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6-Prenylnaringenin (6PN) is a chiral prenylflavonoid found most prevalently in hops (Humulus lupulus) and present in hops and hop products. It is an isomer of the potent phytoestrogen, 8-prenylnaringenin. An enantiospecific method for quantitation 6PN by LC-ESI-MS has been developed. Baseline enantiomeric resolution of 6PN was attained on a Chiralpak® AD-RH column with an isocratic mobile phase consisting of acetonitrile and 10 mM ammonium formate (pH 8.5) (39:61, v/v) and a flow rate of 1.25 mL/min. Quantitative MS data were obtained by selected ion monitoring of the [M-H]--ion of both enantiomers of 6PN (m/z 339.10) and the internal standard, 4-acetamidobenzoic acid (m/z 178.05). The method was found to be accurate and precise for enantiospecific quantification of 6PN. The method was successfully applied to the content analysis of 39 commercially available natural health products and dietary supplements reported to contain H. lupulus plant material, extracts and label claims of 6PN. 6PN was present in 25 of 34 products containing plant material or extracts of H. lupulus. Of the five products with claimed amounts of 6PN, all were found to possess <50% of label claims. Results of the content analysis indicated a lack of uniformity in botanical nutraceuticals claiming 6PN content. [ABSTRACT FROM AUTHOR]

Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), is the first specific inhibitor of cyclo-oxygenase-2 (COX-2) approved to treat patients with rheumatism and osteoarthritis. Preliminary data suggest that celecoxib also has analgesic and anticancer properties. The selective inhibition of COX-2 is thought to lead to a reduction in the unwanted effects of NSAIDs. Upper gastrointestinal complication rates in clinical trials are significantly lower for celecoxib than for traditional nonselective NSAIDs (e.g. naproxen, ibuprofen and diclofenac). The rate of absorption of celexocib is moderate when given orally (peak plasma drug concentration occurs after 2 to 4 hours), although the extent of absorption is not known. Celexocib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455+/-166L in humans. The area under the plasma concentration-time curve (AUC) of celecoxib increases in proportion to increasing oral doses between 100 and 800mg. Celecoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little drug (2%) being eliminated unchanged in the urine. Celecoxib is metabolised primarily by the cytochrome P450 (CYP) 2C9 isoenzyme and has an elimination half-life of about 11 hours in healthy individuals. Racial differences in drug disposition and pharmacokinetic changes in the elderly have been reported for celecoxib. Plasma concentrations (AUC) of celecoxib appear to be 43% lower in patients with chronic renal insufficiency [glomerular filtration rate 2.1 to 3.6 L/h (35 to 60 ml/min)] compared with individuals with healthy renal function, with a 47% increase in apparent clearance. Compared with healthy controls, it has been reported that the steady-state AUC is increased by approximately 40% and 180% in patients with mild and moderate hepatic impairment, respectively. Celecoxib does not appear to interact with warfarin, ketoconazole or methotrexate; however, clinically significant drug interactions with fluconazole and lithium have been documented. As celecoxib is metabolised by CYP2C9, increased clinical vigilance is required during the coadministration of other substrates or inhibitors of this enzyme. [ABSTRACT FROM AUTHOR]

Objective To compare ordinary least squares (OLS) and instrumental variable (IV) estimates of the effects of COX-2 selective inhibitor non-steroidal anti-inflammatory drugs (COX-2s) relative to non-selective NSAIDs (non-selectives) on incidence of gastrointestinal (GI) bleeding, and acute myocardial infarction (MI). We test the validity of the IV estimates, and compare to estimates from randomised controlled trials (RCTs). Design Cohort study using administration data. Setting Primary care. Participants 93 562 patients aged over 65 years attending one of 104 general practices (GP) in the UK. Main outcomes GI bleeding and acute MI. Methods We use data from the UK general practice research database. Our outcomes are incident gastrointestinal bleeding and myocardial infarctions within 60, 120, 180 and 360 days of the first prescription. We estimate risk differences in outcomes using OLS and IVs, using physician prior prescribing as an IV, and compare them to RCT estimates. Results The OLS estimates suggested COX-2s were positively associated with GI bleeds, and were negatively associated with MI. Adjusted OLS estimates were attenuated. In contrast our IV estimates imply –0.43(–1.54,0.68) fewer GI bleeds per 100 people treated with COX-2s after 180 days. The IV estimates provide little evidence, −0.55(−1.2, 1.5), of a difference in MI between treatments. These are comparable to previously published IV estimates and RCT evidence. Conclusions Deriving causal treatment effects using observational health data has proven to be problematic. We demonstrate that in contrast to IV based estimates, conventional OLS methods fail to estimate casual effects as indicated by RCTs. [ABSTRACT FROM AUTHOR]

Objective To compare ordinary least squares (OLS) and instrumental variable (IV) estimates of the effects of COX-2 selective inhibitor non-steroidal anti-inflammatory drugs (COX-2s) relative to non-selective NSAIDs (non-selectives) on incidence of gastrointestinal (GI) bleeding, and acute myocardial infarction (MI). We test the validity of the IV estimates, and compare to estimates from randomised controlled trials (RCTs). Design Cohort study using administration data. Setting Primary care. Participants 93 562 patients aged over 65 years attending one of 104 general practices (GP) in the UK. Main outcomes GI bleeding and acute MI. Methods We use data from the UK general practice research database. Our outcomes are incident gastrointestinal bleeding and myocardial infarctions within 60, 120, 180 and 360 days of the first prescription. We estimate risk differences in outcomes using OLS and IVs, using physician prior prescribing as an IV, and compare them to RCT estimates. Results The OLS estimates suggested COX-2s were positively associated with GI bleeds, and were negatively associated with MI. Adjusted OLS estimates were attenuated. In contrast our IV estimates imply –0.43(–1.54,0.68) fewer GI bleeds per 100 people treated with COX-2s after 180 days. The IV estimates provide little evidence, −0.55(−1.2, 1.5), of a difference in MI between treatments. These are comparable to previously published IV estimates and RCT evidence. Conclusions Deriving causal treatment effects using observational health data has proven to be problematic. We demonstrate that in contrast to IV based estimates, conventional OLS methods fail to estimate casual effects as indicated by RCTs. [ABSTRACT FROM PUBLISHER]

Intra-articular bupivacaine helps alleviate pain in animals receiving joint surgery, but its use has become controversial as ex vivo studies have illuminated the potential for chondrotoxicity. Such studies typically involve cell cultures incubated in solutions containing high bupivacaine concentrations for long durations. The aim of this study was to measure the actual synovial fluid bupivacaine concentrations after intra-articular injection. Eight healthy beagles with normal stifles and 22 large and giant-breed dogs with stifle osteoarthritis (OA) were treated with a single intra-articular injection of bupivacaine (1 mg/kg) into a stifle. Joint fluid samples were taken from the treated stifle immediately after injection and 30 min after injection and analyzed for bupivacaine concentrations. Immediately after injection, the median bupivacaine concentrations in normal and OA stifles were 3.6 and 2.5 mg/mL, respectively. Thirty minutes after injection, bupivacaine concentrations in normal and OA stifles were 0.4 and 0.6 mg/mL, respectively. These results provide insight into the pharmacokinetics of bupivacaine after injection into a joint. Given its immediate dilution and rapid drop in synovial fluid concentration, bupivacaine is unlikely to damage chondrocytes when administered as a single intra-articular injection. [ABSTRACT FROM AUTHOR]

Effective use of the growing number of nonsteroidal anti-inflammatory drugs (NSAIDs), a group that has recently been augmented by the introduction of the selective cyclo-oxygenase-2 inhibitors, requires adequate knowledge of their pharmacokinetics. After oral administration, the absorption of NSAIDs is generally rapid and complete. NSAIDs are highly bound to plasma proteins, specifically to albumin (>90%). The volume of distribution of NSAIDs is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding. NSAID binding in plasma can be saturated when the concentration of the NSAID exceeds that of albumin. Most NSAIDs are metabolised by the liver, with subsequent excretion into urine or bile. Enterohepatic recirculation occurs when a significant amount of an NSAID or its conjugated metabolites are excreted into the bile and then reabsorbed in the distal intestine. NSAID elimination is not dependent on hepatic blood flow. Hepatic NSAID elimination is dependent on the free fraction of NSAID within the plasma and the intrinsic enzyme activities of the liver. Renal elimination is not an important elimination pathway for NSAIDs, except for azapropazone. The plasma half-life of NSAIDs ranges from 0.25 to >70 hours, indicating wide differences in clearance rates. Hepatic or renal disease can alter NSAID protein binding and metabolism. Some NSAIDs with elimination predominantly via acylglucuronidation can have significantly altered disposition. Pharmacokinetics are also influenced by chronobiology, and many NSAIDs exhibit stereoselectivity. There appear to be relationships between NSAID concentration and effects. At therapeutically equivalent doses, NSAIDs appear to be equally efficacious. The major differences between NSAIDs are their therapeutic half-lives and safety profiles. NSAIDs undergo drug interactions through protein binding displacement and competition for active renal tubular secretion with other organic acids. When choosing the right NSAID for the right patient, individual patient-specific and NSAID-specific pharmacokinetic principles should be considered. [ABSTRACT FROM AUTHOR]

Wright, H. M., Chen, A. V., Martinez, S. E., Davies, N. M. Pharmacokinetics of oral rufinamide in dogs. J. vet. Pharmacol. Therap. 35, 529-533. The objective of this study was to determine the pharmacokinetic properties and short-term adverse effect profile of single-dose oral rufinamide in healthy dogs. Six healthy adult dogs were included in the study. The pharmacokinetics of rufinamide were calculated following administration of a single mean oral dose of 20.0 mg/kg (range 18.6-20.8 mg/kg). Plasma rufinamide concentrations were determined using high-performance liquid chromatography, and pharmacokinetic data were analyzed using commercial software. No adverse effects were observed. The mean terminal half-life was 9.86 ± 4.77 h. The mean maximum plasma concentration was 19.6 ± 5.8 μg/mL, and the mean time to maximum plasma concentration was 9.33 ± 4.68 h. Mean clearance was 1.45 ± 0.70 L/h. The area under the curve (to infinity) was 411 ± 176 μg·h/mL. Results of this study suggest that rufinamide given orally at 20 mg/kg every 12 h in healthy dogs should result in a plasma concentration and half-life sufficient to achieve the therapeutic level extrapolated from humans without short-term adverse effects. Further investigation into the efficacy and long-term safety of rufinamide in the treatment of canine epilepsy is warranted. [ABSTRACT FROM AUTHOR]

Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA. [ABSTRACT FROM AUTHOR]

We have identified differences in transport properties of intestinal epithelia in the marsupial brushtail possum, compared to eutherian mammals. To determine whether differences in its permeability to hydrophilic compounds also occur, the absorption of sodium fluorescein and luteinizing hormone releasing hormone (LHRH) was assessed in vitro and the ability of chemical enhancers and a metabolic inhibitor to promote their absorption investigated. The apparent permeability of colonic and caecal tissues to fluorescein and LHRH and transepithelial resistance (Rt) in the absence or presence of ethylenediamine tetra-acetic acid (EDTA), sodium deoxycholic acid (SDA), dithiothreitol (DTT), polyacrylic acids (PAA), or the inhibitor bacitracin were determined. The effects of SDA and/or DTT on adherent mucus and the release of lactate dehydrogenase (LDH) were also assessed. In the absence of treatment, both tissues had comparable amounts of adherent mucus, Rt and low permeabilities to fluorescein and LHRH. All chemical enhancers increased fluorescein permeability, but SDA at concentrations >0.5 mM also induced LDH release. DTT alone and in combination with SDA reduced the amount of adherent mucus. Bacitracin inhibited LHRH metabolism and increased LHRH permeability. These data indicate that the possum hindgut epithelium represents a significant barrier to the uptake of hydrophilic compounds, similar to that in eutherians. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2262–2273, 2007 [ABSTRACT FROM AUTHOR]