Laparoscopic approach in perforated appendicitis: increased incidence of surgical site infection?

BACKGROUND: The role of laparoscopy in the setting of perforated appendicitis remains controversial. A retrospective study was conducted to evaluate the early postoperative outcomes of laparoscopic appendectomy (LA) compared to open appendectomy (OA) in patients with perforated appendicitis. METHODS: A total of 1,032 patients required an appendectomy between January 2005 and December 2009. Among these patients, 169 presented with perforated appendicitis. Operation times, length of hospital stay, overall complication rates within 30 days, and surgical site infection (SSI) rates were analyzed. RESULTS: Out of the 169 evaluated patients, 106 required LA and 63 OA. Although operation times were similar in both groups (92 ± 31 min for LA vs. 98 ± 45 for OA, p = 0.338), length of hospital stay was shorter in the LA group (6.9 ± 3.8 days vs. 11.5 ± 9.2, p < 0.001). Overall complication rates were significantly lower in the LA group (32.1 vs. 52.4 %, p < 0.001), as were incisional SSI (1.9 vs. 22.2 %, p < 0.001). Organ/space SSI rates were similar in both groups (23.6 % after LA vs. 20.6 % after OA, p = 0.657). CONCLUSIONS: For perforated appendicitis, LA results in a significantly shorter hospital stay, fewer overall postoperative complications, and fewer wound infections compared to OA. Organ/space SSI rates were similar for both procedures. LA provides a safe option for treating patients with perforated appendicitis.

Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis: effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation.

OBJECTIVES: To investigate the effect of prolonged neutralisation of tumour necrosis factor alpha (TNFalpha) on the radiological course in rheumatoid arthritis (RA). To assess whether the radiological course can be predicted by clinical variables or biological markers of cartilage and synovium turnover and of endothelial activation. PATIENTS AND METHODS: Forty seven patients with active RA enrolled at our centre in monotherapy trials with adalimumab (D2E7), a fully human anti-TNFalpha monoclonal antibody, were studied for two years. Radiographs of hands and feet obtained at baseline and after one and two years were scored in chronological order by a single, blinded observer using the modified Sharp method. Radiological course was classified as stable or progressive using the smallest detectable difference as cut off point. The relation between radiological course and serum markers of cartilage and synovium turnover (metalloproteinases (MMP-1 and MMP-3), cartilage oligomeric matrix protein (COMP), human cartilage glycoprotein-39 (HC gp-39)), endothelial activation (soluble E-selectin and intercellular adhesion molecule (ICAM-1)), and integrated measures of disease activity were assessed using univariate and multivariate analysis. RESULTS: Radiological evaluation was performed in 36 patients with paired sets of radiographs at baseline and two years. After two years a total of 15/36 (42%) presented no radiological progression. More patients with stable radiological course were still receiving anti-TNFalpha treatment after two years (13/15 (87%) v 11/21 (52%); p=0.03) and had lower baseline COMP and sICAM-1 levels (p=0.01 and 0.04, respectively) than those in the group with progressive disease. In a logistic regression model the combination of sustained TNF neutralisation and baseline COMP and sICAM-1 levels was predictive for radiological outcome (p=0.03). C reactive protein and disease activity score area under the curve were significantly correlated with changes in radiological scores after two years (r=0.40 and 0.37, p<0.05). Long term TNFalpha neutralisation decreased the levels of COMP, sICAM, MMPs, and HC gp-39, but not sE-selectin. CONCLUSION: The results suggest that long term monotherapy with anti-TNFalpha has a positive effect on radiological outcome and modulates cartilage and synovium turnover as measured by biological markers. Baseline serum sICAM-1 levels and COMP levels may be helpful to identify patients with progressive or non-progressive radiological outcome.

Standardizing assessment of adverse effects in rheumatology clinical trials. Status of OMERACT Toxicity Working Group March 2000: towards a common understanding of comparative toxicity/safety profiles for antirheumatic therapies.

This paper describes the background and current status of an OMERACT facilitated effort to improve the consistency of adverse event reporting in rheumatology clinical trials. The overall goal is the development of an adverse event assessment tool that would provide a basis for use of common terminology and improve the consistency of reporting severity of side effects within rheumatology clinical trials and during postmarketing surveillance. The resulting Rheumatology Common Toxicity Criteria Index encompassed the following organ systems: allergic/immunologic, cardiac, ENT, gastrointestinal, musculoskeletal, neuropsychiatric, ophthalmologic, pulmonary and skin/integument. Before this tool is widely accepted, its validity, consistency, and feasibility need to be assessed in clinical trials.

The effect of HLA-DRB1 genes, rheumatoid factor, and treatment on radiographic disease progression in rheumatoid arthritis over 6 years.

OBJECTIVE: To investigate the relationship between radiographic disease progression in the presence or absence of rheumatoid arthritis (RA) linked HLA-DRB1 alleles after early introduction of disease modifying antirheumatic drug therapy in patients with RA over a study period of 6 years. METHODS: One hundred nine patients of a trial comparing intramuscular (im) gold sodium thiomalate (GSTM) and im methotrexate (MTX) in early erosive RA were followed for 6 years with regular assessments of clinical and laboratory data and yearly radiographs of hands and feet, and they were typed for HLA-DRB1 genes. Radiographic progression was analyzed for an influence of rheumatoid factor (RF) status and HLA-DRB1 genes. RESULTS: Twenty-seven patients (25%) were positive for two, 46 (42%) for one, and 36 (33%) for none of the disease linked alleles. A decrease of the rate of radiographic disease progression with treatment in this group of patients was reflected by the decline in the slope of the radiographic score. Seropositive patients (n = 71, 68%) had a significantly more destructive disease course than RF negative patients. In seropositive disease, patients with a "double dose" of RA linked alleles showed a tendency to greater progression during the first 12-24 mo of treatment, but no significant difference in the longterm radiographic outcome could be detected between subgroups defined by the presence or absence of HLA-DRB1 genes. There was no significant difference throughout the study period with respect to the clinical disease course as assessed by joint swelling, C-reactive protein, and erythrocyte sedimentation rate. The majority of the seronegative population (n = 38, 32%) had a benign disease course with the exception of patients (n = 6) with the double allele; they had radiographic disease progression comparable with the seropositive patients. CONCLUSION: Our data do not provide evidence for a more aggressive disease course in patients bearing double RA linked HLA-DRB1 alleles.

Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The International Consensus Meeting on the Mode of Action of COX-2 Inhibition (ICMMAC) brought together 17 international experts in arthritis, gastroenterology and pharmacology on 5 6 December 1997. The meeting was convened to provide a definition of COX-2 specificity and to consider the clinical relevance of COX-2-specific agents. These compounds are a new class of drugs that specifically inhibit the enzyme COX-2 while having no effect on COX-1 across the whole therapeutic dose range. The objectives of the meeting were to review the currently available data regarding the roles and biology of COX-1 and COX-2, and to foster a consensus definition on COX-2 specificity. At the present time, no guidelines exist for the in vitro and in vivo assessment of COX specificity, and it was felt that consensus discussion might clarify some of these issues. The meeting also reviewed recent clinical data on COX-2-specific inhibitors. The following article reflects discussion at this meeting and provides a consensus definition of COX-2-specific inhibitors.

[Immunopharmacologic profile and therapeutic prospects of anti-TNF-alpha therapy]. / Immunpharmakologisches Profil und therapeutische Perspektiven von anti-TNF alpha-Therapien.

Clinical trials with monoclonal antibodies directed against TNF alpha (anti-TNF mAbs) and soluble TNF receptor fusion proteins (sTNFR-IgGs) have demonstrated that systemic and synovial trapping of TNF alpha results in long lasting anti-inflammatory and anti-nociceptive effects in patients with rheumatoid arthritis. Clinical indices of inflammatory synovitis and laboratory parameters (CRP and ESR) respond to single and repeated administrations of anit-TNF alpha therapies in a dose-dependent fashion. Studies on the immuno-pharmacological profile in patients suggest evidence that TNF alpha trapping down-regulates the effector mechanisms involved in the immuno-inflammatory response in rheumatoid arthritis. Inhibition of PLA 2- and COX-2-derived pathways of mediators of inflammation (prostanoids and leukotrienes) decreases signs and symptoms of inflammatory synovitis such as joint swelling, tenderness and pain. Down-regulating of the cytokine-inducible adhesion molecules ICAM-1, VCAM-1 and ELAM-1 in endothelial cells and synoviocytes results in a marked inhibition of transendothelial migration of inflammatory and immune cells. A decrease of cytokine-regulated metalloproteinase expression results in normalization of circulating MMP-1 and MMP-3 levels. The effect of TNF alpha neutralization on mechanisms of rheumatoid joint destruction has the long-term potential for preventing or decreasing the rate of erosive changes of cartilage and bone.

Differentiating among nonsteroidal antiinflammatory drugs by pharmacokinetic and pharmacodynamic profiles.

Cyclooxygenase (COX)-1 inhibition by nonsteroidal antiinflammatory drugs (NSAIDs) is associated with gastrointestinal and renal toxicity, while COX-2 inhibition has beneficial antiinflammatory, analgesic, and antipyretic effects. The measurement of inhibitory potency of NSAIDs on COX isoforms is strongly influenced by variations in experimental conditions in different models. The concentration of protein in the assay medium is particularly important because NSAIDs are highly protein-bound in vivo, and assays based on human whole blood provide the most suitable test system available. Of the drugs investigated in the human whole blood assay, only meloxicam showed selectivity for COX-2 at therapeutically relevant concentrations. In contrast, standard NSAIDs, such as naproxen, inhibited both COX isoforms to an equal degree at therapeutically relevant concentrations. Thus, the selectivity of NSAIDs against COX-2 relative to COX-1 may provide a means of differentiating between them according to their risk of toxicity at therapeutic doses. This may be more clinically meaningful than the traditional classification of NSAIDs based on chemical structure.

[TNF inhibitors: a new therapeutic perspective in chronic inflammatory diseases in rheumatology?]. / TNF-Inhibitoren: Eine neue therapeutische Perspektive bei chronisch-entzündlichen Erkrankungen in der Rheumatologie?

Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF alpha) have been identified as important mediators of chronic immuno-inflammatory disease states such as rheumatoid arthritis. Effector cells are triggered by these cytokines to release molecules involved in synovitis and rheumatoid joint destruction, namely prostanoids, leukotrienes, adhesion molecules and metalloproteinases. Modifications of natural inhibitors of IL-1 and TNF alpha, which have been shown to maintain the homeostasis of the cytokine system, are now available by DNA technology. Monoclonal antibodies to TNF and the TNF receptor fusion proteins TNFR 55-IgG and TNFR 75-IgG are currently under clinical investigation in rheumatoid arthritis, inflammatory bowel disease and septic shock. Preliminary results from clinical trials in rheumatoid arthritis suggest that TNF inhibition represents a promising novel interventional strategy providing anti-inflammatory activity and inhibition of effector molecules of structural joint damage.

The role of cytokines and their inhibitors in arthritis.

The role of cytokines in inflammatory joint diseases is well documented, especially with regard to tissue destruction and remodelling. In these processes, IL-1 and TNF alpha play a prominent part by stimulating protease production. The regulation of their production, their release and their effects on target cells (e.g. synovial cells, chondrocytes and bone-derived cells) has therefore been the subject of intensive investigations. In this context a new dimension has emerged recently due to the observation of the existence of natural specific cytokine inhibitors. IL-1-ra and the soluble fragments of both TNF receptors--inhibitory by binding to TNF alpha--are natural products. These appear to be the molecules best suited for controlling the imbalance between pro- and anti-inflammatory processes. The use of the recombinant forms of these inhibitors may open new perspectives for therapeutic intervention. The fact that the respective mechanisms of action of receptor antagonists and inhibitory binding proteins differ does not rule out their complementarity. Preliminary experiments with animal models have yielded promising results which should be followed up by clinical trials.

Nonsteroidal antiinflammatory drugs: benefit/risk evaluation in rheumatic diseases.

Side effects of nonsteroidal antiinflammatory drug (NSAID) therapy are attributed to direct damage by the acidic compounds and to the secondary effects of prostaglandin inhibition. In general, gastrointestinal, skin and central nervous system effects predominate, followed by general adverse hepatic and renal events. Advanced age, female gender, history of gastrointestinal disorders and renal impairment increase the risk of NSAID induced side effects. Pharmacologic modifications that may help minimize side effects include lowered cyclooxygenase inhibitor activity, more stable plasma/tissue concentrations, decreased lipophilicity, avoidance of biliary excretion and renal excretion in inactive form. Prescribing NSAID according to their differing pharmacokinetic profiles may help maximize clinical efficacy and reduce side effects.

Blood distribution of tenoxicam in humans: a particular HSA drug interaction.

Blood binding of tenoxicam was studied in vitro by equilibrium dialysis. Isolated human plasma proteins and blood cells were checked, and the distribution of the bound form was then calculated. The results showed that tenoxicam is mainly bound to HSA and that binding percentages are not different when measured in plasma (98.4%) and in an HSA solution at physiological concentration (704 microM, 98.15%). In these conditions, within the range of 1-150 microM, the tenoxicam binding percentage remained constant, evidence of a nonsaturable process. When a lower HSA concentration (10 microM) was used, the binding parameters of the tenoxicam interaction were calculated by using the same equilibrium dialysis data, by 3 methods of analysis- a stoichiometric method and site-oriented methods, fixing or not the number of HSA binding sites (n) as integer values. The best fit was observed with the first method, suggesting that two main interactions occurred. The site-oriented method gave lesser fits, the better being observed when n was not fixed. Its value, 1.77, suggest the possibility of two binding sites, one of them not preformed. The effects of known markers of site I, warfarin and apazone, of site II, diazepam and ibuprofen and of palmitic acid showed that tenoxicam is bound simultaneously to both sites I and II. The binding capacity of site I for tenoxicam is enhanced by diazepam: as this compound alone is bound to site II, this result suggests that the two HSA binding sites are not independent.

Evaluation of the efficacy and safety of NSAIDs. A new methodological approach.

When rheumatic patients were questioned concerning the most desired attributes for a nonsteroidal anti-inflammatory drug (NSAID), the majority of replies related to tolerability. For example; low frequency of gastrointestinal side-effects, safety in the elderly, a low frequency of renal side-effects and a superior anti-inflammatory effect than other drugs available, were all regarded as important NSAID properties. This focus on safety issues by patients is probably due to problems experienced in recent years with non-steroidals on the market. In particular, the withdrawal of benoxaprofen was of major concern for both doctors and patients, and this together with other events over the last few years has not really contributed to an improvement of the relationship between rheumatic patients and doctors. The NSAIDs which have experienced problems and resulted in withdrawal from the market are as follows: benoxaprofen (Coxigon), indoprofen (Flosin), indomethacin (Osmosin, Osmogit), isoxicam (Pacyl) and oxyphenbutazone (Tanderil). Additionally, there were restrictions on the usage of phenylbutazone. This has resulted in the major authorities requiring more data concerning safety issues. The following paper will discuss an overview of the methodology which is now used in the development of a NSAID, using data and procedures obtained from the evaluation of tenoxicam.

Future trends in non-steroidal anti-inflammatory drug therapy.

In assessing future trends in non-steroidal anti-inflammatory drug (NSAID) development, there are four areas of particular interest: (i) Are the existing classifications still useful? New drugs currently under development may not be covered by the classification as it stands today. (ii) What are the new targets for drug development? The key objectives are to develop drugs with anti-inflammatory and analgesic properties which are not cyclo-oxygenase inhibitors. An area of keen interest is the inhibition of interleukin-1 production. (iii) What are the requirements for new drugs? New agents need to be better tolerated--increasing amounts of data on safety are required by the drug regulatory authorities. (iv) When will patients benefit from the new drugs? Since the development of new drugs remains extremely time-consuming, patients will not benefit from drugs currently undergoing research until at least the mid-1990's. Therefore, since there is no prospect of an alternative to the currently available NSAIDs in the foreseeable future, more theoretical and practical work needs to be undertaken in order for them to be deployed more specifically and selectively.

Comparative biochemical pharmacology of the oxicams.

The chronicity of the inflammatory process requires persistent tissue concentrations of non-steroidal anti-inflammatory drugs (NSAIDs), best achieved by using a drug with a long half-life as a once-daily regimen. The oxicams proved to be one of the most promising classes of NSAIDs. They have a similar molecular structure, though substitution of the benzothiazine ring by a thienothiazine system gives tenoxicam a more hydrophilic character. Tenoxicam is thus characterised by lower penetration into tissues requiring more lipophilic properties, e.g. the CNS and skin and, consequently, a lower incidence of adverse reactions at these target organs. Poor diffusion into hepatic cells--as a result of a small free fraction, tight binding to proteins and hydrophilic character--explains its low hepatic extraction ratio and--as a consequence--a long half-life. Compared to indomethacin and diclofenac, the oxicams have a moderate inhibitory activity on the synthesis and release of prostaglandins; tenoxicam is half as active as piroxicam, reflecting the correspondent difference in their steady-state plasma concentrations.

Comparative biochemical pharmacology of the oxicams.

The chronicity of the inflammatory process requires persistent tissue concentrations of non-steroidal anti-inflammatory drugs (NSAIDs), best achieved by using a drug with a long half-life as a once-daily regimen. The oxicams proved to be one of the most promising classes of NSAIDs. They have a similar molecular structure, though substitution of the benzothiazine ring by a thienothiazine system gives tenoxicam a more hydrophilic character. Tenoxicam is thus characterised by lower penetration into tissues requiring more lipophilic properties, e.g. the CNS and skin, and this may explain the lower incidence of adverse reactions at these target organs in comparison with more lipophilic NSAIDs. Poor diffusion into hepatic cells--as a result of a small free fraction, tight binding to proteins and hydrophilic character--explains its low hepatic extraction ratio and--as a consequence--a long half-life. Compared to indomethacin and diclofenac, the oxicams have a moderate inhibitory activity on the synthesis and release of prostaglandins; tenoxicam is half as active as piroxicam, reflecting the correspondent difference in their steady-state plasma concentrations.

Pharmacokinetics of piroxicam: new aspects.

Some new aspects of the pharmacokinetics of piroxicam have recently become of interest because of the wide use of this compound. Recent studies have provided data on several questions: Are the disposition kinetics of piroxicam different from those of nonsteroidal anti-inflammatory drugs (NSAIDs) with a short half-life, and are the differences in transsynovial distribution relevant to anti-inflammatory activity and significant in the clinical use of these drugs in acute and chronic rheumatic conditions? Are there important differences in the disposition and elimination of piroxicam from patient to patient and in special subgroups such as elderly patients? Is the variation in the half-life of a drug within a given population significant, especially with regard to the rate of metabolic degradation, enterohepatic recirculation, and tubular reabsorption?

[Clinical pharmacokinetics of allopurinol. 3. Allopurinol/oxipurinol pharmacokinetics following administration of a controlled release allopurinol preparation]. / Untersuchungen zur klinischen Pharmakokinetik von Allopurinol. 3. Mitteilung: Allopurinol/Oxipurinol-Pharmakokinetik nach Verabreichung einer Allopurinol-Formulierung mit verzögerter Freisetzung.

Studies of the Clinical Pharmacokinetics of Allopurinol/3rd Communication: Allopurinol/oxipurinol bioavailability and pharmacokinetics following the administration of a controlled release allopurinol formulation. Regarding the results of our studies on the localization of the absorption of allopurinol and the kinetic behavior of allopurinol/oxipurinol following multiple administration the bioavailability and kinetic properties of the drug delivered from controlled release tablets were studied in healthy volunteers. Allopurinol controlled release tablets (Sigapurol CR), containing 200 mg of the drug characterized by rapid absorption and 100 mg characterized by pH-dependent delivery, were identified as a formulation with advantages pharmacokinetic properties.