[Stressors for patients in the intensive care unit : An analysis taking controllability into consideration]. / Belastungen für Patienten auf der Intensivstation : Eine Analyse unter Berücksichtigung der Kontrollierbarkeit.

OBJECTIVE: Studies on stress factors for patients in intensive care units (ICU) have so far concentrated on whether certain stressors have occurred or how stressful they were. There are no studies on stress for patients in ICUs that measured both the perception of stress and the chances perceived to control it; however, loss of control can result in long-term psychopathological consequences, such as depression or posttraumatic stress disorder. Therefore, a questionnaire was developed to evaluate the influence of controllability on perception of stress. The aim of this study was to answer the following questions: which situations were experienced as stressful by patients in ICUs, whether patients perceived them as being controllable and whether the experience of stress depended on the controllability? Furthermore, it was examined which stressful situations are specific to ICUs. MATERIAL AND METHODS: The questionnaire included 18 potentially stressful situations for ICU patients. These situations were assessed with respect to the occurrence, frequency and duration, the impact of stress and the perception of control. In addition, anxiety was assessed using STAI-X1. A total of 198 ICU patients and 100 patients hospitalized in a general surgery ward were interviewed. RESULTS: Patients in ICUs remembered significantly more stressful situations than those on the normal ward (M ± SD = 10.2 ± 2.7 vs. 6.6 ± 2.0; d = 1.48; p < 0.001) and perceived them as more stressful (mean stress: M ± SD = 3.6 ± 1.5 vs. 2.2 ± 1.3; d = 1.01; p < 0.001). The most stressful situations for ICU patients were fixation of the arms (M ± SD = 7.47 ± 3.27), mechanical ventilation (M ± SD = 7.36 ± 3.29) and endotracheal suctioning (M ± SD = 7.19 ± 2.99). Approximately one third of patients underwent these situations. Situations experienced by more than 90% of ICU patients were evaluated as being the least stressful experiences, including infusion (M ± SD = 2.7 ± 2.7), measuring heart activity (M ± SD = 2.3 ± 2.7), taking blood samples (M ± SD = 2.2 ± 2.7), and temperature control (M ± SD = 0.9 ± 1.7). Controllability experienced by ICU patients negatively correlated with anxiety (r = -0.20, p = 0.004) and mean sensation of stress (r = -0.36; p < 0.001). When comparing stress levels of ICU patients who perceived controllability in a given situation to those who did not, the greatest effects (Cohen's d > 1.4) were observed for the situations presence of a bed barrier (M ± SD = 0.1 ± 0.4 vs. 5.9 ± 2.8), lighting at night (M ± SD = 0.7 ± 1.7 vs. 5.7 ± 3.3), presence of a ventilation tube (M ± SD = 2.5 ± 2.1 vs. 6.7 ± 3.0) and repositioning of the patient (M ± SD = 2.5 ± 2.9 vs. 6.7 ± 2.9). CONCLUSION: The experience of loss of control seems to negatively modify the impact of stressors. Thus, an increase in aspects of controllability could reduce the burden on patients during intensive care.

[Comparable results after arthroscopic replacement of the anterior cruciate ligament : Clinical and functional results after single bundle and double bundle reconstruction]. / Vergleichbare Ergebnisse nach arthroskopischem Ersatz des vorderen Kreuzbandes : Klinische und funktionelle Ergebnisse nach Einzelbündel- und Doppelbündelrekonstruktion.

INTRODUCTION: Rupture of the anterior cruciate ligament (ACL) has been surgically reconstructed mainly arthroscopically for many years. The long-propagated single bundle replacement was followed by recommendations for the anatomical double-bundle reconstruction. The aim of this study is the evaluation of clinical follow-up results in terms of function and stability after performing an ACL reconstruction with both the single bundle (SB) and the double bundle (DB) technique. METHODOLOGY: Eighty patients receiving ACL reconstruction were included (41 SB / 39 DB). The follow-up period was 17.4 months. To assess knee joint stability, anteroposterior translation and rotation translation were determined. In addition, arthrometric measurement and the implementation of standardized scores were performed. Data were statistically evaluated using the Pearson χ2 test and Fisher's exact test (p = 0.05). RESULTS: While the Lachman test in the SB group showed a significant (p = 0.032) greater stability of the knee joints, a higher stability of the knee joints in the DB group was documented by the anterior drawer test and the stability measurement with the rolimeter. In the DB group a significantly higher number of patients with local sensitivity deficits (p = 0.045) and paresthesia as well as a significantly higher active and passive flexion deficit were noted compared to the SB group (p = 0.09 / p = 0.038, respectively). CONCLUSION: Based on the results of this study it is currently not possible to give any recommendations regarding any operating procedure after a follow-up period of at least 12 months. However, there is evidence of a higher complication rate in the DB group. Clinically, these results should be considered in the evaluation of the indications.

[Violence in the emergency department of a maximum care hospital]. / Gewalt in der Notaufnahme eines Maximalversorgers.

INTRODUCTION: The emergency department of hospitals is known as a violent place, nevertheless the true incidence of violent acts in emergency departments in the German-speaking area has been little studied. The goal of this study was to record the occurrence of violence in a university hospital located in the inner city and to evaluate parameters, such as type of violence and accumulation in certain patient groups. MATERIAL AND METHODS: Cases of violence in the emergency department were documented by the personnel over the time frame of 1 year (March 2017 to February 2018) and retrospectively evaluated. RESULTS: An increase of violence during the evening hours (10.3% vs. 67.8%) could be shown. Intoxicated patients were responsible for the highest proportion of acts of violence. In addition, intoxicated patients were shown to be significantly more frequently aggressive than sober patients (63.72% vs. 31.65%). Non-intoxicated patients were as a rule only verbally aggressive. De-escalation by emergency room personnel was shown to be successful in 62.5% of the cases. In the rest of the cases help from outside, such as security personnel or the police was necessary, especially for intoxicated patients. DISCUSSION: Violence occurs with high regularity in emergency departments. The average incidence of acts of violence of every 0.7 days shows the need for safety precautions for hospital personnel.

[High pain expectation and impairment from pre-existing pain are risk factors for severe postoperative pain : Results of a study using the Lübeck Pain Risk Questionnaire]. / Hohe Schmerzerwartung und Beeinträchtigung durch vorbestehende Schmerzen sind Risikofaktoren für hohe postoperative Schmerzen : Ergebnisse einer Untersuchung mit dem Lübecker "Schmerzrisiko-Fragebogen".

BACKGROUND: The intensity of postoperative pain is characterized by large interindividual variability. Furthermore, strong postoperative pain is known to influence physical recovery after surgery. High (preoperative) pain expectation and pre-existing pain, which are associated with pain-related disability (impairing pain) are risk factors for strong postoperative pain. They can be determined with the Lübeck Pain Risk Questionnaire used for the first time in this study. The aim of this study was to explore the hypothesis that patients with a combination of the characteristics (1) preoperative impairing pain and (2) high pain expectation are more likely to have strong postoperative pain. Patients with these characteristics represent a unique group of patients and are more likely to develop distinct postoperative pain and can therefore be characterized as a risk group. MATERIAL AND METHODS: A total of 501 patients at the departments of general surgery, plastic surgery, trauma surgery and orthopedic surgery of the UKSH Campus Lübeck were included in this study. All underwent elective surgery. Study patients were 18 years and older. Those needing postoperative treatment in an intensive care unit were excluded from this study (n = 18). The characteristics "preoperative pain" and "pain expectation" were measured with the Lübeck Pain Risk Questionnaire the day before surgery. The primary outcome variable was the average postoperative pain intensity, which was measured with a numeric rating scale (NRS 0-10) and scores > 4 were defined as severe pain. RESULTS: The NRS range for "preoperative pain" was subdivided as follows: "no pain" (NRS = 0), "functional pain" (NRS = 1-3), and "impairing pain" (NRS = 4-10); that for "pain expectation" as: "low expectation" (NRS = 0-4) and "high expectation" (NRS = 5-10). To determine these cut-off points, they were varied from > 1 to > 8 and those with highest effect size for strong postoperative pain were chosen. Patients with a high pain expectation had significantly stronger postoperative pain (p < 0.001) and significantly more often higher pain intensity than patients with a low expectation (53.3% vs. 20.6%, respectively, p < 0.001). Patients with pre-existing impairing pain had significantly stronger and more frequently higher postoperative pain than patients with pre-existing functional pain (43.4% vs. 18.4%, p < 0.05). Patients with a combination of the factors "preoperative impairing pain" and "high pain expectation" showed distinct postoperative pain with NRS > 4 significantly more often (59.4%, p < 0.001). These findings could be demonstrated for the departments general surgery, plastic surgery and trauma surgery. CONCLUSION: The combination of both risk factors results in a unique risk group for the appearance of strong postoperative pain. This group can be economically determined in the daily clinical routine using the Lübeck Pain Risk Questionnaire. Further studies must be carried out to show if additional perioperative procedures can be profitable for the risk group identified with the Lübeck Pain Risk Questionnaire; however, patients falling outside the risk group must not be neglected because they too can develop severe postoperative pain.

Autologous cell-based therapy for treatment of large bone defects: from bench to bedside.

OBJECTIVES: Reconstruction of long segmental bone defects is demanding for patients and surgeons, and associated with long-term treatment periods and substantial complication rates in addition to high costs. While defects up to 4-5 cm length might be filled up with autologous bone graft, heterologous bone from cadavers, or artificial bone graft substitutes, current options to reconstruct bone defects greater than 5 cm consist of either vascularized free bone transfers, the Masquelet technique or the Ilizarov distraction osteogenesis. Alternatively, autologous cell transplantation is an encouraging treatment option for large bone defects as it eliminates problems such as limited autologous bone availability, allogenic bone immunogenicity, and donor-site morbidity, and might be used for stabilizing loose alloplastic implants. METHODS: The authors show different cell therapies without expansion in culture, with ex vivo expansion and cell therapy in local bone defects, bone healing and osteonecrosis. Different kinds of cells and scaffolds investigated in our group as well as in vivo transfer studies and BMC used in clinical phase I and IIa clinical trials of our group are shown. RESULTS: Our research history demonstrated the great potential of various stem cell species to support bone defect healing. It was clearly shown that the combination of different cell types is superior to approaches using single cell types. We further demonstrate that it is feasible to translate preclinically developed protocols from in vitro to in vivo experiments and follow positive convincing results into a clinical setting to use autologous stem cells to support bone healing.

[Medical Emergency Preparedness in offshore wind farms : New challenges in the german north and baltic seas]. / Notfallmedizinische Versorgung in Offshore-Windparks : Neue Herausforderungen in der deutschen Nord- und Ostsee.

BACKGROUND: Offshore windfarms are constructed in the German North and Baltic Seas. The off-coast remoteness of the windfarms, particular environmental conditions, limitations in offshore structure access, working in heights and depths, and the vast extent of the offshore windfarms cause significant challenges for offshore rescue. Emergency response systems comparable to onshore procedures are not fully established yet. Further, rescue from offshore windfarms is not part of the duty of the German Maritime Search and Rescue Organization or SAR-Services due to statute and mandate reasons. Scientific recommendations or guidelines for rescue from offshore windfarms are not available yet. The present article reflects the current state of medical care and rescue from German offshore windfarms and related questions. The extended therapy-free interval until arrival of the rescue helicopter requires advanced first-aid measures as well as improved first-aider qualification. Rescue helicopters need to be equipped with a winch system in order to dispose rescue personnel on the wind turbines, and to hoist-up patients. For redundancy reasons and for conducting rendezvous procedures, adequate sea-bound rescue units need to be provided. In the light of experiences from the offshore oil and gas industry and first offshore wind analyses, the availability of professional medical personnel in offshore windfarms seems advisible. Operational air medical rescue services and specific offshore emergency reaction teams have established a powerful rescue chain. Besides the present development of medical standards, more studies are necessary in order to place the rescue chain on a long-term, evidence-based groundwork. A central medical offshore registry may help to make a significant contribution at this point.

Effects of positive blood alcohol concentration on outcome and systemic interleukin-6 in major trauma patients.

BACKGROUND: The influence of alcohol on the outcome after major trauma remains controversial. In several recent studies, alcohol has been associated with neuroprotective effects in head injuries, while others reported negative or no effects on survival and/or the in-hospital stay in major trauma patients (TP). The purpose of this study was to examine the relationship of alcohol with injury characteristics and outcome as well as to analyze possible anti-inflammatory properties in major TP. PATIENTS/METHODS: 184 severely injured TP with an Injury Severity Score (ISS) ≥16 were successively enrolled. All patients had measured blood alcohol concentration (BAC). Patients were grouped according to their positive BAC (>0.5‰, BAC) vs. <0.5‰ alcohol (no BAC) upon arrival at the emergency department (ED). Injury characteristics, physiologic parameters and outcome with respect to organ or multiple organ failure (MOF), SIRS, sepsis, pneumonia, ARDS or mortality were assessed. Systemic levels of interleukin (IL)-6 at ED were determined. RESULTS: Forty-nine TP had positive BAC without chronic alcohol abuse history and 135 patients had BAC levels below 0.5‰. Overall injury severity and age were comparable in both groups. No BAC TP received significantly higher numbers of packed red blood cells and fresh frozen plasma (transfused within the initial 24h or in total) compared to BAC TP. Organ failure, MOF, SIRS, sepsis, pneumonia, ARDS and the in-hospital mortality were not different between both groups. Trauma patients with positive BAC had significantly decreased leukocyte numbers and systemic IL-6 levels compared to no BAC group. There was a significant positive correlation between leukocyte counts and IL-6 as well as BAC and leukocytes. BAC levels did not correlate with IL-6. CONCLUSIONS: Positive BAC is associated with reduced leukocyte numbers and lowered systemic IL-6 levels at admittance indicating immune-suppressive effects of alcohol in major trauma patients.

Antibiotic use and childhood body mass index trajectory.

BACKGROUND/OBJECTIVES: Antibiotics are commonly prescribed for children. Use of antibiotics early in life has been linked to weight gain but there are no large-scale, population-based, longitudinal studies of the full age range among mainly healthy children. SUBJECTS/METHODS: We used electronic health record data on 163 820 children aged 3-18 years and mixed effects linear regression to model associations of antibiotic orders with growth curve trajectories of annual body mass index (BMI) controlling for confounders. Models evaluated three kinds of antibiotic associations-reversible (time-varying indicator for an order in year before each BMI), persistent (time-varying cumulative orders up to BMIj) and progressive (cumulative orders up to prior BMI (BMIj-1))-and whether these varied by age. RESULTS: Among 142 824 children under care in the prior year, a reversible association was observed and this short-term BMI gain was modified by age (P<0.001); effect size peaked in mid-teen years. A persistent association was observed and this association was stronger with increasing age (P<0.001). The addition of the progressive association among children with at least three BMIs (n=79 752) revealed that higher cumulative orders were associated with progressive weight gain; this did not vary by age. Among children with an antibiotic order in the prior year and at least seven lifetime orders, antibiotics (all classes combined) were associated with an average weight gain of approximately 1.4 kg at age 15 years. When antibiotic classes were evaluated separately, the largest weight gain at 15 years was associated with macrolide use. CONCLUSIONS: We found evidence of reversible, persistent and progressive effects of antibiotic use on BMI trajectories, with different effects by age, among mainly healthy children. The results suggest that antibiotic use may influence weight gain throughout childhood and not just during the earliest years as has been the primary focus of most prior studies.

Establishment and characterization of the Masquelet induced membrane technique in a rat femur critical-sized defect model.

The Masquelet induced membrane technique for reconstructing large diaphyseal defects has been shown to be a promising clinical treatment, yet relatively little is known about the cellular, histological and biochemical make-up of these membranes and how they produce this positive clinical outcome. We compared cellular make-up, histological changes and growth factor expression in membranes induced around femur bone defects and in subcutaneous pockets at 2, 4 and 6 weeks after induction, and to the periosteum. We found that membranes formed around bone defects were similar to those formed in subcutaneous pockets; however, both were significantly different from periosteum with regard to structural characteristics, location of blood vessels and overall thickness. Membranes induced at the femur defect (at 2 weeks) and in periosteum contain mesenchymal stem cells (MSCs; STRO-1+ ) which were not found in membranes induced subcutaneously. BMP-2, TGFß and VEGF were significantly elevated in membranes induced around femur defects in comparison to subcutaneously induced membranes, whereas SDF-1 was not detectable in membranes induced at either site. We found that osteogenic and neovascular activity had mostly subsided by 6 weeks in membranes formed at both sites. It was conclude that cellular composition and growth factor content in induced membranes depends on the location where the membrane is induced and differs from periosteum. Osteogenic and neovascular activity in the membranes is maximal between 2 and 4 weeks and subsides after 6. Based on this, better and quicker bone healing might be achieved if the PMMA cement were replaced with a bone graft earlier in the Masquelet technique. Copyright © 2013 John Wiley & Sons, Ltd.

[Thoracic and lumbar spinal injuries in children and adolescents]. / Brust- und Lendenwirbelsäulenverletzungen im Kindes- und Jugendalter.

Spinal injuries are generally very rare in childhood. Fractures of the thoracic and lumbar spine occur mainly in older children and adolescents. Exact knowledge of the anatomy is essential for accurate diagnosis in still incomplete ossification. With increasing age the classification can be performed by using the AO classification over the age of 8 years. Neurological symptoms in the thoracic and lumbar spine occur mainly in adolescence. Conventional radiography is the standard diagnostic tool for thoracic and lumbar spinal injuries. With the appearance of abnormal neurological deficits magnetic resonance imaging (MRI) diagnostics should also be performed and for operative cases computed tomography (CT) scans are mandatory. The most common fractures of the thoracic and lumbar spine are compression fractures (type A) which can generally be treated conservatively due to the stable situation but unstable fractures of the thoracic and lumbar spine (types B and C) are stabilized dorsally (internal fixation). Ventral stabilization with vertebral body replacement is occasionally necessary in adolescents. Spinal injuries in children have a good overall prognosis.

[Traumatic vertebral body fractures and osteoporosis: value of cement augmentation]. / Traumatische Wirbelsäulenfrakturen und Osteoporose : Stellenwert der Zementaugmentation.

Traumatic vertebral body fractures are different from the osteoporotic vertebral sintering fractures with regard to accruement, classification and surgical treatment. The standard therapeutic regimen for traumatic vertebral fracture implies sufficient analgetic as well as antiosteoporotic medication and physiotherapy. In cases of A1 fractures and A2.1/A2.2 fractures, minimally invasive treatment strategies have proven to be appropriate treatment options when conservative treatment fails. Unstable fractures, the presence of neurological deficits or stenosis of the canal require conventional operative treatment. Due to reduced bone quality and age-dependent biomechanical changes, distinct operative procedures and strategies - cement augmentation of pedicle screws, additional cement augmentation of the fractured vertebra - for complex traumatic vertebral fractures have been established.

Seroprotection against serogroup C meningococcal disease in adolescents in the United Kingdom: observational study.

OBJECTIVE: To determine the persistence of bactericidal antibody titres following immunisation with serogroup C meningococcal glycoconjugate vaccine at age 6-15 years in order to examine changes in persistence of antibodies with age. DESIGN: Observational study. SETTING: Secondary and tertiary educational institutions in the United Kingdom. PARTICIPANTS: Healthy adolescents aged 11-20 years previously immunised between 6 and 15 years of age with one of the three serogroup C meningococcal vaccines. INTERVENTION: Serum obtained by venepuncture. MAIN OUTCOME MEASURES: Percentage of participants with (rabbit complement) serum bactericidal antibody titres of at least 1:8; geometric mean titres of serogroup C meningococcal serum bactericidal antibody. RESULTS: Five years after immunisation, 84.1% (95% confidence interval 81.6% to 86.3%) of 987 participants had a bactericidal antibody titre of at least 1:8. Geometric mean titres of bactericidal antibody were significantly lower in 11-13 year olds (147, 95% confidence interval 115 to 188) than in 14-16 year olds (300, 237 to 380) and 17-20 year olds (360, 252 to 515) (P<0.0001 for both comparisons). Within these age bands, no significant difference in geometric mean titres of bactericidal antibody between recipients of the different serogroup C meningococcal vaccines was seen. More than 70% of participants had received a vaccine from one manufacturer; in this cohort, geometric mean titres were higher in those immunised at aged 10 years or above than in those immunised before the age of 10. CONCLUSIONS: Higher concentrations of bactericidal antibody are seen five years after immunisation with serogroup C meningococcal vaccine at age 10 years or above than in younger age groups, possibly owing to immunological maturation. This provides support for adolescent immunisation programmes to generate sustained protection against serogroup C meningococcal disease not only for the vaccine recipients but also, through the maintenance of herd immunity, for younger children.

Automated assessment of keratocyte density in clinical confocal microscopy of the corneal stroma.

Cell density in the corneal stroma is typically determined by counting the number of bright objects, presumably keratocyte nuclei, in images from clinical confocal microscopy. We present a program that identifies bright objects and counts those that most likely represent cells. Selection variables were determined from 125 normal corneas with cell densities that had been assessed manually. The program was tested on 17 corneas of patients before and at several intervals to 5 years after laser in situ keratomileusis (LASIK) surgery. In these corneas, which showed a decrease in cell density after surgery, the program identified cells as well as human observers did.

Voltage-gated ion channels.

How and where simple volatile organic molecules act in the central nervous system to cause loss of consciousness and insensitivity to pain has eluded investigation; yet remarkable progress has been made recently towards identifying possible molecular targets through which the mechanism of anesthesia is tranduced. It is likely that anesthetics act by binding directly to protein targets; several possible candidates have been identified and the debate now focuses on whether general anesthesia is due to large effects at a relatively small number of critical molecular sites or due to the combined effects of small perturbations at a very large number of sites; voltage-gated ion channels are contenders for either possibility and are the subject of this review.

The TRPV1/2/3 activator 2-aminoethoxydiphenyl borate sensitizes native nociceptive neurons to heat in wildtype but not TRPV1 deficient mice.

TRPV1 gene disruption results in a loss of capsaicin and proton responsiveness, but has minimal effects on heat-induced nocifensive behavior, suggesting that sensory transduction of heat is independent of TRPV1. TRPV3, another heat-activated ion channel but insensitive to capsaicin, was shown to be expressed in keratinocytes as well as in sensory neurons projecting to the skin. Recently, 2-aminoethoxydiphenyl borate was introduced as a TRPV3 agonist, but its selectivity was questioned by showing that it activated recombinant TRPV1 and TRPV2 as well. We used the isolated mouse skin-saphenous nerve preparation and whole-cell patch-clamping of cultured dorsal root ganglia neurons from TRPV1-/- and wildtype mice. We found no phenotypic differences between the heat responses of polymodal C-fibers, whereas cultured dorsal root ganglia neurons of TRPV1-/- hardly showed any heat-activated currents. Only C-fibers of wildtype but not TRPV1-/- mice were clearly sensitized to heat by 2-aminoethoxydiphenyl borate 10 and 100 microM; heat-activated current in wildtype neurons was only facilitated at 100 microM. Noxious heat-induced calcitonin gene-related peptide release showed clear deficits (<50%) in TRPV1 deficient skin, but the stimulated calcitonin gene-related peptide release from the isolated skull dura was unaffected. In both models, 2-aminoethoxydiphenyl borate was able to potentiate the heat response (46 degrees C, 5 min) in a concentration-dependent manner, again, only in wildtype but not TRPV1-/- mice, suggesting that TRPV2/3 are not involved in this sensitization to heat. The results further suggest that TRPV1 is not responsible for the normal heat response of native nociceptors but plays the essential role in thermal sensitization and a prominent one in controlling dermal calcitonin gene-related peptide release, i.e. neurogenic inflammation.

Interactions of local anesthetics with voltage-gated Na+ channels.

Voltage-gated Na+ channels are dynamic transmembrane proteins responsible for the rising phase of the action potential in excitable membranes. Local anesthetics (LAs) and structurally related antiarrhythmic and anticonvulsant compounds target specific sites in voltage-gated Na+ channels to block Na+ currents, thus reducing excitability in neuronal, cardiac, or central nervous tissue. A high-affinity LA block is produced by binding to open and inactivated states of Na+ channels rather than to resting states and suggests a binding site that converts from a low- to a high-affinity conformation during gating. Recent findings using site-directed mutagenesis suggest that multiple S6 segments together form an LA binding site within the Na+ channel. While the selectivity filter may form the more extracellular-located part of this binding site, the role of the fast inactivation gate in LA binding has not yet been resolved. The receptor of the neurotoxin batrachotoxin (BTX) is adjacent to or even overlaps with the LA binding site. The close proximity of the LA and BTX binding sites to residues critical for inactivation, together with gating transitions through S6 segments, might explain the strong impact of LAs and BTX on inactivation of voltage-gated Na+ channels and might help elucidate the mechanisms underlying voltage- and frequency-dependent LA block.

Effects of AGN 192024, a new ocular hypotensive agent, on aqueous dynamics.

PURPOSE: To determine the mechanism of intraocular pressure lowering for the Ocular Hypotensive Lipid, AGN 192024 (Allergan, Inc, Irvine, California). METHODS: Twenty-five normal human volunteers between the ages of 21 and 48 took part in a randomized, double-masked, placebo-controlled, paired-comparison study in which intraocular pressure, aqueous humor flow, and tonographic resistance to outflow were studied. Measurements of aqueous flow were made during the day and at night while subjects slept. Intraocular pressure was measured with the Goldmann tonometer, and resistance to outflow was measured by electronic recording Schiötz tonography. RESULTS: Intraocular pressure was decreased by 20% on day 3 in AGN 192024-treated eyes in comparison with placebo-treated eyes in normal subjects (P <.001). Aqueous humor flow was stimulated 13% during the day (P =.007) and 14% at night (P =.014) by the drug. Tonographic resistance to outflow was decreased 26% by AGN 192024 (P <.001), and apparent resistance to outflow (the ratio of intraocular pressure to aqueous flow) was decreased 31% (P <.001). Assuming that AGN 192024 does not cause prolonged lowering of episcleral venous pressure, the results show that pressure-insensitive outflow is enhanced by 50%, whereas tonographic facility of outflow (reciprocal of resistance) was enhanced 35%. CONCLUSIONS: AGN 192024 is an ocular hypotensive agent that works by enhancing both pressure-sensitive and pressure-insensitive aqueous humor outflow without diminishing aqueous humor formation.

Block of human heart hH1 sodium channels by the enantiomers of bupivacaine.

BACKGROUND: S(-)-bupivacaine reportedly exhibits lower cardiotoxicity but similar local anesthetic potency compared with R(+)-bupivacaine. The bupivacaine binding site in human heart (hH1) Na+ channels has not been studied to date. The authors investigated the interaction of bupivacaine enantiomers with hH1 Na+ channels, assessed the contribution of putatively relevant residues to binding, and compared the intrinsic affinities to another isoform, the rat skeletal muscle (mu1) Na+ channel. METHODS: Human heart and mu1 Na+ channel alpha subunits were transiently expressed in HEK293t cells and investigated during whole cell voltage-clamp conditions. Using site-directed mutagenesis, the authors created point mutations at positions hH1-F1760, hH1-N1765, hH1-Y1767, and hH1-N406 by introducing the positively charged lysine (K) or the negatively charged aspartic acid (D) and studied their influence on state-dependent block by bupivacaine enantiomers. RESULTS: Inactivated hH1 Na+ channels displayed a weak stereoselectivity with a stereopotency ratio (+/-) of 1.5. In mutations hH1-F1760K and hH1-N1765K, bupivacaine affinity of inactivated channels was reduced by approximately 20- to 40-fold, in mutation hH1-N406K by approximately sevenfold, and in mutations hH1-Y1767K and hH1-Y1767D by approximately twofold to threefold. Changes in recovery of inactivated mutant channels from block paralleled those of inactivated channel affinity. Inactivated hH1 Na+ channels exhibited a slightly higher intrinsic affinity than mu1 Na+ channels. CONCLUSIONS: Differences in bupivacaine stereoselectivity and intrinsic affinity between hH1 and mu1 Na+ channels are small and most likely of minor clinical relevance. Amino acid residues in positions hH1-F1760, hH1-N1765, and hH1-N406 may contribute to binding of bupivacaine enantiomers in hH1 Na+ channels, whereas the role of hH1-Y1767 remains unclear.