Regional anaesthesia and pain management.

Despite recent advances in analgesia delivery techniques and the availability of new analgesic agents with favourable pharmacokinetic profiles, current evidence suggests that postoperative pain continues to be inadequately managed, with the proportion of patients reporting severe or extreme postoperative pain having changed little over the past decade. Regional techniques are superior to systemic opioid agents with regards to analgesia profile and adverse effects in the context of general, thoracic, gynaecological, orthopaedic and laparoscopic surgery. Outcome studies demonstrate that regional analgesic techniques also reduce multisystem co-morbidity and mortality following major surgery in high risk patients. This review will discuss the efficacy of regional anaesthetic techniques for acute postoperative analgesia, the impact of regional block techniques on physiological outcomes, and the implications of acute peri-operative regional anaesthesia on chronic (persistent) postoperative pain.

The effects of different analgesic regimens on transcutaneous CO2 after major surgery.

Ventilatory impairment may be detected by a rise in transcutaneous carbon dioxide levels (PtcCO(2)). This observational study assessed the clinical utility of PtcCO(2) monitoring in the postoperative period, and quantified the effect of different peri-operative analgesic regimens on postoperative respiratory function. Following pre-operative baseline PtcCO(2) recording, continuous PtcCO(2) monitoring was performed in 30 patients after major colorectal surgery for up to 24 h. Mean postoperative values of PtcCO(2) were 1.3 kPa (95% CI 1.0-1.5) higher than pre-operative values (p < 0.001). Patients receiving intravenous opioid patient controlled analgesia had a significantly higher elevation in postoperative PtcCO(2) compared to patients receiving epidural infusion analgesia, 1.8 kPa (CI 1.5-2.1) vs 0.7 kPa (CI 0.5-0.9) respectively (p < 0.001). The mean rise in PtcCO(2) following a single intravenous bolus of morphine delivered via PCA was 0.05 kPa (SEm 0.01), peaking at 12 min post-dose. The transcutaneous capnometer successfully recorded data for 98% of the total time it was applied to patients.

Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions.

AIMS/HYPOTHESIS: We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators (GKAs), especially through acute and subchronic studies in rodent diabetes models with (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a novel and potent GKA. MATERIALS AND METHODS: The action of PSN-GK1 on or in the following were investigated: (1) on human liver glucokinase, insulin secretion from MIN6 cells and 2-deoxy-D: -[(3)H]glucose (2-DG) uptake into rat hepatocytes; and (2) in Zucker diabetic fatty rats and in non-diabetic C57Bl/6, diabetic db/db and ob/ob mice. RESULTS: At 5 mmol/l glucose, PSN-GK1 activated glucokinase (4.3-fold, median effective concentration [EC(50)] 130 nmol/l), increased MIN6 insulin secretion (26-fold, EC(50) 267 nmol/l) and 2-DG hepatocytic uptake (threefold, EC(50) 1 micromol/l); at higher glucose concentrations, EC(50)s and fold-effectiveness were both lower. In C57Bl/6 mice, PSN-GK1 reduced blood glucose at 1 and 10 mg/kg (by mouth), but insulin was increased significantly at only the higher dose. In hyperinsulinaemic 10-mmol/l glucose clamps, PSN-GK1 increased 2-DG incorporation into liver glycogen sixfold, directly demonstrating liver effects. PSN-GK1 improved glycaemic profiles in db/db mice and Zucker diabetic fatty rats, diabetic animal models in which GKA efficacy has not previously been described, without causing hypoglycaemia. In ob/ob mice, it dose-dependently reduced excursions in OGTTs. Moreover, after subchronic administration, no tachyphylaxis was evident and glycaemia was improved without alterations to lipid levels, liver weight, glycogen content or body weight. CONCLUSIONS/INTERPRETATION: PSN-GK1 was potently antihyperglycaemic through its effects on insulin release and hepatic glucose metabolism. It is one of the most potent GKAs described in the literature and is active in diabetic animal models where GKAs have not been reported to show efficacy to date. Ongoing human trials are investigating the potential of this novel therapeutic approach.

Applying science to drug discovery.

Scientists and science in the pharmaceutical industry rely heavily on the more academically orientated basic research carried out at Universities, for first of all training, but also as a source of new ideas and approaches to drug discovery. Progress in the discovery and development of novel therapeutics benefits from a healthy alliance with, and the output from, more basic research institutions, and the reverse is also true, with many advances in understanding of physiological and pathological processes being as the result of the application of novel targeted molecules. To illustrate this, some examples related to the themes of this meeting from my experiences in three different companies will be described. The first involves a metabolic angle in the unravelling of the mechanism of the novel anti-anginal agent ranolazine. The second describes the application of detailed knowledge of insulin structure and action to then use recombinant approaches to design novel molecules to be able to offer the Type I (insulin-dependent) diabetic patient therapies allowing a more physiological treatment regime, and also the further application of learned technology to then discover a means of harnessing the potential of GLP-1 (glucagon-like polypeptide 1) for treating Type II (non-insulin-dependent) diabetes. The last illustrates how findings of novel binding sites on glycogen phosphorylase and glucokinase as the result of drug discovery programmes have led to increased understanding of these key metabolic enzymes and also potential new therapies for Type II diabetes.

Macrolides in cystic fibrosis.

Macrolide antibiotics have been licensed since the 1950s and have an important role in the treatment of a diverse range of infectious diseases. Macrolide antibiotics have antibacterial activity against gram-positive bacteria, some gram-negative bacteria and intracellular pathogens. The spectrum of antibacterial activity combined with excellent intracellular and tissue penetration has led to the extensive use of this class of drugs in respiratory disease. Macrolide antibiotics also have demonstrated anti-inflammatory properties in various in vitro and in vivo model systems. Novel antimicrobial and anti-inflammatory properties of macrolide may result in clinical benefits, particularly in conditions where the infectious agent is inherently resistant to macrolides. Three randomized control trials have demonstrated improved lung function in patients treated with the macrolide antibiotic, azithromycin. Azithromycin was generally well tolerated and resulted in reduction in the inflammatory response which may be due to an immunomodulatory role. Short term studies (three to six months) have not demonstrated the development of increased bacterial resistance or the emergence of new pathogens following azithromycin.

A randomized trial of home vs hospital intravenous antibiotic therapy in adults with infectious diseases.

OBJECTIVE: Despite widespread adoption of home care services, few randomised trials have compared health outcomes in the hospital and at home. We report a prospective, randomised trial of home versus hospital therapy in adults receiving intravenous (IV) antibiotics. Our objective was to show that home care is a feasible alternative to hospitalisation over a broad range of infections, without compromise to quality of life (QOL) or clinical outcomes. METHODS: Consenting adults requiring IV antibiotics were randomised to complete therapy at home or in hospital. Short Form 36 and Perceived Health Competence Scale (PHCS) were used for assessment of QOL. Statistical analysis used unpaired t-tests, Mann-Whitney tests and ANOVA. RESULTS: One hundred and twenty-nine admissions were referred. Recruitment was hampered by patient preference for one therapy over another. 82 (62%) were included and randomised: 44 to home, 38 to hospital; the two groups had comparable characteristics. There were no differences in improvements in QOL and PHCS scores between the two groups after treatment. Treatment duration was median 11.5 days (range 3-57) and 11 days (range 4-126) for home and hospital groups, respectively. Home therapy costs, approximately, half that of hospital therapy. Time to readmission was longer after hospital therapy. CONCLUSION: Out study showed that home IV therapy is well tolerated, is less costly, is not associated with any major disadvantage to QOL or clinical outcomes compared to hospital therapy, and is an appropriate treatment option for selected patients.

Pharmacokinetics and anti-hyperglycaemic efficacy of a novel inhibitor of glycogen phosphorylase, 1,4-dideoxy-1,4-imino-d- arabinitol, in glucagon-challenged rats and dogs and in diabetic ob/ob mice.

AIM: To further characterize the properties of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), a recently described novel and potent inhibitor of glycogen phosphorylase and potential anti-diabetic agent, we have determined its pharmacokinetic properties in rats, dogs and mice and compared these to its pharmacodynamic anti-hyperglycaemic efficacy. METHODS: Male Sprague Dawley rats, beagle dogs and diabetic Umeå ob/ob mice were administered DAB or 14C-DAB at various doses and by different routes and in either the conscious or the unconscious state and with or without glucagon, as appropriate. At different time points thereafter, blood, tissue and urine samples were withdrawn for analyses of DAB or 14C-DAB, and blood samples were taken for glucose concentration. RESULTS: DAB suppressed the blood glucose excursion in glucagon-challenged rats with an ID100 of 1-2 mg/kg per orally and intravenously and had a pharmacodynamic t50 for 1.6 mg/kg intravenously and for 1.2 mg/kg per orally of 50 and 60 min respectively. The pharmacokinetics of c. 2 mg/kg DAB in rats revealed elimination half-lives of 25 min after intravenous (i.v.) and 49 min after per oral (p.o.) administration; the oral bioavailability was 89%. In rats, DAB was distributed preferentially in liver vs. skeletal muscle and was eliminated predominantly through urine as parent compound. The pharmacokinetics of 4 mg/kg DAB in dogs showed elimination half-lives of 107 min after i.v. and 129 min after p.o. administration with an estimated oral availability of 78%. At 4 mg/kg DAB p.o., glucagon-induced hyperglycaemia in dogs was reduced in a time-dependent manner with an estimated t50 of 4 h. DAB was very rapidly cleared in mice; nevertheless, a dose-dependent reduction of blood glucose of up to 9 mmol/l was seen in diabetic ob/ob mice dosed subcutaneously, with statistically significant effects evident from 30 to 120 min. CONCLUSIONS: These data show that DAB is nearly completely orally available in rats and dogs and that it can reduce glucagon-induced and spontaneous hyperglycaemia. Inhibition of hepatic glycogen phosphorylase may benefit glycaemic control in patients with type 2 diabetes.

Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections.

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, P(corrected)=0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

Pharmacological approaches to inhibit endogenous glucose production as a means of anti-diabetic therapy.

The inappropriate overproduction of glucose by the liver is one of the key contributors to the hyperglycaemia of the diabetic state, and thus is a logical site of intervention for novel anti-diabetic approaches. Metformin is the only currently marketed anti-hyperglycaemic drug whose action is attributed largely to its having inhibitory effects on hepatic glucose production, but its molecular site and mechanism(s) of action remain unknown, whereas the liver acting PPAR alpha agonists have their effects primarily on lipid metabolism. This review therefore rather focuses on candidate molecular targets within the liver for anti-hyperglycaemic therapy, and describes potential rate-controlling receptors and enzymes within the glucose producing pathways (glycogenolysis and gluconeogenesis). Most focus is directed towards inhibitors of the enzymes glucose-6-phosphatase, fructose-1,6-bisphosphatase and glycogen phosphorylase, and towards glucagon receptor antagonists, as these appear to be the most advanced in preclinical and clinical development, although progress with other potential targets is also described. Evidence of the anti-diabetic potential of such agents from animal studies is presented, and the relative merits of each approach are reviewed and compared. It is likely that such agents will become important additions to the therapeutic approaches to combat diabetes.

Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory.

Although extended-spectrum beta-lactamases (ESBLs) hydrolyze cephalosporin antibiotics, some ESBL-producing organisms are not resistant to all cephalosporins when tested in vitro. Some authors have suggested that screening klebsiellae or Escherichia coli for ESBL production is not clinically necessary, and when most recently surveyed the majority of American clinical microbiology laboratories did not make efforts to detect ESBLs. We performed a prospective, multinational study of Klebsiella pneumoniae bacteremia and identified 10 patients who were treated for ESBL-producing K. pneumoniae bacteremia with cephalosporins and whose infecting organisms were not resistant in vitro to the utilized cephalosporin. In addition, we reviewed 26 similar cases of severe infections which had previously been reported. Of these 36 patients, 4 had to be excluded from analysis. Of the remaining 32 patients, 100% (4 of 4) patients experienced clinical failure when MICs of the cephalosporin used for treatment were in the intermediate range and 54% (15 of 28) experienced failure when MICs of the cephalosporin used for treatment were in the susceptible range. Thus, it is clinically important to detect ESBL production by klebsiellae or E. coli even when cephalosporin MICs are in the susceptible range (

Effects of tumor necrosis factor-alpha on insulin action in cultured human muscle cells.

Reported discrepancies in the effects of tumor necrosis factor (TNF)-alpha in modulating insulin sensitivity of cultured cells may relate both to cell types studied and to the time course of exposure to the cytokine. Additionally, the relationship of effects on glucose metabolism to changes in the insulin signaling pathway cannot be assumed. For in vitro study, the cell type most relevant to insulin resistance in humans is the cultured human muscle cell. In the present study, TNF brought about no change in the rate of glycogen synthesis in cultured human muscle cells unless present during differentiation. The presence of TNF (5 ng/ml) during the process of differentiation of myoblasts into mature myotubes diminished the response of glycogen synthesis to acute insulin stimulation. This finding was associated with an impairment of differentiation-dependent increases in total cellular glycogen synthase (GS) activity. Under the same conditions of TNF exposure, there was no effect on the response to acute insulin stimulation of the fractional activity of GS. Similarly, there was no effect on the insulin stimulation of protein kinase B (PKB) and inhibition of glycogen synthase kinase 3 (GSK-3). Acute insulin stimulation brought about a 4.08 +/- 0.44-fold stimulation of activity of PKB in the absence of TNF, with 4.81 +/- 0.70-fold stimulation in cells exposed to TNF. GSK-3 activity decreased to 74.0 +/- 5.8% of basal after insulin stimulation without TNF and 78.3 +/- 5.0% after TNF exposure. However, differentiation of myocytes, as defined by an increase in the acetylcholine receptor, myogenin, and mature creatine kinase isoform expression, was impaired in TNF-treated cells. These studies demonstrate that TNF, if present during differentiation, decreases insulin-stimulated rates of storage of glucose as glycogen and total GS activity but does not downregulate the insulin-signaling system to GS. More generally, TNF also inhibits differentiation of human muscle cells in culture.

Control of glycogen synthesis by glucose, glycogen, and insulin in cultured human muscle cells.

A key feature of type 2 diabetes is impairment in the stimulation of glycogen synthesis in skeletal muscle by insulin. Glycogen synthesis and the activity of the enzyme glycogen synthase (GS) have been studied in human myoblasts in culture under a variety of experimental conditions. Incubation in the absence of glucose for up to 6 h caused an approximately 50% decrease in glycogen content, which was associated with a small decrease in the fractional activity of GS. Subsequent reincubation with physiological concentrations of glucose led to a dramatic increase in the rate of glycogen synthesis and in the fractional activity of GS, an effect which was both time- and glucose concentration-dependent and essentially additive with the effects of insulin. This effect was seen only after glycogen depletion. Inhibitors of signaling pathways involved in the stimulation of glycogen synthesis by insulin were without significant effect on the stimulatory action of glucose. These results indicate that at least two distinct mechanisms exist to stimulate glycogen synthesis in human muscle: one acting in response to insulin and the other acting in response to glucose after glycogen depletion, such as that which results from exercise or starvation.

Epidemiology of ciprofloxacin resistance and its relationship to extended-spectrum beta-lactamase production in Klebsiella pneumoniae isolates causing bacteremia.

A prospective study of Klebsiella pneumoniae bacteremia was performed in 12 hospitals in 7 countries. Of 452 episodes of bacteremia, 25 (5.5%) were caused by K. pneumoniae that was resistant in vitro to ciprofloxacin. Extended-spectrum beta-lactamase (ESBL) production was detected in 15 (60%) of 25 ciprofloxacin-resistant isolates, compared with 68 (16%) of 427 ciprofloxacin-susceptible strains (P=.0001). Multivariate analysis revealed that risk factors for ciprofloxacin resistance in K. pneumoniae included prior receipt of a quinolone (P=.0065) and an ESBL-producing strain (P=.012). In all, 18% of ESBL-producing isolates were also ciprofloxacin-resistant. Pulsed-field gel electrophoresis showed that 11 of the 15 ciprofloxacin-resistant ESBL-producing strains belonged to just 4 genotypes, suggesting that patient-to-patient transmission of such strains occurred. The close relationship between ESBL production and ciprofloxacin resistance is particularly worrisome because the first reported instance of plasmid-mediated ciprofloxacin resistance has been in an isolate of K. pneumoniae also possessing an ESBL.

Direct costs associated with a nosocomial outbreak of Salmonella infection: an ounce of prevention is worth a pound of cure.

BACKGROUND: Nosocomial outbreaks of Salmonella infections in Australia are an infrequent but significant source of morbidity and mortality. Such an outbreak results in direct, measurable expenses for acute care management, as well as numerous indirect (and less quantifiable) costs to those affected, the hospital, and the wider community. This article describes the significant direct costs incurred as a result of a nosocomial outbreak of Salmonella infection involving patients and staff. METHOD: Information on costs incurred by the hospital was gathered from a number of sources. The data were grouped into 4 sections (medical costs, investigative costs, lost productivity costs, and miscellaneous) with use of an existing tool for calculating the economic impact of foodborne illness. RESULTS: The outbreak cost the hospital more than AU $120, 000. (US $95,000). This amount is independent of more substantial indirect costs. CONCLUSION: Salmonella infections are preventable. Measures to aid the prevention of costly outbreaks of nosocomial salmonellosis, although available, require an investment of both time and money. We suggest that dedication of limited resources toward such preventive strategies as education is a practical and cost-effective option for health care facilities.