Biomedical subjects

Markus W Hollmann

Publications and source records attributed to Markus W Hollmann.

15 recordsLinked to original sources

PubMed2006

Perioperative strategy in colonic surgery; LAparoscopy and/or FAst track multimodal management versus standard care (LAFA trial).

BACKGROUND: Recent developments in large bowel surgery are the introduction of laparoscopic surgery and the implementation of multimodal fast track recovery programs. Both focus on a faster recovery and shorter hospital stay. The randomized controlled multicenter LAFA-trial (LAparoscopy and/or FAst track multimodal management versus standard care) was conceived to determine whether laparoscopic surgery, fast track perioperative care or a combination of both is to be preferred over open surgery with standard care in patients having segmental colectomy for malignant disease. METHODS/DESIGN: The LAFA-trial is a double blinded, multicenter trial with a 2 x 2 balanced factorial design. Patients eligible for segmental colectomy for malignant colorectal disease i.e. right and left colectomy and anterior resection will be randomized to either open or laparoscopic colectomy, and to either standard care or the fast track program. This factorial design produces four treatment groups; open colectomy with standard care (a), open colectomy with fast track program (b), laparoscopic colectomy with standard care (c), and laparoscopic surgery with fast track program (d). Primary outcome parameter is postoperative hospital length of stay including readmission within 30 days. Secondary outcome parameters are quality of life two and four weeks after surgery, overall hospital costs, morbidity, patient satisfaction and readmission rate. Based on a mean postoperative hospital stay of 9 +/- 2.5 days a group size of 400 patients (100 each arm) can reliably detect a minimum difference of 1 day between the four arms (alfa = 0.95, beta = 0.8). With 100 patients in each arm a difference of 10% in subscales of the Short Form 36 (SF-36) questionnaire and social functioning can be detected. DISCUSSION: The LAFA-trial is a randomized controlled multicenter trial that will provide evidence on the merits of fast track perioperative care and laparoscopic colorectal surgery in patients having segmental colectomy for malignant disease.

Clinical Protocols↗

PubMed2006

Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine.

BACKGROUND: Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central nervous system after neuraxial administration of S(+)-ketamine are conflicting. In this study, neurologic and toxicologic effects on the spinal cord from repeated daily intrathecal administration of commercially available, preservative-free S(+)-ketamine were evaluated against placebo in a randomized, blinded design. METHODS: Eighteen white New Zealand rabbits were assigned to two groups receiving either 0.5 ml intrathecal S(+)-ketamine, 0.5% solution (12 rabbits), or 0.5 ml saline (6 rabbits) once a day for 7 consecutive days. During general anesthesia, an intrathecal catheter was placed between the fifth and sixth spinous processes (lumbar). Neurologic (according to Tarlov criteria) and histopathologic assessments were performed after 7 days of treatment. RESULTS: Postmortem investigation of the spinal cord and nerve roots revealed histopathologic lesions suggestive of toxic damage in 11 rabbits, from the group of 12 animals receiving S(+)-ketamine. These results were significantly different compared with 5 control animals (no histologic changes observed). There was no significant difference in neurologic status between the two groups after 7 days of intrathecal treatment. CONCLUSIONS: The authors conclude that repeated intrathecal administration of preservative-free S(+)-ketamine in a clinically relevant concentration and dosage has, considering the extent and severity of the lesions, a toxic effect on the central nervous system of rabbits.

Anesthesia, Spinal↗

PubMed2006

Orthogonal polarization spectral imaging of the microcirculation during acute hypervolemic hemodilution and epidural lidocaine injection.

We used Orthogonal Polarization Spectral Imaging to examine the microcirculation of the vaginal mucosa in nine anesthetized patients during two consecutive anesthetic interventions: hypervolemic hemodilution using hydroxyethyl starch followed by thoracic epidural lidocaine. Images taken before and after each intervention were compared. During hypervolemic hemodilution, systolic blood pressures increased significantly, but functional capillary density remained unchanged. Epidural anesthesia decreased systolic and diastolic blood pressures, but there was no change in capillary density, venular diameter, or flow velocity. We concluded that when using Orthogonal Polarization Spectral imaging, no consistent effects on the microcirculation of the vaginal wall can be detected.

Adult↗

PubMed2005

Receptors, G proteins, and their interactions.

Membrane receptors coupling to intracellular G proteins (G protein-coupled receptors) form one of the major classes of membrane signaling proteins. They are of great importance to the practice of anesthesiology because they are involved in many systems of relevance to the specialty (cardiovascular and respiratory control, pain transmission, and others) and many drugs target these systems. In recent years, understanding of these signaling systems has grown. The structure of receptors and G proteins has been elucidated in more detail, their regulation is better understood, and the complexity of interactions between the various parts of the system (receptors, G proteins, effectors, and regulatory molecules) has become clear. These findings may help explain both actions and side effects of drugs. In addition, these newly discovered targets are likely to play important roles in disease states of relevance to anesthesiologists.

Anesthetics↗

PubMed2004

Regional anaesthesia, local anaesthetics and the surgical stress response.

Epidural anaesthesia has the potential to improve patients' outcome after major surgical procedures by reducing postoperative morbidity and duration of recovery. Possible benefits include the attenuation of cardiac complications, an earlier return of gastrointestinal function associated with an increase in patients' comfort overall, decreased incidence of pulmonary dysfunction, beneficial effects on the coagulation system and a reduction in the inflammatory response. The underlying mechanisms, however, remain unclear. Since local anaesthetics (LAs), reabsorbed from the epidural space, seem to contribute to these effects, it is not easy to differentiate between the systemic effects of LAs and the effects of neuraxial blockade by epidural anaesthesia. Thus, in patients not able or willing to receive intra- and/or postoperative epidural analgesia, systemic administration of LAs may be considered to be a new therapeutic approach for the prevention of postoperative disorders by modulation of the peri- and postoperative inflammatory.

Anesthesia, Conduction↗

PubMed2004

The poor man's epidural: systemic local anesthetics for improving postoperative outcomes.

The inflammatory response is an important determinant of outcome after major surgery. Perioperative excessive stimulation of the inflammatory and hemostatic systems plays a role in the development of postoperative ileus, ischemia-reperfusion syndromes (e.g. myocardial infarction), hypercoagulation syndromes (e.g. deep venous thrombosis) and pain; together, these represent a significant fraction of major postoperative disorders. Epidurally administered local anesthetics prevent or modulate many of these processes. Since local anesthetics show inflammatory modulating properties in vitro and in vivo, they might also prevent these postoperative inflammatory processes when administered intravenously. Clinical studies have shown that perioperative local anesthetic administration significantly reduces the incidence of thrombosis and postoperative pain, shortens postoperative ileus and decreases hospital stay. On this basis we hypothesize that continuous intravenous administration of local anesthetic perioperatively might prevent or reduce several postoperative disorders resulting from excessive stimulation of inflammatory and hemostatic systems, and thereby improve surgical outcome.

Anesthesia, Epidural↗

PubMed2004

Time-dependent inhibition of G protein-coupled receptor signaling by local anesthetics.

BACKGROUND: Several beneficial effects of local anesthetics (LAs) were shown to be due to inhibition of G protein-coupled receptor signaling. Differences in exposure time might explain discrepancies in concentrations of LAs required to achieve these protective effects in vivo and in vitro (approximately 100-fold higher). Using Xenopus oocytes and human neutrophils, the authors studied time-dependent effects of LAs on G protein-coupled receptor signaling and characterized possible mechanisms and sites of action. METHODS: Measurement of agonist-induced Ca2+-activated Cl currents, using a two-electrode voltage clamp technique, and determination of superoxide anion production by cytochrome c assay were used to assess the effects of LAs on G protein-coupled receptor signaling in oocytes and primed and activated human neutrophils, respectively. Antisense knockdown of G alpha q protein and inhibition of various proteins within the signaling pathway served for defining mechanisms and sites of action more specifically. RESULTS: LAs attenuated G protein-coupled receptor signaling in both models in a time-dependent and reversible manner (lidocaine reduced lysophosphatidic acid signaling to 19 +/- 3% after 48 h and 25 +/- 2% after 6 h of control response in oocytes and human neutrophils, respectively). Whereas no effect was observed after extracellularly applied or intracellularly injected QX314, a lidocaine analog, using G alpha q-depleted oocytes, time-dependent inhibition also occurred after intracellular injection of QX314 into undepleted oocytes. Inhibition of phosphatases or protein kinases and agonist-independent G-protein stimulation, using guanosine 5'-O-3-thiotriphosphate or aluminum fluoride, did not affect time-dependent inhibition by LAs. CONCLUSION: Inhibition of G protein-coupled receptor signaling by LAs was found to be time dependent and reversible. Critically requiring G alpha q-protein function, this effect is located downstream of guanosine diphosphate-guanosine triphosphate exchange and is not dependent on increased guanosine triphosphatase activity, phosphatases, or protein kinases.

Aluminum Compounds↗

PubMed2004

Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes.

BACKGROUND: Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-D-aspartate (NMDA) receptors are thought to play a major role in development of postoperative pain and opiate tolerance. The authors hypothesized that Ultiva directly stimulates human NMDA receptors. METHODS: To test this hypothesis, the authors expressed human NR1A/NR2A and NR1A/NR2B NMDA receptors in Xenopus laevis oocytes by injection of messenger RNA prepared in vitro. After protein expression, they used a two-electrode voltage clamp to measure currents induced by NMDA receptor agonists and opioids. RESULTS: Noninjected cells were unresponsive to all compounds tested. Glutamate/glycine (1 nM-1 mM each) or Ultiva (0.01 pM-0.1 mM) stimulated NMDA receptors concentration dependently. NR1A/2A EC50 values were 8.0 microM/12 microM for glutamate/glycine and 3.5 nM for Ultiva, and NR1A/2B EC50 values were 3.9 microM/1.9 microM for glutamate/glycine and 0.82 microM for Ultiva. Glycine in combination with Ultiva showed no additive effect compared with Ultiva alone. Ultiva-induced currents were inhibited by MK-801 (pore blocker) but not by 7-CK (glycine antagonist), D-AP5 (glutamate antagonist), or naloxone. Fentanyl (10 microM) did not stimulate NMDA receptors. CONCLUSION: These data indicate that Ultiva but not fentanyl stimulates NMDA receptors of different subunit combinations (NR1A/2A, NR1A/2B). The mechanism seems to be allosteric activation of the NMDA receptor.

Animals↗

PubMed2004

Local anesthetics inhibit thromboxane A2 signaling in Xenopus oocytes and human k562 cells.

Thromboxane A(2) (TXA(2)) has been proposed as a mediator of perioperative myocardial ischemia, vasoconstriction, and thrombosis. As these adverse events are minimized with epidural anesthesia, rather than general anesthesia, we hypothesized that local anesthetics would inhibit TXA(2)-receptor signaling. We used fluorometric determination of intracellular [Ca(2+)] in human K562 cells and 2-electrode voltage clamp measurements in Xenopus laevis oocytes expressing TXA(2) receptors. After 10-min incubation, lidocaine (IC(50): 1.02 +/- 0.2 x 10(-3) M), ropivacaine (IC(50): ropivacaine 6.3 +/- 0.9 x 10(-5) M), or bupivacaine (IC(50): 1.42 +/- 0.08 x 10(-7) M) inhibited TXA(2)-induced [Ca(2+)](i) in K562 cells. These data were confirmed in Xenopus oocytes recombinantly expressing TXA(2) receptors, with IC(50)s of bupivacaine 1.2 +/- 0.2 x 10(-5) M, R(+) ropivacaine 4.9 +/- 1.7 x 10(-4) M, S(-) ropivacaine 5.3 +/- 0.9 x 10(-5) M, and lidocaine 6.4 +/- 2.8 x 10(-4) M. Intracellular pathways activated by IP(3) and GTPgammaS were not significantly affected by the local anesthetics tested. QX314, a positively charged lidocaine analog, inhibited only if injected intracellularly (IC(50): 5.3 +/- 1.7 x 10(-4) M), indicating one local anesthetic target is most likely inside the cell. Benzocaine (largely uncharged) inhibited with an IC(50) of 8.7 +/- 1.8 x 10(-4) M. This suggests that some of the beneficial effects of regional anesthesia techniques might be due to direct interaction of local anesthetics with the functioning of membrane proteins.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2003

Effects of antidepressants on function and viability of human neutrophils.

BACKGROUND: Antidepressants are frequently used in chronic pain therapy and are under investigation as long-acting local anesthetics. Because of the structural similarities between antidepressants and local anesthetics, the authors hypothesized that these compounds act similarly, and they investigated the effects of nortriptyline, amitriptyline, imipramine, and fluoxetine on priming and activation of human polymorphonuclear neutrophils (hPMNs). METHODS: Effects of 30-, 120-, and 240-min preincubation with nortriptyline (10(-7)-10(-4) M), amitriptyline (10(-6)-10(-3) M), imipramine (10(-6)-10(-3) M), or fluoxetine (10(-7)-10(-4) M) on O(2)- generation of platelet activating factor-primed (10-6 M) and/or formyl-methionyl-leucyl-phenylalanine-activated (10(-6) M) isolated hPMNs were determined. All data are reported as mean +/- SD (statistics: t test, P < 0.05). RESULTS: Brief incubation in low concentrations of nortriptyline, amitriptyline, or fluoxetine (all at 10(-5) M) did inhibit priming but not activation of hPMNs. Imipramine (10(-5) M) affected neither priming nor activation. Prolonged incubation in lower concentrations of all antidepressants influenced neither priming nor activation. However, at higher concentrations, all four compounds exerted cytotoxic effects: virtually all hPMNs were killed by amitriptyline and imipramine (both at 10(-3) M) or nortriptyline and fluoxetine (both at 10(-4) M). CONCLUSION: Antidepressants, in low concentrations, inhibited priming but not activation of hPMNs. However, at concentrations similar to those attained after local injection, and in marked contrast to local anesthetics, antidepressants are profoundly toxic to hPMNs.

Antidepressive Agents↗

PubMed2003

Effects of antidepressants on G protein-coupled receptor signaling and viability in Xenopus laevis oocytes.

BACKGROUND: Tricyclic antidepressants are structurally related to local anesthetics, suggesting that part of their analgesic action may result from properties shared with local anesthetics. Because local anesthetics block G protein-coupled receptor signaling (which explains, in part, their inflammatory modulating properties), the authors studied whether antidepressants have similar effects. METHODS: Peak Ca-activated Cl currents induced in Xenopus laevis oocytes by lysophosphatidic acid (10(-4) m) were measured using a voltage clamp. The effects of a 30-, 120-, or 240-min incubation in amitriptyline, nortriptyline, imipramine, or fluoxetine were determined. RESULTS: After a 30-min incubation, low concentrations (10(-7)-10(-5) m) of antidepressants had no effect on lysophosphatidic acid-induced currents. After prolonged incubation, only amitriptyline or nortriptyline inhibited lysophosphatidic acid signaling (each to 58% of the control response at 10(-7) m after 240 min). At low concentrations, none of the compounds induced membrane damage (defined as a holding current of > 1 microA, 2% in control cells). Imipramine at 10(-3) m induced damage in 100% of oocytes, and fluoxetine at 10(-4) m induced damage in 71% of oocytes (P < 0.05 vs. control). Amitriptyline and nortriptyline had no effect. CONCLUSIONS: These findings are in part different from those obtained with local anesthetics and suggest that interference with G protein-coupled signaling might explain, in part, the analgesic properties of some antidepressants. However, use of antidepressants in high concentrations may be associated with cellular toxicity.

Animals↗

PubMed2003

Lidocaine enhances Galphai protein function.

BACKGROUND: Local anesthetics inhibit several G protein-coupled receptors by interaction with the Galphaq protein subunit. It is not known whether this effect on G protein function can be extrapolated to other classes of G proteins. The authors investigated interactions of lidocaine with the human adenosine 1 receptor (hA1R)-coupled signaling pathway. Activated A1Rs couple to adenylate cyclase via the pertussis toxin sensitive Galphai protein, thereby decreasing cyclic adenosine monophosphate formation. A1Rs are widely expressed and abundant in the spinal cord, brain, and heart. Interactions of LAs with the hA1R-coupled transduction cascade therefore might produce a broad range of clinically relevant effects. METHODS: The function of hA1Rs stably expressed in Chinese hamster ovary cells was determined with assays of cyclic adenosine monophosphate, receptor binding, and guanosine diphosphate/guanosine triphosphate gamma35S exchange by using reconstituted defined G protein subunits. Involvement of phosphodiesterase and Galphai was characterized by using the phosphodiesterase inhibitor rolipram and pertussis toxin, respectively. RESULTS: Lidocaine (10-9-10-1 M) had no significant effects on agonist or antagonist binding to the hA1R or on receptor-G protein interactions. However, cyclic adenosine monophosphate levels were reduced significantly to 50% by the LAs, even in the absence of an A1R agonist or presence of an A1R antagonist. This effect was unaffected by rolipram (10 mum), but abolished completely by pretreatment with pertussis toxin, which inactivates the Galphai protein. Therefore, the main target site for LAs in this pathway is located upstream from adenylate cyclase. CONCLUSIONS: Lidocaine potentiates Galphai-coupled A1R signaling by reducing cyclic adenosine monophosphate production. The study suggests an interaction site for LAs in a Galphai-coupled signaling pathway, with the Galphai protein representing the prime candidate. Taken together with previous results showing inhibitory LA interactions on the Galphaq protein subunit, the data in the current study support the hypothesis that specific G protein subunits represent alternative sites of LA action.

Anesthetics, Local↗

PubMed2003

The effects of S(-)-, R(+)-, and racemic bupivacaine on lysophosphatidate-induced priming of human neutrophils.

UNLABELLED: Local anesthetics modulate inflammatory responses and may therefore be potentially useful in mitigating perioperative inflammatory injury. The inflammatory modulating effects of S(-)-bupivacaine are not known. Therefore, we compared the effects of S(-)-bupivacaine, R(+)-bupivacaine, and racemic bupivacaine on neutrophil function and receptor signaling. Priming (by lysophosphatidic acid [LPA]) and activation (by N-formylmethionine-leucyl-phenylalanine) of superoxide release by isolated human neutrophils was studied by using a cytochrome c-reduction assay. LPA receptor signaling in Xenopus oocytes was studied by using voltage clamp. All three local anesthetics were without effect on activation. S(-)-Bupivacaine inhibited priming more than did racemic bupivacaine; R(+)-bupivacaine was without effect. At 10(-4) M, S(-)-bupivacaine inhibited approximately 50%. Comparable results were obtained in our recombinant model, where S(-)-bupivacaine most effectively inhibited LPA signaling. Compared with racemic bupivacaine and other anesthetics, S(-)-bupivacaine appears particularly effective in suppressing neutrophil priming, a process responsible in part for the overactive neutrophil response. IMPLICATIONS: Overactive inflammatory responses underlie several perioperative disorders. Compared with racemic bupivacaine and other anesthetics, S(-)-bupivacaine appears particularly effective in suppressing neutrophil priming, a process responsible in part for the overactive neutrophil response.

Algorithms↗

PubMed2002

Inhibition of mammalian Gq protein function by local anesthetics.

BACKGROUND: Local anesthetics have been shown to selectively inhibit functioning of Xenopus laevis Gq proteins. It is not known whether a similar interaction exists with mammalian G proteins. The goal of this study was to determine whether mammalian Gq protein is inhibited by local anesthetics. METHODS: In Xenopus oocytes, the authors replaced endogenous Gq protein with mouse Gq (expressed in Sf9 cells using baculovirus vectors). Cells endogenously expressing lysophosphatidic acid or recombinantly expressing muscarinic m3 receptors were injected with phosphorothioate DNA antisense (or sense as control) oligonucleotides against Xenopus Gq. Forty-eight hours later, oocytes were injected with purified mouse Gq (5 x 10(-8) M) or solvent as control. Two hours later, the authors injected either lidocaine, its permanently charged analog QX314 (at IC50, 50 nl), or solvent (KCl 150 mM) as control and measured Ca-activated Cl currents in response to lysophosphatidic acid or methylcholine (one tenth of EC50). RESULTS: Injection of anti-Gq reduced the mean response size elicited by lysophosphatidic acid to 33 +/- 7% of the corresponding control response. In contrast, responses were unchanged (131 +/- 29% of control) in cells in addition injected with mouse Gq protein. Injection of mouse Gq protein "rescued" the inhibitory effect of intracellularly injected QX314: whereas QX314 was without effect on Gq-depleted oocytes, responses to lysophosphatidic acid after QX314 injection were inhibited to 44 +/- 10% of control response in cells in addition injected with mouse Gq protein (5 x 10(-8) M). Similar results were obtained for m3 signaling and intracellularly injected lidocaine. CONCLUSION: Inhibition of Gq function by local anesthetics is not restricted to Xenopus G proteins. Therefore, Gq should be considered as one additional intracellular target site for local anesthetics, especially relevant for those effects not explainable by sodium channel blockade (e.g., antiinflammatory effects).

Anesthetics, Local↗

PubMed2002

Inflammatory responses after surgery.

The inflammatory response after major surgery is of great importance for patients, physicians and perioperative medicine in general. This article, although not intended to be comprehensive, provides an overview of present knowledge about inflammatory mechanisms, predictive parameters and therapeutic approaches.

Blood Coagulation↗