Activity and connectivity changes of central projection areas revealed by functional magnetic resonance imaging in NaV1.8-deficient mice upon cold signaling.

The voltage-gated sodium channel subtype NaV1.8 is expressed in the peripheral nervous system in primary afferent nociceptive C-fibers and is essential for noxious cold signaling. We utilized functional magnetic resonance imaging on NaV1.8-deficient (NaV1.8-/-) compared with wildtype (WT) mice to identify brain structures decoding noxious cold and/or heat signals. In NaV1.8-/- mice functional activity patterns, activated volumes and BOLD signal amplitudes are significantly reduced upon noxious cold stimulation whereas differences of noxious heat processing are less pronounced. Graph-theoretical analysis of the functional connectivity also shows dramatic alterations in noxious cold sensation in NaV1.8-/- mice and clearly reduced interactions between certain brain structures. In contrast, upon heat stimulation qualitatively quite the same functional connectivity pattern and consequently less prominent connectivity differences were observed between NaV1.8-/- and WT mice. Thus, the fact that NaV1.8-/- mice do not perceive nociceptive aspects of strong cooling in contrast to their WT littermates seems not only to be a pure peripheral phenomenon with diminished peripheral transmission, but also consists of upstream effects leading to altered subsequent nociceptive processing in the central nervous system and consequently altered connectivity between pain-relevant brain structures.

Acetaminophen/paracetamol: A history of errors, failures and false decisions.

Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side-effect 'epidemy' (phenacetin nephropathy, drug-induced interstitial nephritis) and ends with the discovery of second-generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound.

[Unexpected hemorrhage complications in association with celecoxib. Spontaneously reported case series after perioperative pain treatment in gynecological operations]. / Unerwartete Blutungskomplikationen im Zusammenhang mit Celecoxib. Spontanmeldung einer Fallserie nach perioperativer Schmerzbehandlung bei gynäkologischen Operationen.

A series of cases of postoperative bleeding were reported to the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft, AkdÄ) within the spontaneous reporting system after the regimen for postoperative pain treatment was changed from diclofenac (150 mg per day) to celecoxib (400 mg per day). All patients underwent elective gynecological surgery and 7 out of 11 patients with postoperative bleeding required revision surgery. Although alternative causes for the hemorrhage incidents could not be excluded, the documented circumstances could have been indicative of a possible causal association. Studies on perioperative pain treatment with celecoxib had previously shown no increased risk of hemorrhage. The tendency to hemorrhage observed in the registered cases could not be pharmacologically explained; however, due to the high dosages of celecoxib and the extensive co-medications used, a relative overdosing due to drug interactions or differences in the metabolism of the affected patients was conceivable. Celecoxib is not approved for the treatment of acute postoperative pain although a number of studies were carried out on the effectiveness and safety in patients undergoing surgery.

[Evaluation and choice of imaging protocols on the Elekta XVI(®) kilovoltage cone-beam computed tomography imaging system]. / Évaluation et choix des protocoles d'imagerie sur le système de tomographie conique de basse énergie XVI(®) d'Elekta.

PURPOSE: This work proposes an evaluation of the Elekta XVI(®) kilovoltage cone-beam computed tomography imaging system. The average dose delivered for each acquisition protocol proposed by default by the manufacturer was measured with several detectors and compared to theoretical dose values given by Elekta. At the same time, an evaluation of image quality for pelvic protocols correlated to dose measurements in homogeneous and heterogeneous mediums allowed to optimize the use of the XVI(®) system. MATERIALS AND METHODS: The dose was measured for each acquisition protocol (varying filters, FOV and collimations) with four detectors (CT pencil ion chamber, 0.3 and 0.125 cm(3) cylindrical ion chambers, radiothermoluminescent dosimeters) in a CTDI phantom. The dose evaluation in a heterogeneous medium was performed in an experimental anthropomorphic phantom simulating a male pelvis. Image quality was assessed with a Catphan(®) 600 phantom. RESULTS: The average dose measured in a homogeneous medium was about 17 mGy and 25 mGy per acquisition for Pelvis and Prostate protocols and about 17 mGy and 1 mGy for Lung and Head protocols. The study performed with different detectors showed that doses obtained were of the same order of magnitude (± 10 %) and agreed with those supplied by the manufacturer. The evaluation of image quality correlated to the average dose measured allowed to optimize the use of XVI(®) acquisition protocols. Measurement results in a heterogeneous medium showed a dose decrease by a factor 1.5 for bone and by a factor 2 for titanium. CONCLUSION: The study showed that theoretical values proposed by the manufacturer could be used to estimate the average dose delivered to the patient by the kV-CBCT imaging system. The analysis of all the results led to the implementation of a procedure allowing to optimize and account for the dose delivered to the patient by the CBCT imaging system and to report it in the patient folder.

Preoperative administration of etoricoxib in patients undergoing hip replacement causes inhibition of inflammatory mediators and pain relief.

OBJECTIVE: Administering cyclooxygenase-2 inhibitors preoperatively appears attractive since these drugs reduce post-operative pain, but do not increase the risk of post-operative bleeds, asthmatic attacks and stress-related gastrointestinal ulcers. In a former investigation, we could show that post-operative administration of etoricoxib reduces prostaglandin production in wound fluid, but the onset of action is variable due to delayed post-operative absorption. METHODS: In this study, we investigated the preoperative administration of etoricoxib in patients undergoing hip replacement. They received 120 mg etoricoxib or placebo 2 h before surgery and 1 day after in a double-blinded, randomized, parallel group design. RESULTS: A total of 11 patients were randomized (placebo n = 5; verum n = 6). We found high and constant levels of the drug in blood, central nervous system and wound fluid already at the end of surgery (t(max) < 2 h). This was accompanied by inhibition of prostaglandin production in the wound tissue (treatment p < 0.05), suppression of interleukin 6 increase in plasma (treatment p < 0.01), and - despite existing standard pain relief procedures - higher satisfaction with analgesics (time vs. treatment p < 0.05) and less demand for opioids (treatment p < 0.01) and intrathecal bupivacaine (treatment p = 0.05) administration. CONCLUSION: Administration of etoricoxib 2 h before surgery allows for an effective drug concentration in critical tissues, a reduction of the production of pro-inflammatory mediators and for better pain relief.

[Cardiovascular complications with cyclooxygenase inhibitors : Myths and facts]. / Kardiovaskuläre Komplikationen unter Zyklooxygenasehemmern : Mythen und Fakten.

During the last decade there have been nearly 10,000 publications dealing with the cardiovascular risk of cyclooxygenase inhibitors and it can be concluded that the use of both selective and non-selective inhibitors is accompanied by a substantial cardiovascular risk (e.g. infarction, thromboembolic events, cardiac insufficiency and possibly stroke). As these pharmaceuticals, including paracetamol and acetylsalicylic acid, belong to the most used medications and safer alternatives are still lacking it will be the aim in the future to keep the risk connected with the therapy with these drugs limited despite the fact that the aging population will demand an increased consumption of analgesics. Choosing the right substance (e.g. selective versus non-selective, fast elimination versus slow elimination) and the correct dosage, i.e. the lowest possible dosing range, will help to keep the risk within tolerable limits. In addition biomarkers have emerged which will allow the identification of patients with a high risk of cardiovascular hepatic and gastrointestinal side effects.

Gender-based differences in drug prescription: relation to adverse drug reactions.

BACKGROUND/AIM: The female gender appears to suffer from more adverse drug reactions (ADRs) than the male gender. So far, there has been no epidemiologic study analyzing gender-based differences in drug prescribing and its ADR risks. The aim of the present study was to establish a drug risk stratification adjusted to age, number of prescriptions and drug classes with respect to gender differences based on intensive data acquisition methods. METHOD: A prospective multicenter study was conducted in several departments in Germany and Israel (pediatrics, medicine and geriatrics) enclosing 2,371 inpatients. RESULTS: A total of 25,532 drug prescriptions during hospitalization were evaluated. At least 1 ADR was found in 774 patients (32.6%). Drugs for the cardiovascular system, nervous system, alimentary tract and musculoskeletal system were prescribed most often in females. The following drug classes led significantly more often to ADRs in women as compared to men: alimentary tract (OR 0.5; p = 0.0002), cardiovascular system (OR 0.72; p = 0.0140), musculoskeletal system (OR 0.31; p = 0.0004) and nervous system (OR 0.62; p = 0.0023). After adjustment to age, total number of prescriptions and drug class, only anti-infectives (antibacterials) and musculoskeletal system (anti-inflammatory) drugs stand out as causing more ADRs in women. CONCLUSION: Antibacterials and anti-inflammatory agents cause more ADRs in females as compared to males.

[Cyclooxygenase inhibitors: adverse drug reactions are unavoidable, but only a few are (acutely) dangerous]. / Zyklooxygenasehemmer: Arzneimittelinteraktionen sind unvermeidlich, nur wenige sind (akut) gefährlich.

Non-steroidal, anti-inflammatory drugs are the most widely used remedies worldwide. Drug interactions are frequent, life threatening ones are rare: Bleeds on the basis of inhibition of platelet aggregation and loss of organ protection (GI-tract), thrombotic events due to loss of vasoprotection and increased propensity for blood coagulation (stroke), acute kidney failure on the basis of loss of kidney protection by prostaglandins together with stress to the organ and/or drugs interfering with the renal blood flow. Acute liver toxicity is typical for acetaminophen. Whether the risk is increased by other hepatotoxic drugs, as diclofenac, is uncertain at present. All risks can be reduced considerably by avoiding problematic drug interactions.

Women encounter ADRs more often than do men.

BACKGROUND: Several publications indicate that the female gender experiences a higher incidence of adverse drug reactions (ADRs) than does the male gender. The reasons, however, remain unclear. Gender-specific differences in the pharmacokinetic and pharmacodynamic behaviour of drugs could not be identified as an explanation. The aim of this study was to analyse ADR risk with respect to gender, age and number of prescribed drugs. METHODS: A prospective multicenter study based on intensive pharmacovigilance was conducted. Information on patient characteristics and evaluated ADRs was stored in a pharmacovigilance database--KLASSE. RESULTS: In 2,371 patients (1,012 female subjects), 25,532 drugs were prescribed. In 782 patients, at least one ADR was found. A multivariate regression analysis adjusting for age, body mass index (BMI) and number of prescribed drugs showed a significant influence of female gender on the risk of encountering ADRs [odds ratio (OR) 1.596, confidence interval (CI) 1.31-1.94; p < 0.0001). Dose-related ADRs (51.8%) were the dominant type in female subjects. Comparing system organ classes of the World Health Organisation (SOC-WHO), cardiovascular (CV) ADRs were particularly frequent in female subjects (OR 1.92, CI 1.15-3.19; p = 0.012). CONCLUSION: Our data confirm the higher risk of ADRs among female subjects compared with a male cohort. Several explanations were investigated. No single risk factor could be identified.

Impact of naproxen sodium at over-the-counter doses on cyclooxygenase isoforms in human volunteers.

OBJECTIVE: Over the last few years, there has been concern regarding the cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors and high-dose regimens of nonsteroidal anti-inflammatory drugs (NSAIDs). On the other hand, those compounds which elicit an almost complete (> 95%) and continuous suppression of platelet COX-1 may represent an exception. Apart from aspirin, which irreversibly inactivates COX-1, high-dose naproxen causes sustained COX-1 inhibition throughout the dose interval in some individuals. The present study examines whether naproxen sodium after a single dose administration and at steady state using "over-the-counter (OTC) doses" produces sufficient COX-1 inhibition. COX-2 inhibition was assessed concomitantly. METHODS: Ex vivo inhibition of COX enzymes and the pharmacokinetics of naproxen were assessed in four volunteers receiving 220 mg naproxen sodium b.i.d. for 7 days. Blood samples were obtained pre-dose, at specified time points after the first dose on Day 1, and 12 hours after the previous evening dose on Days 2, 3, 4, 5 and 8. Recovery was assessed up to 36 hours after the last dose. Coagulation-induced thromboxane B2 formation and lipopolysaccharide-induced prostaglandin E2 synthesis were measured ex vivo in human whole blood as indices of COX-1 and COX-2 activity. RESULTS: Maximal inhibition after a single dose and at steady state were as follows: 94% and 93% (COX-1), and 79% and 85% (COX-2). A greater than 95% COX-1 inhibition was observed transiently in 2 of 4 volunteers at the time of maximal plasma concentration after a single-dose administration and in 1 of 4 volunteers throughout the 12-hour dose interval at steady state. For both isoenzymes, COX inhibition correlated with naproxen plasma levels (ex vivo IC50 values of 35.48 micromol/l (COX-1) and 64.62 micromol/l (COX-2)). CONCLUSIONS: Administration of naproxen sodium at OTC doses was associated with a profound inhibition of both COX enzymes. Although low-dose naproxen may elicit a virtually complete COX-1 inhibition in some individuals, it does not mimic the reliable, sustained and complete COX-1 blockade produced by aspirin. In conclusion, prolonged treatment with 220 mg naproxen sodium b.i.d. is not expected to provide sufficient cardioprotection in all patients, but may influence platelet function in some.

The venous graft as an effector of early angiogenesis in a fibrin matrix.

The arteriovenous loop (AV loop) model is gaining importance as a means of initiating and sustaining perfusion in tissue engineering constructs in vivo. This study represents an attempt to dissect the morphology of early arterialization and angiogenesis in the AV loop in a fibrin matrix with special focus on the interpositional venous graft (IVG) segment. An AV loop was constructed in 30 rats using the femoral vessels and an IVG. The AV loop was encased in an isolation chamber filled with a fibrin matrix. Evaluation methods included scanning electron microscopy (SEM) of corrosion casts, immune histology and micro magnetic resonance angiography (MRA). Direct luminal neovascular sprouting was evident between day 10 and day 14 from the vein and the IVG but not from the arterial segment. Arterialization of the IVG manifested itself on the corrosion casts as a gradual reduction in luminal caliber with onset after day 7. Microdissection of the microvascular replicas could demonstrate for the first time the presence of direct luminal sprouts from the IVG. MRA was used to display the shunt pattern of perfusion in the patent AV loop. From the three segments of the vascular axis in the AV loop the IVG is the most versatile for applications in the clinical as well as the experimental setting. Kinetics of angiogenesis warrant further investigation in the IVG.

[From willow bark to the coxibs. Development of antiphlogistic analgesics]. / Von der Weidenrinde zu den Coxiben. Entwicklung der antiphlogistischen Analgetika.

Antiphlogistic analgesics comprise the most widely used class of drugs worldwide. These compounds derive more or less directly from three prototypes which were discovered about 130 years ago in Central Europe: acetylsalicylic acid (aspirin), acetanilide (the forerunner of acetaminophen), and phenazone. All of them are still available. Attempts to improve their effect/side effect spectrum and enhance their analgesic activity led to the development of animal models of inflammatory pain which allowed for the screening and discovery of the so-called aspirin-like drugs, also termed nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase inhibitors. This group presently dominates the market despite the fact that all these compounds imply the risk of unwanted drug effects, including gastrointestinal ulcers, renal dysfunction, inhibition of blood coagulation, pseudoallergic reactions, and possibly also accelerated development of atherosclerosis. Attempts to reduce these unwanted drug effects on the basis of molecular pharmacological insights resulted in the development of the so-called selective cyclooxygenase-2 inhibitors which are presently discussed ambiguously. These compounds appear to go along with less gastrointestinal toxicity, they do not inhibit blood coagulation, and have a reduced propensity for causing pseudoallergic asthmatic attacks. They may, on the other hand, cause more unwanted cardiovascular effects than the traditional NSAIDs. Hope for further reduction of unwanted drug effects comes from the recently discovered role of glycinergic spinal pain control. It is hoped that new classes of analgesic compounds may result from these new glycinergic mechanisms.

Combining enzyme specificity and tissue selectivity of cyclooxygenase inhibitors: towards better tolerability?

Inhibitors of cyclooxygenases (COXs) are the most widely used drugs. They reduce discomfort and fever, inhibit peri-operative and inflammatory pain. These effects are largely mediated by inhibition of cyclooxygenase-1 and -2 (COX-1 and COX-2)-enzymes found throughout the body producing prostaglandins, which are important mediators of pain and fever, but also adaptive and protective reactions in many organs. A first step to reduce the overall toxicity and to increase the anti-inflammatory activity of these drugs was achieved with the development of acidic 'non-selective' (traditional) non-steroidal anti-inflammatory drugs (tNSAIDs). These agents distribute unequally throughout the body, reaching effective concentrations in inflamed tissue (effect compartment) for prolonged time periods. They can also reach effective concentrations in the bloodstream, kidney and gastrointestinal (GI) mucosa, where they can cause unwanted effects, such as GI toxicity, kidney dysfunction and cardiovascular impairment. All these effects are particularly prominent with compounds which are eliminated slowly [half-life (T((1/2))) >12 h] and thus also block prostaglandin production permanently outside the effect compartment. A second step towards improving safety was achieved with selective COX-2 inhibitors. These agents reduce the incidence of GI toxicity, pseudo-asthmatic reactions and blood loss following surgical interventions. However, they may be more toxic to the cardiovascular and renal systems than some tNSAIDs, possibly because they distribute homogeneously throughout the body and inhibit COX-2 in the endothelial layer of the vessels and the kidney permanently due to their slow elimination. Another step towards improvement in safety appears possible by combining both enzyme specificity and tissue selectivity, to achieve a further reduction of unwanted drug effects while maintaining the anti-inflammatory/analgesic efficacy.

[Pain therapy with antipyretic analgesics]. / Schmerztherapie mit antipyretischen Analgetika.

The pharmacotherapy of musculoskeletal pain remains of high importance in Western countries. The present review concentrates on the use of acidic (nonsteroidal anti-inflammatory drugs) and nonacidic (paracetamol, selective cyclooxygenase-2 inhibitors) antipyretic analgesics in the therapy of musculoskeletal pain disorders with particular emphasis on the diverse pharmacokinetic properties and unwanted side effects of these substances.

Antipyretic analgesics: nonsteroidal antiinflammatory drugs, selective COX-2 inhibitors, paracetamol and pyrazolinones.

Antipyretic analgesics are a group of heterogeneous substances including acidic (nonsteroidal antiinflammatory drugs, NSAIDs) and nonacidic (paracetamol, pyrazolinones) drugs. Moreover, various selective cyclooxygenase-2 (COX-2) inhibitors with improved gastrointestinal tolerability as compared with conventional NSAIDs have been established for symptomatic pain treatment in recent years. The present review summarizes the pharmacology of all of these drugs with particular emphasis on their rational use based on the diverse pharmacokinetic characteristics and adverse drug reaction profiles. Referring to the current debate, potential mechanisms underlying cardiovascular side effects associated with long-term use of COX inhibitors are discussed.