Improve hip fracture outcome in the elderly patient (iHOPE): a study protocol for a pragmatic, multicentre randomised controlled trial to test the efficacy of spinal versus general anaesthesia.

INTRODUCTION: Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse. METHODS AND ANALYSIS: The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60. ETHICS AND DISSEMINATION: iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals. TRIAL REGISTRATION NUMBER: DRKS00013644; Pre-results.

Combatting pain after orthopedic/trauma surgery- perioperative oral extended-release tapentadol vs. extended-release oxycodone/naloxone.

BACKGROUND: High post-operative pain scores after "minor" orthopedic/trauma surgery are in part attributed to inadequate prescription of opioid analgesics. Novel concepts aiming to achieve sufficient analgesia while minimizing opioid-related side effects by avoiding fluctuating plasma levels are based on perioperative oral administration of extended-release opioids beginning with the first dose pre-operatively. This is the first study to evaluate analgesic efficacy and side effect rates of extended-release tapentadol compared to oxycodone/naloxone following orthopedic/trauma surgery. METHODS: This randomized, observer-blinded, active-controlled prospective clinical trial had 2 co-primary endpoints: (1) Analgesic efficacy: Mean pain level on a numeric rating scale (NRS) from 0 to 10 during exercise over 5 days. (2) Safety: Side effect sum score of the following events: Nausea, vomiting, constipation, sedation, vertigo, somnolence. The study was powered to detect superiority of tapentadol for at least one endpoint pending statistical proof of non-inferiority for both endpoints in a first step. RESULTS: Two hundred sixty-six trauma patients were randomized to receive either tapentadol (n = 133) or oxycodone/naloxone (n = 133). Analgesic efficacy: Mean (±SD) daily pain levels in the first five post-operative days were 2.8 ± 1.3 in both groups. Mean maximum pain intensity during exercise in the first 24 h after surgery was 3.8 ± 1.9 (tapentadol) and 3.8 ± 2.1 (oxycodone/naloxone). Statistically tapentadol was non-inferior but not superior to oxycodone/naloxone. SAFETY: Vomiting on day 1 occurred in 11%, constipation in 35% of the tapentadol patients and in 16% and 30% of the oxycodone/naloxone patients (p = 0.60 and 0.33), respectively. The incidence of sedation/ vertigo was <10%, that of somnolence <2% in both groups (p > 0.3, respectively). The sum score of side effect events was 51% in the tapentadol vs. 49% in the oxycodone/naloxone group; risk difference 3% [95% CI, -8 to 14%]; p = 0.6). Non-inferiority of tapentadol could not be concluded as the pre-defined non-inferiority margin was exceeded. CONCLUSIONS: With both concepts, mean maximum pain intensity during exercise within the first 24 h after orthopedic/trauma surgery was reduced to a score of <4. This analgesic efficacy came at the cost of mainly gastro-intestinal side effects. Thus, we now use a prophylaxis against nausea and vomiting and pre-emptive laxatives as part of these concepts. TRIAL REGISTRATION: https://eudract.ema.europa.eu (EudraCT- Nr. 2011-003238-15 ); October 24th, 2012.

Outcome of acute respiratory distress syndrome in university and non-university hospitals in Germany.

BACKGROUND: This study investigates differences in treatment and outcome of ventilated patients with acute respiratory distress syndrome (ARDS) between university and non-university hospitals in Germany. METHODS: This subanalysis of a prospective, observational cohort study was performed to identify independent risk factors for mortality by examining: baseline factors, ventilator settings (e.g., driving pressure), complications, and care settings-for example, case volume of ventilated patients, size/type of intensive care unit (ICU), and type of hospital (university/non-university hospital). To control for potentially confounding factors at ARDS onset and to verify differences in mortality, ARDS patients in university vs non-university hospitals were compared using additional multivariable analysis. RESULTS: Of the 7540 patients admitted to 95 ICUs from 18 university and 62 non-university hospitals in May 2004, 1028 received mechanical ventilation and 198 developed ARDS. Although the characteristics of ARDS patients were very similar, hospital mortality was considerably lower in university compared with non-university hospitals (39.3% vs 57.5%; p = 0.012). Treatment in non-university hospitals was independently associated with increased mortality (OR (95% CI): 2.89 (1.31-6.38); p = 0.008). This was confirmed by additional independent comparisons between the two patient groups when controlling for confounding factors at ARDS onset. Higher driving pressures (OR 1.10; 1 cmH2O increments) were also independently associated with higher mortality. Compared with non-university hospitals, higher positive end-expiratory pressure (PEEP) (mean ± SD: 11.7 ± 4.7 vs 9.7 ± 3.7 cmH2O; p = 0.005) and lower driving pressures (15.1 ± 4.4 vs 17.0 ± 5.0 cmH2O; p = 0.02) were applied during therapeutic ventilation in university hospitals, and ventilation lasted twice as long (median (IQR): 16 (9-29) vs 8 (3-16) days; p < 0.001). CONCLUSIONS: Mortality risk of ARDS patients was considerably higher in non-university compared with university hospitals. Differences in ventilatory care between hospitals might explain this finding and may at least partially imply regionalization of care and the export of ventilatory strategies to non-university hospitals.

Combined Negative- and Positive-Pressure Ventilation for the Treatment of ARDS.

Objective. Tracheal intubation and positive-pressure ventilation as the current standard of care for the adult respiratory distress syndrome (ARDS) seem to have reached their limit in terms of a further relevant reduction of the still very high mortality. Case Presentation. A 75-year-old male patient developed ARDS after abscess drainage with deteriorating oxygenation, despite positive end-expiratory pressure (PEEP) values above 15 cm H2O. We applied external negative-pressure ventilation with a chamber respirator using -33 cm H2O at inspiration and -15 cm H2O at expiration, combined with conventional pressure support using a PEEP of about 8 cm H2O and a pressure support of 4-12 cm H2O. Alveolar infiltrates disappeared rapidly and PaO2/FiO2 values surpassed 300 mmHg after the first application and 500 mmHg after the second. Negative-pressure ventilation was used for 6-18 hours/day over five days. Now, 13 years later, the patient is still alive and has a good quality of life. Conclusion. Using this or similar concepts, not only in intubated patients but also as a noninvasive approach in patients with ARDS, offers new options that may genuinely differ from the present therapeutic approaches and may, therefore, have the potential to decrease the present high mortality from ARDS.

A combination of topical antiseptics for the treatment of sore throat blocks voltage-gated neuronal sodium channels.

Amylmetacresol and dichloro-benzylalcohol are ingredients of lozenges used for the treatment of sore throat. In a former in vitro study, a local anaesthetic-like effect of these substances has been described. Since amylmetacresol and dichloro-benzylalcohol are co-administered in over-the-counter lozenges, the intention of this study is to evaluate the in vitro effects of the combination of these compounds on the voltage-gated sodium channel. We analysed the block of inward sodium currents induced by the combination of amylmetacresol, dichloro-benzylalcohol and the local anaesthetic lidocaine. Tonic and use-dependent block and effects on the inactivated channel state of the neuronal sodium channel were examined. Therefore, the α-subunit of the voltage-gated NaV1.2 sodium channel was heterologously expressed in HEK 293 cells in vitro. Inward sodium currents were investigated in the whole-cell configuration of the patch-clamp technique. The combination of amylmetacresol and dichloro-benzylalcohol and the combination of amylmetacresol and lidocaine induced a block of resting and inactivated sodium channels both displaying a pronounced block at the inactivated channel state. In addition, the combination of all three compounds also resulted in a voltage-dependent block of inward sodium currents. While use-dependent block by co-application of amylmetacresol and dichloro-benzylalcohol was moderate (<20 %), lidocaine and amylmetacresol induced a robust use-dependent block (up to 50 %). This study demonstrates local anaesthetic-like effects of a combination of amylmetacresol and dichloro-benzylalcohol as established ingredients of lozenges. In the presence of amylmetacresol, dichloro-benzylalcohol and lidocaine, a prominent block of inward sodium currents is apparent.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

BACKGROUND: Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. METHODS: The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. RESULTS: Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. CONCLUSIONS: This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

Inhibition of voltage-gated Na⁺ channels by the synthetic cannabinoid ajulemic acid.

BACKGROUND: The synthetic cannabinoid ajulemic acid has been demonstrated to alleviate pain in patients suffering from chronic neuropathic pain. Cannabinoids interact with several molecules within the pain circuit, including a potent inhibition of voltage-gated sodium channels. In this study, we closely characterized this property on neuronal and nonneuronal sodium channels. METHODS: The inhibition of sodium inward currents by ajulemic acid was studied in vitro. Human embryonic kidney 293t cells were used as the expression system for Nav1.2, 1.3, 1.4, 1.5, 1.5N406K, 1.5F1760A, and 1.7; Nav1.8 was transiently expressed in ND7/23 cells. Nav1.2, Nav1.3, and Nav 1.8 were from rats, and Nav1.4, Nav1.5, and Nav1.7 were of human origin. Sodium currents were analyzed by means of the whole cell patch-clamp technique. The investigated concentrations of ajulemic acid were 0.1, 0.3, 1, 3, 10, and 30 µmol/L. RESULTS: Ajulemic acid reversibly and concentration-dependently inhibited all voltage-gated sodium channel (Nav) isoforms investigated in this study, including Nav1.2, 1.3, 1.4, 1.5, 1.7, and 1.8. Tonic block of resting channels yielded half-maximal inhibitory concentration values between 2 and 9 µmol/L and was strongly enhanced on inactivated channels, suggesting state-dependent inhibition by ajulemic acid. Tonic block did not differ significantly when comparing Nav1.2 and Nav1.3, Nav1.4 and Nav1.5, and Nav1.7 and Nav1.8. Statistical analysis of other combinations of subunits (e.g., Nav1.2 and Nav1.4) by analysis of variance yielded a significant difference in block. Although we did not observe any relevant use-dependent block, ajulemic acid induced a strong hyperpolarizing shift of the voltage dependency of fast inactivation and modest shift of slow inactivation. The local anesthetic-insensitive Nav1.5 constructs N406K and F1760A displayed a preserved sensitivity to block by ajulemic acid. Finally, we found that low concentrations of ajulemic acid efficiently inhibited Navß4 peptide-mediated resurgent currents in Nav1.5. CONCLUSIONS: Our data suggest that block of sodium channels can be a relevant mechanism by which ajulemic acid alleviates neuropathic pain. The potent inhibition of resurgent currents and the preserved block on local anesthetic-insensitive channels indicates that ajulemic acid interacts with a conserved but yet unknown site of sodium channels.

The distinct effects of lipid emulsions used for "lipid resuscitation" on gating and bupivacaine-induced inhibition of the cardiac sodium channel Nav1.5.

BACKGROUND: Systemic administration of lipid emulsions is an established treatment for local anesthetic intoxication. However, it is unclear by which mechanisms lipids achieve this function. The high cardiac toxicity of the lipophilic local anesthetic bupivacaine probably results from a long-lasting inhibition of the cardiac Na channel Nav1.5. In this study, we sought to determine whether lipid emulsions functionally interact with Nav1.5 or counteract inhibition by bupivacaine. METHODS: Human embryonic kidney cells expressing human Nav1.5 were investigated by whole-cell patch clamp. The effects of Intralipid® and Lipofundin® were explored on functional properties and on bupivacaine-induced inhibition. RESULTS: Intralipid and Lipofundin did not affect the voltage dependency of activation, but induced a small hyperpolarizing shift of the steady-state fast inactivation and impaired the recovery from fast inactivation. Lipofundin, but not Intralipid, induced a concentration-dependent but voltage-independent tonic block (42% ± 4% by 3% Lipofundin). The half-maximal inhibitory concentration (IC50) values for tonic block by bupivacaine (50 ± 4 µM) were significantly increased when lipids were coapplied (5% Intralipid: 196 ± 22 µM and 5% Lipofundin: 103 ± 8 µM). Use-dependent block by bupivacaine at 10 Hz was also reduced by both lipid emulsions. Moreover, the recovery of inactivated channels from bupivacaine-induced block was faster in the presence of lipids. CONCLUSIONS: Our data indicate that lipid emulsions reduce rather than increase availability of Nav1.5. However, both Intralipid and Lipofundin partly relieve Nav1.5 from block by bupivacaine. These effects are likely to involve not only a direct interaction of lipids with Nav1.5 but also the ability of lipid emulsions to absorb bupivacaine and thus reduce its effective concentration.

4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors.

BACKGROUND: The mammalian neurological disorder hereditary hyperekplexia can be attributed to various mutations of strychnine sensitive glycine receptors. The clinical symptoms of "startle disease" predominantly occur in the newborn leading to convulsive hypertonia and an exaggerated startle response to unexpected mild stimuli. Amongst others, point mutations R271Q and R271L in the α1-subunit of strychnine sensitive glycine receptors show reduced glycine sensitivity and cause the clinical symptoms of hyperekplexia.Halogenation has been shown to be a crucial structural determinant for the potency of a phenolic compound to positively modulate glycine receptor function.The aim of this in vitro study was to characterize the effects of 4-chloropropofol (4-chloro-2,6-dimethylphenol) at four glycine receptor mutations. METHODS: Glycine receptor subunits were expressed in HEK 293 cells and experiments were performed using the whole-cell patch-clamp technique. RESULTS: 4-chloropropofol exerted a positive allosteric modulatory effect in a low sub-nanomolar concentration range at the wild type receptor (EC50 value of 0.08 ± 0.02 nM) and in a micromolar concentration range at the mutations (1.3 ± 0.6 µM, 0.1 ± 0.2 µM, 6.0 ± 2.3 µM and 55 ± 28 µM for R271Q, L, K and S267I, respectively). CONCLUSIONS: 4-chloropropofol might be an effective compound for the activation of mutated glycine receptors in experimental models of startle disease.

Differentiated human midbrain-derived neural progenitor cells express excitatory strychnine-sensitive glycine receptors containing α2ß subunits.

BACKGROUND: Human fetal midbrain-derived neural progenitor cells (NPCs) may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A) receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2ß subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1)-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. CONCLUSIONS/SIGNIFICANCE: These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.

Interaction of alfaxalone with the neuronal and the skeletal muscle sodium channel.

The neurosteroid alfaxalone exerts potent anesthetic activity in humans and animals. In former studies on myelinated axons, alfaxalone was assumed to produce a local anesthetic-like effect on the peripheral nervous system. Therefore,the present in vitro study aimed to characterize possible modulatory actions of alfaxalone on voltage-gated sodium channels. -Subunits of voltage-gated neuronal (Nav1.2)and skeletal muscle (Nav1.4) sodium channels were stably expressed in human embryonic kidney cells, and in vitro effects of alfaxalone were compared with lidocaine by means of the patch clamp technique. Alfaxalone preferentially blocked slow inactivated channels and therefore could provide membrane-stabilizing effects in ischemic/hypoxic tissues where slow inactivation is regarded to play a crucial role.

Negative- versus positive-pressure ventilation in intubated patients with acute respiratory distress syndrome.

INTRODUCTION: Recent experimental data suggest that continuous external negative-pressure ventilation (CENPV) results in better oxygenation and less lung injury than continuous positive-pressure ventilation (CPPV). The effects of CENPV on patients with acute respiratory distress syndrome (ARDS) remain unknown. METHODS: We compared 2 h CENPV in a tankrespirator ("iron lung") with 2 h CPPV. The six intubated patients developed ARDS after pulmonary thrombectomy (n = 1), aspiration (n = 3), sepsis (n = 1) or both (n = 1). We used a tidal volume of 6 ml/kg predicted body weight and matched lung volumes at end expiration. Haemodynamics were assessed using the pulse contour cardiac output (PiCCO) system, and pressure measurements were referenced to atmospheric pressure. RESULTS: CENPV resulted in better oxygenation compared to CPPV (median ratio of arterial oxygen pressure to fraction of inspired oxygen of 345 mmHg (minimum-maximum 183 to 438 mmHg) vs 256 mmHg (minimum-maximum 123 to 419 mmHg) (P < 0.05). Tank pressures were -32.5 cmH2O (minimum-maximum -30 to -43) at end inspiration and -15 cmH2O (minimum-maximum -15 to -19 cmH2O) at end expiration. NO Inspiratory transpulmonary pressures decreased (P = 0.04) and airway pressures were considerably lower at inspiration (-1.5 cmH2O (minimum-maximum -3 to 0 cmH2O) vs 34.5 cmH2O (minimum-maximum 30 to 47 cmH2O), P = 0.03) and expiration (4.5 cmH2O (minimum-maximum 2 to 5) vs 16 cmH2O (minimum-maximum 16 to 23), P =0.03). During CENPV, intraabdominal pressures decreased from 20.5 mmHg (12 to 30 mmHg) to 1 mmHg (minimum-maximum -7 to 5 mmHg) (P = 0.03). Arterial pressures decreased by approximately 10 mmHg and central venous pressures by 18 mmHg. Intrathoracic blood volume indices and cardiac indices increased at the initiation of CENPV by 15% and 20% (P < 0.05), respectively. Heart rate and extravascular lung water indices remained unchanged. CONCLUSIONS: CENPV with a tank respirator improved gas exchange in patients with ARDS at lower transpulmonary, airway and intraabdominal pressures and, at least initially improving haemodynamics. Our observations encourage the consideration of further studies on the physiological effects and the clinical effectiveness of CENPV in patients with ARDS.

Thyroid gland rupture: a rare case of respiratory distress.

BACKGROUND: Rupture of a normal thyroid gland after blunt cervical trauma is a rare case of airway compression. This case report describes the case of a 79-year-old woman who developed severe respiratory distress after a bicycle crash. CASE REPORT: Presenting about 2 h after the crash, the patient noted cervical swelling and increasing dyspnea. The diagnosis of thyroid gland rupture was made with a combination of computed tomography scan, cervical radiography, and bronchoscopy. Invasive airway management was required in the first few hours after the crash. The patient underwent a left hemithyroidectomy, and recovered without complications. CONCLUSION: This case report highlights the fact that thyroid gland rupture can be a threatening complication of blunt cervical trauma.

Defective polysialylation and sialylation induce opposite effects on gating of the skeletal Na+ channel NaV1.4 in Chinese hamster ovary cells.

Polysialic acid (polySia) is a large, negatively charged homopolymer of 2,8-linked N-acetylneuraminic acid residues resulting from remodeling and extension of protein-bound sialic acid (Sia) residues and seems to have a key role in regulating neural cell development and function. The aim of this study was to explore and compare the effects of polySia and sialylation on gating of voltage-gated sodium channels. The skeletal muscle α-subunit NaV1.4 was transiently expressed in wild-type Chinese hamster ovary (CHO) cells or in mutant CHO cells with deficits in their capacity to produce sialylated or polysialylated membrane components. Expression in both mutant cell lines resulted in larger peak current amplitudes as compared to wild-type CHO cells. Loss of Sia and polySia also resulted in significant shifts of voltage-dependent activation and steady-state inactivation, however, in opposite directions. Furthermore, only the loss of Sia had a significant effect on recovery from fast inactivation. Our data demonstrate for the first time that gating of voltage-gated sodium channels seems to be differentially regulated by polySia and Sia.

Paracetamol fails to positively modulate and directly activate chloride currents in human α1-glycine receptors.

Paracetamol (acetaminophen) is a widely used antipyretic and analgesic drug for mild or moderate pain states. As the primary site of action of paracetamol is still the subject of ongoing discussion, the focus of this study is the investigation of a potential mechanism which might contribute to its beneficial effects in the therapy of pain. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. In this study we investigated the interaction of paracetamol with strychnine-sensitive α(1)-glycine receptors (α(1)-GlyR). α(1)-GlyR subunits transiently expressed in HEK-293 cells were studied using the whole-cell patch-clamp technique and a piezo-controlled liquid filament fast application system. Paracetamol fails to show a positive allosteric modulatory effect in low nano- to micromolar concentrations and lacks direct activation in micromolar concentrations at the α(1)-GlyR. Consequently, the analgesic actions of paracetamol leading to pain relief appear to be mediated via other mechanisms, but not via activation of spinal glycinergic pathways.

Role of cannabinoids in the treatment of pain and (painful) spasticity.

Both the discovery of the endocannabinoid system (ECS) and its role in the control of pain and habituation to stress, as well as the significant analgesic and antihyperalgesic effects in animal studies, suggest the usefulness of cannabinoids in pain conditions. However, in human experimental or clinical trials, no convincing reduction of acute pain, which may be caused by a pronociceptive, ECS-triggered mechanism on the level of the spinal cord, has been demonstrated. In contrast, in chronic pain and (painful) spasticity, an increasing number of randomized, double-blind, placebo-controlled studies have shown the efficacy of cannabinoids, which is combined with a narrow therapeutic index. Patients with unsatisfactory response to other methods of pain therapy and who were characterized by failed stress adaptation particularly benefited from treatment with cannabinoids. None of the attempts to overcome the disadvantage of the narrow therapeutic index, either by changing the route of application or by formulating balanced cannabinoid preparations, have resulted in a major breakthrough. Therefore, different methods of administration and other types of cannabinoids, such as endocannabinoid modulators, should be tested in future trials.

Lack of positive allosteric modulation of mutated alpha(1)S267I glycine receptors by cannabinoids.

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Ajulemic acid and HU210 are non-psychotropic, synthetic cannabinoids. Cannabidiol is a non-psychotropic plant constituent of cannabis sativa. There are hints that non-cannabinoid receptor mechanisms of these cannabinoids might be mediated via glycine receptors. In this study, we investigated the impact of the amino acid residue serine at position 267 on the glycine-modulatory effects of ajulemic acid, cannabidiol and HU210. Mutated alpha(1)S267I glycine receptors transiently expressed in HEK293 cells were studied by utilising the whole-cell clamp technique. The mutation of the alpha(1) subunit TM2 serine residue to isoleucine abolished the co-activation and the direct activation of the glycine receptor by the investigated cannabinoids. The nature of the TM2 (267) residue of the glycine alpha(1) subunit is crucial for the glycine-modulatory effect of ajulemic acid, cannabidiol and HU210. An investigation of the impact of such mutations on the in vivo interaction of cannabinoids with glycine receptors should permit a better understanding of the molecular determinants of action of cannabinoids.

Reduced post-operative neutrophil activation in liver transplant recipients suffering from post-hepatitic cirrhosis.

BACKGROUND: It has been supposed that liver transplant recipients with hepatitis C virus infection have a higher incidence of infectious complications after transplantation. This study was designed to investigate whether neutrophil function is immediately affected by liver transplantation. METHODS: Biochemical values, plasma levels of myeloperoxidase (MPO), hydrogen peroxide production of neutrophils and neutrophil-platelet complexes were analyzed in 32 patients who underwent liver transplantation and 20 healthy volunteers. RESULTS: MPO levels were significantly increased 24 h after reperfusion. In post-hepatitic patients levels were significantly lower three d up to one wk post-transplant than in patients due to other liver diseases. One wk post-operatively the respiratory burst activity following N-formyl-methionyl-leucylphenylalanine (fMLP) or (tumor necrosis factor-alpha) TNF-alpha/fMLP stimulation was depressed in post-hepatitic recipients. Respiratory burst stimulated with phorbol 12-myristate 13-acetate in these patients was increased one wk after transplantation. One d after transplantation the neutrophil-platelet complexes decreased significantly throughout the post-operative period. CONCLUSIONS: The results of this study suggest a reduced post-operative neutrophil activation in liver transplant recipients suffering from post-hepatitic cirrhosis compared to cirrhosis due to other causes. We hypothesized that neutrophil dysfunction in those patients depends on the underlying disease with an increased susceptibility to bacterial or fungal infections.