Comparison of four different protocols using levobupivacaine for spinal anaesthesia in red-footed tortoises (Chelonoidis carbonarius).

Background: The popularity of tortoises kept in captivity is increasing and has caused concern regarding the necessity to establish safe and straightforward anaesthesia for those reptiles. Aim: This study aimed to compare four protocols using levobupivacaine in spinal anaesthesia for the blockade of the caudal neuraxis of red-footed tortoises (Chelonoidis carbonarius). Methods: Twenty-four tortoises were randomly assigned into four groups: G1, levobupivacaine 0.75% (1.15 mg kg-1); G2, levobupivacaine 0.37% (1.15 mg kg-1); G3, levobupivacaine 0.75% (2.3 mg kg-1); and G4, levobupivacaine 0.75% (0.1 ml 5 cm-1 of straight carapace length). Tortoises were evaluated for respiratory rate, muscle relaxation, response to hindlimb or tail pinch, and cloacal reflex. Results: A 1.15 mg kg-1 dose of levobupivacaine 0.37% appears adequate for shorter procedures, whereas a 1.15 mg kg-1 dose of levobupivacaine 0.75% should be appropriate for longer procedures in red-footed tortoises. Conclusion: Our results are the first to show the effects of levobupivacaine on spinal anaesthesia in reptiles. Weight-based doses presented more intense and more homogeneous effects than carapace length-based doses in red-footed tortoises. Spinal anaesthesia of red-footed tortoises was safe and effective with any of the weight-based protocols.

Preoperative echocardiography for patients with hip fractures undergoing surgery in a low-resource setting: Asset or obstacle?

The aim of this study was to determine the rate of preoperative transthoracic echocardiography in hip fracture patients and to evaluate its effects on time to surgery and length of stay. We conducted a retrospective review of all patients with hip fractures treated at a tertiary referral hospital. Data examined included age, sex, comorbidities, time to surgery, length of stay, fracture type and transthoracic echocardiography findings. Forty-eight patients with hip fractures underwent surgery (men 41.7%; mean age 77.2 (49-95)). Nine patients (18.7%) had a preoperative transthoracic echocardiography. Preoperative transthoracic echocardiography was associated with a significantly longer time to surgery an abbreviation for days e.g dys should be added after the values to indicate what time frame is being measured (14.7 versus 6.8, p = 0.0051) and length of stay (23.6 versus 10.4, p = 0.0002). This study demonstrates a high rate of preoperative transthoracic echocardiography in hip fracture patients. The role of transthoracic echocardiography should be reassessed in view of its association with significant surgical delays.

Efficacy of type-I and type-II pectoral nerve blocks (PECS I and II) in patients undergoing mastectomy: a prospective randomised clinical trial.

INTRODUCTION: The benefits of type I/II pectoral nerve blocks (PECS I/II), which can be dose dependent, have been examined in different studies. Nonetheless, few randomised trials have been performed in South America. The present randomised trial examined the efficacy of PECS I/II with a higher dose of the local anaesthetic to manage perioperative pain after mastectomy in Brazil. MATERIAL AND METHODS: This was a randomised, parallel, single-centre, and single-blind trial. Eighty participants undergoing elective mastectomy were randomised (1 : 1) to receive PECS I/II plus ultrasound-guided ropivacaine (0.5%) or standard general anaesthesia. The primary outcome was pain intensity at rest 24 hours after surgery, assessed with a numerical rating scale. Haemodynamic outcomes, consumption of opioids, anaesthe-tics and antiemetics, and post-anaesthetic recovery times were also recorded. RESULTS: Sixty participants (75%) completed the study. The mean age was 54 years, with 57% of participants undergoing mastectomy and 43% undergoing quadrantectomy. Median pain intensity (interquartile range) at rest (24 h postoperatively) was lower in the PECS I/II group compared to the control group: 0 (0-1.75) vs. 1 (1-2), P = 0.021. A smaller number of patients in the PECS I/II group required intraoperative fentanyl (23.3% vs. 83.3%; P < 0.001) and postoperative tramadol (20.0 vs. 76.7%; P < 0.001). Mean doses of fentanyl and tramadol were about 4-5 times lower in the PECS I/II group (P < 0.001). PECS I/II significantly reduced sevoflurane consumption during surgery (P = 0.01). No difference was observed regarding adverse effects. CONCLUSIONS: PECS I/II blockade with high-dose local anaesthetic is efficacious and safe, resulting in lower levels of perioperative pain after mastectomy compared to standard general anaesthesia.

Complexity of Brain Dynamics as a Correlate of Consciousness in Anaesthetized Monkeys.

The use of anaesthesia is a fundamental tool in the investigation of consciousness. Anesthesia procedures allow to investigate different states of consciousness from sedation to deep anesthesia within controlled scenarios. In this study we use information quantifiers to measure the complexity of electrocorticogram recordings in monkeys. We apply these metrics to compare different stages of general anesthesia for evaluating consciousness in several anesthesia protocols. We find that the complexity of brain activity can be used as a correlate of consciousness. For two of the anaesthetics used, propofol and medetomidine, we find that the anaesthetised state is accompanied by a reduction in the complexity of brain activity. On the other hand we observe that use of ketamine produces an increase in complexity measurements. We relate this observation with increase activity within certain brain regions associated with the ketamine used doses. Our measurements indicate that complexity of brain activity is a good indicator for a general evaluation of different levels of consciousness awareness, both in anesthetized and non anesthetizes states.

Assessment of surgical capacity in Chiapas, Mexico: a cross-sectional study of the public and private sector.

INTRODUCTION: Surgical, anaesthesia and obstetric (SAO) care are essential, life-saving components of universal healthcare. In Chiapas, Mexico's southernmost state, the capacity of SAO care is unknown. This study aims to assess the surgical capacity in Chiapas, Mexico, as it relates to access, infrastructure, service delivery, surgical volume, quality, workforce and financial risk protection. METHODS: A cross-sectional study of Ministry of Health public hospitals and private hospitals in Chiapas was performed. The translated Surgical Assessment Tool (SAT) was implemented in sampled hospitals. Surgical volume was collected retrospectively from hospital logbooks. Fisher's exact test and Mann-Whitney U test were used to compare public and private hospitals. Catastrophic expenditure from surgical care was calculated. RESULTS: Data were collected from 17 public hospitals and 20 private hospitals in Chiapas. Private hospitals were smaller than public hospitals and public hospitals performed more surgeries per operating room. Not all hospitals reported consistent electricity, running water or oxygen, but private hospitals were more likely to have these basic infrastructure components compared with public hospitals (84% vs 95%; 60% vs 100%; 94.1% vs 100%, respectively). Bellwether surgical procedures performed in private hospitals cost significantly more, and posed a higher risk of catastrophic expenditure, than those performed in public hospitals. CONCLUSION: Capacity limitations are greater in public hospitals compared with private hospitals. However, the cost of care in the private sector is significantly higher than the public sector and may result in catastrophic expenditures. Targeted interventions to improve the infrastructure, workforce availability and data collection are needed.

The effects of anaesthetics and sedatives on brain inflammation.

Microglia are involved in many dynamic processes in the central nervous system (CNS) including the development of inflammatory processes and neuromodulation. Several sedative, analgesic or anaesthetic drugs, such as opioids, ∝2-adrenergic agonists, ketamine, benzodiazepines and propofol can cause both neuroprotective and harmful effects on the brain. The purpose of this review is to present the main findings on the use of these drugs and the mechanisms involved in microglial activation. Alpha 2-adrenergic agonists, propofol and benzodiazepines have several pro- or anti-inflammatory effects on microglia. Long-term use of benzodiazepines and propofol causes neuroapoptotic effects and α2-adrenergic agonists may attenuate these effects. Conversely, morphine and fentanyl may have proinflammatory effects, causing behavioural changes in patients and changes in cell viability in vitro. Conversely, chronic administration of morphine induces CCL5 chemokine expression in microglial cells that promotes their survival.

Efficacy and adverse events of 4% articaine compared with 2% lidocaine on primary molar extraction: A randomised controlled trial.

BACKGROUND: There is no consensus regarding the most effective anaesthetic solution for children; nerve block, especially mandibular, can be difficult for general dentists. Therefore, the study aims to compare the efficacy and the adverse events of articaine 4% with epinephrine 1:100 000 with lidocaine 2% with epinephrine 1:100 000 for primary molar extraction using buccal infiltration. METHODS: These are data from a parallel triple-blind randomised controlled trial with a computer-generated allocation treatment. Forty-three children aged 6-10 years with a clinical and radiographic indication of primary molar extraction were enrolled. The intervention was local buccal infiltration with articaine 4% compared with lidocaine 2%. The main outcome was pain during anaesthetic injection and tooth extraction. Adverse events were examined as secondary outcomes. Children were treated in a University setting from April to June 2019. RESULTS: Both solutions had similar anaesthetic efficacy in primary molar extraction when applied by the infiltrative technique (ß -0.47; 95% CI -3.19 to 2.24; P = .76); however, children reported higher mean pain during articaine deposition (ß 2.43; 95% CI 0.28-4.57; P = .02). The measured lidocaine pH was 3.19 (0.15) and articaine was 2.43 (0.00) (P = .04). Post-operative pain, oedema and nausea were observed without differences between the groups. CONCLUSIONS: There was no difference in the efficacy of articaine compared to lidocaine for primary molar extraction. Articaine was more painful during the injection. PRACTICAL IMPLICATIONS: Primary molar extractions can be performed with both articaine and lidocaine buccal infiltration.

Epidural administration of ropivacaine and its effects on the pharmacodynamics of rocuronium: Randomized controlled trial. Interaction between ropivacaine and rocuronium.

BACKGROUND: Potentiation of neuromuscular blocking agents by local anesthetics has been described in various clinical and experimental studies. This study assessed the influence of epidural ropivacaine on pharmacodynamic characteristics of rocuronium. DESIGN: This was a prospective randomized clinical trial at the women's hospital, an university tertiary hospital in Brazil. Sixty-two patients underwent elective abdominal surgeries requiring general anesthesia. INTERVENTION: Patients were distributed into two groups: Group 1 (general anesthesia and epidural anesthesia) and Group 2 (general anesthesia). In Group 1, 0.2% ropivacaine at a dose of 40 mg (20 ml) was associated with 2 mg (2 ml) of morphine in a single epidural injection. The following parameters were assessed: clinical duration (DC25) and time for recovery of the train-of-four (TOF) 0.9 ratio (T4/T1 = 90%) after an initial 0.6 mg/kg dose of rocuronium. The primary outcomes were DC25 and TOF 0.9 ratio (T4/T1 = 90%). Secondary outcomes were total propofol and remifentanil consumption. RESULTS: Values were presented as median and interquartile range. The results for DC25 and TOF 0.9 of rocuronium were, respectively, 41.5 35.0-55.0 (25.0-63.0) in Group 1 and 44.0 37.0-51.0 (20.0-67.0) in Group 2 (P = 0.88); 88.0 67.0-99.0 (43.0-137.0) in Group 1; and 80.0 71.0-86.0 (38.0-155.0) in Group 2 (P = 0.83). There was no significant difference between the groups, in terms of pharmacodynamic characteristics of rocuronium. Propofol consumption did not show any difference between the groups. However, remifentanil consumption was significantly lower in Group 1 (P < 0.01). CONCLUSION: Epidural ropivacaine, in the dose studied, did not prolong the duration of rocuronium-induced neuromuscular blockade. TRIAL REGISTRY NUMBER: ReBEC (ref: RBR-7cyp6t).

Control-flow analysis of procedural skills competencies in medical training through process mining.

BACKGROUND: Procedural skills are key to good clinical results, and training in them involves a significant amount of resources. Control-flow analysis (ie, the order in which a process is performed) can provide new information for those who train and plan procedural training. This study outlines the steps required for control-flow analysis using process mining techniques in training in an ultrasound-guided internal jugular central venous catheter placement using a simulation. METHODS: A reference process model was defined through a Delphi study, and execution data (event logs) were collected from video recordings from pretraining (PRE), post-training (POST) and expert (EXP) procedure executions. The analysis was performed to outline differences between the model and executions. We analysed rework (activity repetition), alignment-based fitness (conformance with the ideal model) and trace alignment analysis (visual ordering pattern similarities). RESULTS: Expert executions do not present repetition of activities (rework). The POST rework is lower than the PRE, concentrated in the steps of the venous puncture and guidewire placement. The adjustment to the ideal model measure as alignment-based fitness, expressed as a median (25th-75th percentile) of PRE 0.74 (0.68-0.78) is less than POST 0.82 (0.76-0.86) and EXP 0.87 (0.82-0.87). There are no significant differences between POST and EXP. The graphic analysis of alignment and executions shows a progressive increase in order from PRE to EXP executions. CONCLUSION: Process mining analysis is able to pinpoint more difficult steps, assess the concordance between reference mode and executions, and identify control-flow patterns in procedural training courses.

Video-tracking and high-speed bright field microscopy allow the determination of swimming and cardiac effects of D. magna exposed to local anaesthetics.

Local anaesthetics are among the most used drugs in clinical practice, but once they are released to the environment, the effects on the aquatic fauna remain uncertain. This study evaluates, for the first time, the impact of tetracaine, lidocaine and bupivacaine on the survival rate and physiological effects of cladocera Daphnia magna. Video-tracking and image processing allowed us to obtain changes in behaviour parameters like swimming average velocity and mean square displacement. We found that tetracaine shows the most severe effect. A high-speed microscopy system was also used to determine the response of D. magna heart to these drugs. Our results show that tetracaine presents dose-dependent area reduction during all cardiac cycle, while bupivacaine and lidocaine did not present significative effects on heart size. The tested drugs, at environmental high concentrations, altered behaviour, heart function and survival of D. magna.

A systematic review of different substance injection and dry needling for treatment of temporomandibular myofascial pain.

Temporomandibular myofascial pain presents a major challenge in the diagnosis of temporomandibular disorders (TMD). Due to the characteristics of this condition, intramuscular injection procedures are often needed for adequate control of symptoms and treatment. Thus, the aim of this systematic review was to evaluate the effectiveness of dry needling and injection with different substances in temporomandibular myofascial pain. Electronic databases PubMed, EMBASE, CENTRAL/Cochrane, Lilacs, Scopus, Web of Science and CAPES Catalog of Dissertations and Theses were searched for randomized clinical trials until January 2018. Manual search was performed in relevant journals and in the references/citations of the included studies. The selection of studies was carried out by two independent reviewers according to eligibility criteria. From 7128 eligible studies, 137 were selected for full-text analysis and 18 were included. Due to the heterogeneity of the primary studies it was not possible to perform a meta-analysis. The narrative analysis of the results showed that most of the studies had methodological limitations and biases that compromised the quality of the findings. Dry needling and local anaesthesic injections seem promising, but there is a need to conduct further randomized clinical trials, with larger samples and longer follow-up times, to evaluate the real effectiveness of the technique and evaluated substances.

Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients.

BACKGROUND: Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance. METHODS: Forty patients, ASA I-III, 18-60 yr old, weighing 47-126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X-ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non-linear mixed-effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (ΔOFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. RESULTS: A total of 637 dexmedetomidine serum samples were obtained. A two-compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (ΔOFV=-5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (ΔOFV<3.84). CONCLUSIONS: We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance. CLINICAL TRIAL REGISTRATION: NCT02557867.

Effects of volatile anaesthetics on heme metabolism in a murine genetic model of Acute Intermittent Porphyria. A comparative study with other porphyrinogenic drugs.

BACKGROUND: Acute Intermittent Porphyria (AIP) is an inherited disease produced by a deficiency of Porphobilinogen deaminase (PBG-D). The aim of this work was to evaluate the effects of Isoflurane and Sevoflurane on heme metabolism in a mouse genetic model of AIP to further support our previous proposal for avoiding their use in porphyric patients. A comparative study was performed administering the porphyrinogenic drugs allylisopropylacetamide (AIA), barbital and ethanol, and also between sex and mutation using AIP (PBG-D activity 70% reduced) and T1 (PBG-D activity 50% diminished) mice. METHODS: The activities of 5-Aminolevulinic synthetase (ALA-S), PBG-D, Heme oxygenase (HO) and CYP2E1; the expression of ALA-S and the levels of 5-aminolevulinic acid (ALA) were measured in different tissues of mice treated with the drugs mentioned. RESULTS: Isoflurane increased liver, kidney and brain ALA-S activity of AIP females but only affected kidney AIP males. Sevoflurane induced ALA-S activity in kidney and brain of female AIP group. PBG-D activity was further reduced by Isoflurane in liver male T1; in AIP male mice activity remained in its low basal levels. Ethanol and barbital also caused biochemical alterations. Only AIA triggered neurological signs similar to those observed during human acute attacks in male AIP being the symptoms less pronounced in females although ALA-S induction was greater. Heme degradation was affected. DISCUSSION: Biochemical alterations caused by the porphyrinogenic drugs assayed were different in male and female mice and also between T1 and AIP being more affected the females of AIP group. GENERAL SIGNIFICANCE: This is the first study using volatile anaesthetics in an AIP genetic model confirming Isoflurane and Sevoflurane porphyrinogenicity.

The effect of adjusting the pH of local anaesthetics in dentistry: a systematic review and meta-analysis.

The acidic nature of commercial local anaesthetics (LAs) can cause pain during infiltration and delay the onset of anaesthesia. It is suggested that adjusting the pH of anaesthetic agents could minimize these effects. This systematic review aimed to evaluate the efficacy of buffered LAs in reducing infiltration pain and onset time during dental procedures. MEDLINE, Embase, Scopus and Scielo databases were searched up to April 2017. Randomized controlled trials comparing buffered and unbuffered LAs for intraoral injections were included. Risk of bias was assessed using the Cochrane Collaboration tool. Data upon injection pain and onset time were pooled in a random-effects model. Subgroup analyses compared normal and inflamed tissues, and terminal infiltrations and inferior alveolar nerve (IAN) blocks. Meta-regressions were performed to explain heterogeneity. Fourteen articles were included in this review. Lidocaine with epinephrine was the most used anaesthetic combination. Nonlidocaine studies (n = 2) were not pooled in the meta-analysis. Buffered lidocaine did not result in less pain during intraoral injections: mean difference -6.4 (95% CI -12.81 to 0.01) units in a 0-100 scale. Alkalinized lidocaine did not reduce the onset time in normal tissues when terminal infiltration techniques were used, but resulted in a more rapid onset for IAN blocks (-1.26 min) and in inflamed tissues (-1.37 min); however, this change may not be clinically relevant, considering the time required to prepare the buffered agent. Studies performed using other anaesthetic salts did not show robust and clinically significant results in favour of alkalinization.

Los mitos en torno de la relación entre presión sanguínea y flujo / Myths surrounding the relationship between blood pressure and flow

La hipotensión asociada con la vasodilatación inducida por el uso de agentes anestésicos es muy frecuente, un fenómeno que ha motivado la utilización casi generalizada de vasopresores, con la finalidad de restaurar la presión sanguínea a los niveles registrados antes de la anestesia. En Australia, entre todas las medicaciones que se usan en la anestesia, el costo de los vasopresores es un factor significativo en los costos de los sistemas de salud. La utilización de vasopresores debe basarse en los posibles beneficios y riesgos asociados. Desde hace tiempo se acepta que la presión arterial debe mantenerse con la finalidad de preservar la perfusión. Sin embargo, la evaluación detallada indica que este concepto podría surgir de la interpretación errónea de las leyes básicas de la física, como las leyes de Newton y de Ohm. En este trabajo se propone, en función de los principios de la física, que sólo las fuerzas pueden motivar el aceleramiento de los objetos. Para que la presión sea un conductor del flujo, debería ser una fuerza. Sin embargo, la presión es el resultado de fuerzas que actúan sobre una superficie determinada y, por ende, no representa en sí misma una fuerza y no puede ser un conductor de flujo. El flujo sanguíneo es resultado del equilibrio entre las fuerzas de propulsión y de resistencia; en este contexto se debe reconsiderar el supuesto beneficio de aumentar las fuerzas de resistencia, un fenómeno que, en realidad, motivará una reducción del flujo. En el estudio se cuestiona el uso de vasopresores, como también la relación básica, ampliamente aceptada, entre la presión sanguínea y el flujo sanguíneo.

Hypotension resulting from vasodilatation associated with administration of anaesthetic agents is very common. This has resulted in the almost ubiquitous use of vasopressors with a view to restoring blood pressure to pre-anaesthesia levels. In Australia, of all the medications used in anaesthesia, the cost of vasopressors is a significant factor in contributing to healthcare costs. The rationale for use of vasopressors warrants consideration with regard to their benefits as well as potential harm arising from their use. It has long been accepted that blood pressure needs to be maintained in order to maintain perfusion. However, on close scrutiny such thinking may simply be a misinterpretation of the basic laws of physics with respect to both Newton's laws and Ohm's law. This article develops the physics-based argument that only forces can cause objects to accelerate. For pressure to be a driver of flow it must therefore be a force. However, pressure is the result of forces acting over an area, and consequently is not a force in itself. Therefore, it cannot be a driver of flow. Blood flow is the result of the balance of propulsive and resistive forces, which raises the question as to the benefit of increasing resistive forces, which in fact will reduce flow. The use of vasopressors is challenged in this article as is the basic accepted relationship between blood pressure and blood flow.

Metabolismo del hemo: las dos caras de los efectos de la acumulación de precursores y porfirinas / Heme metabolism: the janus nature of precursorsand porphyrins / Metabolismo do hemo: as duas faces dos efeitos da acumulação de precursores e porfirinas

Las porfirias son enfermedades metabólicas consecuencia de fallas en la biosíntesis del hemo, caracterizadas por un patrón específico de acumulación y excreción de intermediarios, responsables de su patofisiología. En las porfirias agudas el exceso de ácido d-aminolevúlico (ALA) produce una sintomatología neuroabdominal asociada al daño oxidativo por formación de especies reactivas de oxígeno (ROS), originadas por autooxidaxión del ALA. En las cutáneas, la sintomatología es producto de la acumulación de porfirinas, que como el ALA, inducen la formación de ROS. Su desencadenamiento se precipita por factores endógenos (ayuno, estrés, hormonas) y/o exógenos (fármacos), en particular algunos anestésicos. Se presenta una revisión de los estudios bioquímicos y genéticos en pacientes con diferentes porfirias obtenidos en el Centro de Investigaciones de Porfirias y Porfirinas (CIPYP), durante los últimos 38 años, que permitieron ampliar el conocimiento sobre las bases moleculares sobre estas patologías. Se describen los logros resultantes del empleo de modelos experimentales de porfiria, inducida farmacológica o genéticamente, que contribuyeron a la clasificación de algunas drogas como prohibidas para pacientes con porfiria. Finalmente, las porfirinas generadoras de ROS, y por ende inductoras de muerte celular, tienen su aplicación para combatir infecciones por organismos hemo-deficientes como Trypanosoma cruzi y también para ser utilizadas como fotosensibilizadores en la terapia fotodinámica (TFD).

Porphyrias comprise a group of metabolic disorders of the heme biosynthesis pathway resulting in a specific accumulation and excretion of intermediates which are responsible for their pathophysiology. Acute porphyrias are characterized by acute neurovisceral symptoms due to the overproduction and accumulation of d-aminolevulinic acid (ALA) which leads to an oxidative damage resulting from the formation of reactive oxygen species (ROS). In cutaneous porphyrias, the symptomatology is a result of porphyrin accumulation which also induces ROS moulding. In both cases, their clinical signs are precipitated by endogenous factors (stress, hormones, low calories intake) and/or exogenous drugs, in particular some anaesthetics. A review of the biochemical and genetic results obtained from patients with different porphyrias, diagnosed at the CIPYP during the last 38 years is presented here, aimed at obtaining additional evidence about the molecular nature of these disorders. The achievements obtained from experimental porphyria models -pharmacologically or genetically induced- are also described, which contributed to the classification of some drugs as prohibited for their use in porphyric patients. Finally, as porphyrins produce ROS and therefore cellular death, they can be used to treat infections by heme-deficient organisms like Trypanosoma cruzi and also as photosensitizers in photodynamic therapy (TFD).

As Porfirias são doenças metabólicas decorrentes de falhas na biossíntese do Hemo, caracterizadas por um padrão específico de acumulação e excreção de intermediários responsáveis de sua patofisiologia. Nas Porfirias Agudas, o excesso de ácido δ-aminolevulínico (ALA) produz uma sintomatologia neuroabdominal associada ao dano oxidativo por formação de espécies reativas de oxigênio (ROS), decorrentes da auto-oxidação do ALA. Nas Cutâneas a sintomatologia é produto da acumulação de porfirinas, que como o ALA, induzem a formação de ROS. Seu desencadeamento precipita-se por fatores endógenos (jejum, estresse, hormônios) e/ou exógenos (fármacos), especialmente alguns anestésicos. Apresenta-se uma revisão dos estudos bioquímicos e genéticos em pacientes com diferentes Porfirias obtidos no Centro de Investigações de Porfirias e Porfirinas (CIPYP), durante os últimos 38 anos, que permitiram ampliar o conhecimento sobre as bases moleculares destas patologias. Descrevem-se as conquistas resultantes do uso de modelos experimentais de Porfiria, induzida farmacológica ou geneticamente, que contribuíram à classificação de algumas drogas como proibidas para pacientes com Porfiria. Afinal, as porfirinas geradoras de ROS e, por conseguinte, indutoras de morte celular têm sua aplicação para combater infecções por organismos hemo-deficientes como Trypanosoma cruzi e também ser utilizadas como fotossensibilizadores na terapia fotodinâmica (TFD).

Plasma mepivacaine concentrations in patients undergoing third molar surgery.

BACKGROUND: Local anaesthetic-related systemic toxicity mainly results from elevated plasma concentrations of these drugs. We hypothesized that intraoral injection of submaximal doses of mepivacaine does not lead to toxic levels of this drug in blood. This study evaluated the plasma levels of mepivacaine in third molars surgeries. METHODS: Twenty-one patients were randomly assigned into two groups: group I (two unilateral third molars; submaximal dose of mepivacaine 108 mg with epinephrine 54 µg) and group II (four third molars; submaximal dose of mepivacaine 216 mg with epinephrine 108 µg). Blood samples were collected before anaesthesia, and 5, 10, 15, 20, 30, 40, 60, 90 and 120 min after anaesthesia. RESULTS: Individual peak plasma concentrations ranged 0.77-8.31 µg/mL (group I) and from 2.36-7.72 µg/mL (group II). An increase in the average dose of mepivacaine from 1.88 ± 0.12 mg/kg (group I) to 3.35 ± 0.17 mg/kg (group II) increased the mean mepivacaine peak plasma levels from 2.33 ± 0.58 to 4.01 ± 0.69 µg/mL, respectively. Four patients obtained plasma levels of mepivacaine above the threshold for toxicity (5 µg/mL). CONCLUSIONS: Toxic levels of mepivacaine are possible, even when a submaximal dose is used. A twofold increase in the dose of mepivacaine caused the mean peak plasma concentration to increase proportionally, indicating that they may be predicted based on the relation of dose per bodyweight.

Anesthesia in oysters of the genus Crassostrea cultured in Brazil / Anestesia em ostras do gênero Crassostrea cultivadas no Brasil

This study evaluated: 1) the time required for anaesthesia induction and recovery of oysters Crassostrea rhizophorae, Crassostrea gasar and Crassostrea gigas using magnesium chloride (MgCl2); 2) the survival after anaesthesia and gonad sampling; and 3) the D-larvae generation after anaesthesia. For each species, three groups of 10 animals were kept in 50 g L-1 MgCl2, salinity of 36 and temperature of 22 ºC. One control group was kept in solution without MgCl2. Every 1 h anaesthetised oysters were recorded, sampled to determine sex and placed in clean seawater to assess recovering every 30 min. Gonad samplings were made beside the posterior adductor muscle, using 1 mL syringes and needles (0.60 x 25 mm). Factorial crosses were generated within and between anaesthetised and non-anaesthetised oyster groups to produce D-larvae in C. gigas. The survival after 10 days of anaesthesia was 100% for the three studied species. For C. rhizophorae and C. gigas, 100% of the animals were anaesthetised after 360 min and were recovered after 240 and 150 min, respectively. For C. gasar, 87% were anesthetised after 720 min and recovered after >240 min. There were no significant differences in D-larvae numbers between factorial crosses. The salt MgCl2 served as an efficient relaxant and caused no deleterious effect on the survival of the three studied species, or on the D-larvae generation in C. gigas.(AU)

Este estudo avaliou: 1) o tempo necessário para indução à anestesia e recuperação das ostras Crassostrea rhizophorae, Crassostrea gasar e Crassostrea gigas utilizando cloreto de magnésio (MgCl2); 2) a sobrevivência após anestesia e amostragem gonadal; e 3) a geração de larvas-D após anestesia. Para cada espécie, três grupos de 10 animais foram mantidos em 50 g L-1 de MgCl2, salinidade de 36 e temperatura de 22 ºC. Um grupo controle foi mantido em solução sem MgCl2. A cada 1 h, ostras anestesiadas foram registradas, amostradas para determinar sexo e colocadas em água do mar limpa para avaliar a recuperação a cada 30 min. Amostragens das gônadas foram feitas ao lado do músculo adutor posterior, usando seringas de 1 mL e agulha de 0,60 x 25 mm. Cruzamentos fatoriais foram gerados dentro e entre grupos de ostras anestesiadas e não anestesiadas para produzir larvas-D em C. gigas. A sobrevivência após 10 dias de anestesia foi de 100% para as três espécies. Para C. rhizophorae e C. gigas, 100% dos animais foram anestesiados após 360 min e recuperados após 240 e 150 min, respectivamente. Para C. gasar, 87% foram anestesiados após 720 min e recuperados após >240 min. Não houve diferença significativa no número de larvas-D entre os cruzamentos. O sal MgCl2 serviu como relaxante eficiente e não causou efeitos deletérios sobre a sobrevivência das três espécies estudadas ou na geração de larvas-D de C. gigas.(AU)

Anesthesia in oysters of the genus Crassostrea cultured in Brazil / Anestesia em ostras do gênero Crassostrea cultivadas no Brasil

This study evaluated: 1) the time required for anaesthesia induction and recovery of oysters Crassostrea rhizophorae, Crassostrea gasar and Crassostrea gigas using magnesium chloride (MgCl2); 2) the survival after anaesthesia and gonad sampling; and 3) the D-larvae generation after anaesthesia. For each species, three groups of 10 animals were kept in 50 g L-1 MgCl2, salinity of 36 and temperature of 22 ºC. One control group was kept in solution without MgCl2. Every 1 h anaesthetised oysters were recorded, sampled to determine sex and placed in clean seawater to assess recovering every 30 min. Gonad samplings were made beside the posterior adductor muscle, using 1 mL syringes and needles (0.60 x 25 mm). Factorial crosses were generated within and between anaesthetised and non-anaesthetised oyster groups to produce D-larvae in C. gigas. The survival after 10 days of anaesthesia was 100% for the three studied species. For C. rhizophorae and C. gigas, 100% of the animals were anaesthetised after 360 min and were recovered after 240 and 150 min, respectively. For C. gasar, 87% were anesthetised after 720 min and recovered after >240 min. There were no significant differences in D-larvae numbers between factorial crosses. The salt MgCl2 served as an efficient relaxant and caused no deleterious effect on the survival of the three studied species, or on the D-larvae generation in C. gigas.

Este estudo avaliou: 1) o tempo necessário para indução à anestesia e recuperação das ostras Crassostrea rhizophorae, Crassostrea gasar e Crassostrea gigas utilizando cloreto de magnésio (MgCl2); 2) a sobrevivência após anestesia e amostragem gonadal; e 3) a geração de larvas-D após anestesia. Para cada espécie, três grupos de 10 animais foram mantidos em 50 g L-1 de MgCl2, salinidade de 36 e temperatura de 22 ºC. Um grupo controle foi mantido em solução sem MgCl2. A cada 1 h, ostras anestesiadas foram registradas, amostradas para determinar sexo e colocadas em água do mar limpa para avaliar a recuperação a cada 30 min. Amostragens das gônadas foram feitas ao lado do músculo adutor posterior, usando seringas de 1 mL e agulha de 0,60 x 25 mm. Cruzamentos fatoriais foram gerados dentro e entre grupos de ostras anestesiadas e não anestesiadas para produzir larvas-D em C. gigas. A sobrevivência após 10 dias de anestesia foi de 100% para as três espécies. Para C. rhizophorae e C. gigas, 100% dos animais foram anestesiados após 360 min e recuperados após 240 e 150 min, respectivamente. Para C. gasar, 87% foram anestesiados após 720 min e recuperados após >240 min. Não houve diferença significativa no número de larvas-D entre os cruzamentos. O sal MgCl2 serviu como relaxante eficiente e não causou efeitos deletérios sobre a sobrevivência das três espécies estudadas ou na geração de larvas-D de C. gigas.

Cytochrome P450 expression in mouse brain: specific isoenzymes involved in Phase I metabolizing system of porphyrinogenic agents in both microsomes and mitochondria.

Brain cytochrome P450 (CYP) metabolizes a variety of drugs to produce their pharmacological effects within the brain. We have previously observed that porphyrinogenic agents altered CYP levels in brain. The aim of this work was to further study the involvement of mice brain mitochondrial and microsomal Phase I drug metabolizing system when porphyrinogenic agents, such as Enflurane, Isoflurane, allylisopropylacetamide, veronal, ethanol, and Griseofulvin were administered. To this end, CYP2E1, CYP2B1, and CYP3A4 expression were measured. NADPH cytochrome P450 reductase (CPR) expression was also determined. Western Blots were performed in microsomes and mitochondria of whole brain. Some of the drugs studied altered expression mainly in microsomes. Chronic Isoflurane augmented mitochondrial isoform, although this anaesthetic diminished microsomal expression. Ethanol and topical Griseofulvin affected expression in microsomes but not in mitochondria. CYP2E1 mitochondrial activity was induced by acute Enflurane; while the activity of the microsomal protein was enhanced in alcoholised animals. Ethanol also induced CYP2E1 expression in microsomes, although Isoflurane provoked opposite effects in mitochondria and microsomes. Expression of CPR was also induced. Several reports support an emergent role of CYP enzymes in the pathogenesis of neurological disorders, so CYP response in brain could be one of the multiples factors influencing porphyria acute attacks.