocaine seemed to be successful in controlling seizures in patients who were refractory to phenytoin. The aforementioned dosages should not be overshot, in order to keep lidocaine levels under 5 mg/L and avoid seizure induction (Hamano et al., 2006). A recent pediatric retrospective survey on 57 RSE episodes (37 patients) described a response in 36%, and no major adverse events; mortality was not given (Hamano et al., 2006 Verapamil, a calcium-channel blocker, also inhibits P-glycoprotein, a multidrug transporter that may diminish AED availability in the brain (Potschka et al., 2002). Few case reports on its use in humans are available; this medication nevertheless appears relatively safe (under cardiac monitoring) up to dosages of 360 mg/day (Iannetti et al., 2005). Magnesium, a widely used agent for seizures elicited by eclampsia, has also been anecdotally reported in RSE (Fisher et al., 1988; Robakis & Hirsch, 2006), but with scarce results even at serum levels of 14 mm. The rationale may be found in the physiologic blockage of NMDA channels by magnesium ions (Hope & Blumenfeld, 2005). Ketogenic diet has been prescribed for decades, mostly in children, to control refractory seizures. Its use in RSE as ''ultima ratio'' has been occasionally described: three of six children (Francois et al., 2003) and one adult (Bodenant et al., 2008) were responders. This approach displays its effect subacutely over several days to a few weeks. Because ''malignant RSE'' seems at times to be the consequence of immunologic processes (Holtkamp et al., 2005), a course of immunomodulatory treatment is often advocated in this setting, even in the absence of definite autoimmune etiologies (Robakis & Hirsch, 2006); steroids, adrenocorticotropic hormone (ACTH), plasma exchanges, or intravenous immunoglobulins may be used alone or in sequential combination. Nonpharmacologic Approaches These strategies are described somewhat less frequently than pharmacologic approaches. Acute implantation of vagus nerve stimulation (VNS) has been reported in RSE (Winston et al., 2001; Patwardhan et al., 2005; De Herdt et al., 2009). Stimulation was usually initiated in the operation room, and intensity progressively adapted over a few days up to 1.25 mA (with various regimens regarding the other parameters), allowing a subacute seizure control; one transitory episode of bradycardia/asystole has been described (De Herdt et al., 2009). Of course, pending identification of a definite seizure focus, resective surgery may also be considered in selected cases (Lhatoo & Alexopoulos, 2007). Low-frequency (0.5 Hz) transcranial magnetic stimulation (TMS) at 90% of the resting motor threshold has been reported to be successful for about 2 months in a patient with epilepsia partialis continua, but with a weaning effect afterward, implying the need for a repetitive use (Misawa et al., 2005). More recently, TMS was applied in a combination of a short ''priming'' high frequency (up to 100 Hz) and longer runs of low-frequency stimulations (1 Hz) at 90-100% of the motor threshold in seven other patients with simple-partial status, with mixed results (Rotenberg et al., 2009). Paradoxically at first glance, electroconvulsive treatment may be found in cases of extremely resistant RSE. A recent case report illustrates its use in an adult patient with convulsive status, with three sessions (three convulsions each) carried out over 3 days, resulting in a moderate recovery; the mechanism is believed to be related to modification of the synaptic release of neurotransmitters (Cline & Roos, 2007). Therapeutic hypothermia, which is increasingly used in postanoxic patients (Oddo et al., 2008), has been the object of a recent case series in RSE (Corry et al., 2008). Reduction of energy demand, excitatory neurotransmission, and neuroprotective effects may account for the putative mechanism of action. Four adult patients in RSE were cooled to 31_-34_C with an endovascular system for up to 90 h, and then passively rewarmed over 2-50 h. Seizures were controlled in two patients, one of whom died; also one of the other two patients in whom seizures continued subsequently deceased. Possible side effects are related to acid-base and electrolyte disturbances, and coagulation dysfunction including thrombosis, infectious risks, cardiac arrhythmia, and paralytic ileus (Corry et al., 2008; Cereda et al., 2009). Finally, anecdotic evidence suggests that cerebrospinal fluid (CSF)-air exchange may induce some transitory benefit in RSE (Kohrmann et al., 2006); although this approach was already in use in the middle of the twentieth century, the mechanism is unknown. Acknowledgment A wide spectrum of pharmacologic (sedating and nonsedating) and nonpharmacologic (surgical, or involving electrical stimulation) regimens might be applied to attempt RSE control. Their use should be considered only after refractoriness to AED or anesthetics displaying a higher level of evidence. Although it seems unlikely that these uncommon and scarcely studied strategies will influence the RSE outcome in a decisive way, some may be interesting in particular settings. However, because the main prognostic determinant in status epilepticus appears to be related to the underlying etiology rather than to the treatment approach (Rossetti et al., 2005, 2008), the safety issue should always represent a paramount concern for the prescribing physician. Conclusion The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this paper is consistent with those guidelines.

Fragmentação de moléculas pela luz síncrotron e por elétrons rápidos. I. O caso do halotano, C2F3HClBr

The photofragmentation of a core-excited halogenated compound, Halotane (C2F3HClBr), generally used as anesthetic by inhalation, has been studied using high energy photons and electrons near C 1s ionization edge (~ 300 eV), using time-of-flight mass spectrometry in multicoincidence mode. We observe strong differences between the molecular fragmentation induced by photons and electron impact.

Synthesis and antifungal activity of halogenated aromatic bis-γ-lactones analogous to avenaciolide

Here we describe the total syntheses and characterization by elemental analyses, infrared and NMR spectroscopy of three new compounds analogous to avenaciolide, a bis-γ-lactone isolated from Aspergillus avenaceus that possesses antifungal activity, where the octyl group of the natural product was replaced by aromatic groups containing chlorine and fluorine atoms. The effects of the avenaciolide, the novel compounds and their synthetic precursors on mycelia development and conidia germination of Colletotrichum gloeosporioides and Fusarium solani were evaluated in vitro. The title compounds were almost as active as avenaciolide. The absolute structures of the chlorinated analogs were determined by X-ray diffraction analysis.

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

Post-training intracerebroventricular administration of procaine (20 µg/µl) and dimethocaine (10 or 20 µg/µl), local anesthetics of the ester class, prolonged the latency (s) in the retention test of male and female 3-month-old Swiss albino mice (25-35 g body weight; N = 140) in the elevated plus-maze (mean ± SEM for 10 male mice: control = 41.2 ± 8.1; procaine = 78.5 ± 10.3; 10 µg/µl dimethocaine = 58.7 ± 12.3; 20 µg/µl dimethocaine = 109.6 ± 5.73; for 10 female mice: control = 34.8 ± 5.8; procaine = 55.3 ± 13.4; 10 µg/µl dimethocaine = 59.9 ± 12.3 and 20 µg/µl dimethocaine = 61.3 ± 11.1). However, lidocaine (10 or 20 µg/µl), an amide class type of local anesthetic, failed to influence this parameter. Local anesthetics at the dose range used did not affect the motor coordination of mice exposed to the rota-rod test. These results suggest that procaine and dimethocaine impair some memory process(es) in the plus-maze test. These findings are interpreted in terms of non-anesthetic mechanisms of action of these drugs on memory impairment and also confirm the validity of the elevated plus-maze for the evaluation of drugs affecting learning and memory in mice

Cardiovascular responses to microinjections of GABA or anesthetics into the rostral ventrolateral medulla of conscious and anesthetized rats

The rostral ventrolateral medulla (RVLM) contains neurons involved in tonic and reflex control of arterial pressure. We describe the effects of gamma-aminobutyric acid (GABA) and anesthetics injected into the RVLM of conscious and urethane (1.2 g/kg, iv) anesthetized Wistar rats (300-350 g). In conscious rats, bilateral microinjection of GABA (50 nmol/200 nl) induced a small but significant decrease in blood pressure (from 130 ± 3.6 to 110 ± 5.6 mmHg, N = 7). A similar response was observed with sodium pentobarbital microinjection (24 nmol/200 nl). However, in the same animals, the fall in blood pressure induced by GABA (from 121 ± 8.9 to 76 ± 8.8 mmHg, N = 7) or pentobarbital (from 118 ± 4.5 to 57 ± 11.3 mmHg, N = 6) was significantly increased after urethane anesthesia. In contrast, there was no difference between conscious (from 117 ± 4.1 to 92 ± 5.9 mmHg, N = 7) and anesthetized rats (from 123 ± 6.9 to 87 ± 8.7 mmHg, N = 7) when lidocaine (34 nmol/200 nl) was microinjected into the RVLM. The heart rate variations were not consistent and only eventually reached significance in conscious or anesthetized rats. The right position of pipettes was confirmed by histology and glutamate microinjection into the RVLM. These findings suggest that in conscious animals the RVLM, in association with the other sympathetic premotor neurons, is responsible for the maintenance of sympathetic vasomotor tone during bilateral RVLM inhibition. Activity of one or more of these premotor neurons outside the RVLM can compensate for the effects of RVLM inhibition. In addition, the effects of lidocaine suggest that fibers passing through the RVLM are involved in the maintenance of blood pressure in conscious animals during RVLM inhibition.

Effects of different general anesthetics on serum hemolysis and hepatic and muscular glycogenolysis in rats

Anesthetics can affect the structure and biological function of tissues and systems differentially. The aim of the present study was to compare three injectable anesthetics generally used in experiments with animals in terms of the degree of hemolysis and glycogenolysis occurring after profound anesthesia. Twenty-four male Wistar rats (330-440 g) were divided into three groups (N = 8): chloral hydrate (CH), ketamine + xylazine (KX), Zoletil 50® (zolazepam and tiletamine) + xylazine (ZTX). After deep anesthesia, total blood was collected. The liver and white (WG) and red gastrocnemius (RG) muscles were also immediately removed. The degree of serum hemolysis was quantified on the basis of hemoglobin concentration (g/L). Hepatic and muscular glycogen concentrations (mmol/kg wet tissue) were quantified by the phenol-sulfuric method. The CH and KX groups exhibited serum hemolysis (4.0 ± 2.2 and 1.9 ± 0.9 g/L, respectively; P < 0.05) compared to the ZTX group, which presented none. Only KX induced elevated glycogenolysis (mmol/kg wet tissue) in the liver (86.9 ± 63.2) and in WG (18.7 ± 9.0) and RG (15.2 ± 7.2; P < 0.05). The CH and ZTX groups exhibited no glycogenolysis in the liver (164.4 ± 41.1 and 176.8 ± 54.4, respectively), WG (28.8 ± 4.4, 32.0 ± 6.5, respectively) or RG (29.0 ± 4.9; 25.3 ± 8.6, respectively). Our data indicate that ZTX seems to be an appropriate general anesthetic for studies that seek to simultaneously quantify the concentration of glycogen and serum biochemical markers without interferences. ZTX is reasonably priced, found easily at veterinary markets, quickly induces deep anesthesia, and presents a low mortality rate.

An investigation into fungal metabolism of halogenated and related steroids

Fungal metabolism of halogenated and related steroids was investigated. The fungi Aspergillus niger ATCC 9142, Curvularia lunata NRRL 2380 and Rhizopus stolonifer ATCC6227b were studied in this regard. 2l-Fluoro-, 2l-chloro, 2l-bromo- and 2l-methyl-pregn-4-ene-3,20diones were prepared and incubated with ~ niger (a C-2l-hydroxylator) in order to observe the effect of the C-2l substituent on the metabolism of these substrates. In all four cases, the C-2l substituent prevented any significant metabolism of these substrates. llB-Fluoropregn-4-ene-3,20-dione was prepared and incubated with C. lunata (an llB-hydroxylator) and ~ stolonifer (an lla-hydroxylator). With ~ lunata, the ll-fluoro- substituent prevent hydroxylation at the 11 position, but diverted it to a site remote from the fluorine atom. In contrast, with ~ stolonifer the llB-fluoro- substituent, although slowing the apparent rate of hydroxylation, did not prevent its occurrence at the 11a- position. llB-Hydroxypregn-4-ene-3,20-dione was also incubated with R. stolonifer. The llB-hydroxy-;group did not appear to have any significant effect on hydroxylation at the lla- position. The incubation of a substrate, unsaturated at a favoured site of hydroxylation with Rhizopus arrhizus ATCC 11145 provided a complex mixture of products; among them were both the a and S epoxides. The formation of these products is rationalized as arising because of the lack of regio- and stereospecificity of the hydroxylase enzyme(s) involved.

Pungent general anesthetics activate transient receptor potential-A1 to produce hyperalgesia and neurogenic bronchoconstriction

BACKGROUND: Volatile anesthetics such as isoflurane and halothane have been in clinical use for many years and represent the group of drugs most commonly used to maintain general anesthesia. However, despite their widespread use, the molecular mechanisms by which these drugs exert their effects are not completely understood. Recently, a seemingly paradoxical effect of general anesthetics has been identified: the activation of peripheral nociceptors by irritant anesthetics. This mechanism may explain the hyperalgesic actions of inhaled anesthetics and their adverse effects in the airways. METHODS: To test the hypothesis that irritant inhaled anesthetics activate the excitatory ion-channel transient receptor potential (TRP)-A1 and thereby contribute to hyperalgesia and irritant airway effects, we used the measurement of intracellular calcium concentration in isolated cells in culture. For our functional experiments, we used models of isolated guinea pig bronchi to measure bronchoconstriction and withdrawal threshold to mechanical stimulation with von Frey filaments in mice. RESULTS: Irritant inhaled anesthetics activate TRPA1 expressed in human embryonic kidney cells and in nociceptive neurons. Isoflurane induces mechanical hyperalgesia in mice by a TRPA1-dependent mechanism. Isoflurane also induces TRPA1-dependent constriction of isolated bronchi. Nonirritant anesthetics do not activate TRPA1 and fail to produce hyperalgesia and bronchial constriction. CONCLUSIONS: General anesthetics induce a reversible loss of consciousness and render the patient unresponsive to painful stimuli. However, they also produce excitatory effects such as airway irritation and they contribute to postoperative pain. Activation of TRPA1 may contribute to these adverse effects, a hypothesis that remains to be tested in the clinical setting.

Radiative forcing and global warming potentials of 11 halogenated compounds

Radiative forcing values have been calculated for 11 halogenated compounds which are in current use or which have been suggested as possible replacements for the chlorofluorocarbons. Absorption cross-sections measured over a range of atmospheric temperature and pressure conditions as part of a multi-laboratory programme have been used together with a narrow band radiative transfer model. We provide a “best estimate” radiative forcing taking into account the likely vertical profile of the gas in each case. The Global Warming Potential over a variety of time horizons has also been calculated where the lifetime is available. We present the first such information for 1,2-dichloroethane. For chloroform our radiative forcing is 5 times higher than the value used in previous assessments, possibly because these ignored the effect of absorption outside the 800–1200 cm−1 “window”. For several of the other compounds considered here, our forcing is between 10 and 30% lower than previous assessments. The perfluorocarbons have been found to have large global warming potentials, many times that of CFC-11, due to both strong absorption and long lifetimes. The importance of absorption features at wavenumbers below 800 cm−1 and the effect of temperature variations in absorption cross-section on the radiative forcing are also investigated.

Infrared absorption spectra, radiative efficiencies, and global warming potentials of newly-detected halogenated compounds: CFC-113a, CFC-112 and HCFC-133a

CFC-113a (CF3CCl3), CFC-112 (CFCl2CFCl2) and HCFC-133a (CF3CH2Cl) are three newly detected molecules in the atmosphere that are almost certainly emitted as a result of human activity. It is important to characterise the possible contribution of these gases to radiative forcing of climate change and also to provide information on the CO2-equivalence of their emissions. We report new laboratory measurements of absorption cross-sections of these three compounds at a resolution of 0.01 cm−1 for two temperatures 250 K and 295 K in the spectral range of 600–1730 cm−1. These spectra are then used to calculate the radiative efficiencies and global warming potentials (GWP). The radiative efficiencies are found to be between 0.15 and 0.3 W∙m−2∙ppbv−1. The GWP for a 100 year time horizon, relative to carbon dioxide, ranges from 340 for the relatively short-lived HCFC-133a to 3840 for the longer-lived CFC-112. At current (2012) concentrations, these gases make a trivial contribution to total radiative forcing; however, the concentrations of CFC-113a and HCFC-133a are continuing to increase. The 2012 CO2-equivalent emissions, using the GWP (100), are estimated to be about 4% of the current global CO2-equivalent emissions of HFC-134a