Sustained response to long-term biologics and switching in psoriatic arthritis: results from real life experience.

OBJECTIVE: To investigate the response to biologic drugs in psoriatic arthritis and to quantify non-response and outcome from switching agents. METHODS: 60 patients (33 men and 27 women, mean age 46 years, median disease duration 16 years) prescribed biologic drugs for psoriatic arthritis between 2001 and 2006 were studied. Response was evaluated using joint counts, C-reactive protein levels and disease activity scores (using 28 joints; DAS28). RESULTS: The mean percentage improvements seen were 56% in tender joint count, 70% in swollen joint count, 64% in C-reactive protein level and 36% in the overall disease activity score. Improvements were sustained beyond 24 months with no loss of effect. Side-effects leading to cessation or switching of first-line therapy were only seen in 5% of patients and non-response occurred in 20% long term. Overall, 90% of patients achieved a significant response, using switching in 20% of cases. Outcomes were similar regardless of drug used, duration of disease and subtype of arthritis. CONCLUSIONS: Treatment of active psoriatic arthritis with anti-tumour necrosis factor agents leads to a sustained response over 3 years with most patients tolerating these drugs well. The rate of non-response is low with the majority of patients responding to second- and third-line therapies.

Real life experience confirms sustained response to long-term biologics and switching in ankylosing spondylitis.

OBJECTIVE: To investigate the long-term response to biological therapies in AS in a real life clinical setting and to quantify non-response and response to 'switching' therapies in these cases. METHODS: All patients prescribed TNF-blocking therapies for AS between 1999 and 2006 were studied. Response was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and CRP results. RESULTS: A total of 113 patients (84 males: 29 females, mean age 45 yrs, median disease duration 16 yrs, 87% HLA-B27 positive) were identified. At baseline they had a mean BASDAI of 6.57, BASFI 6.57 and CRP of 31 g/dl. At the end of follow-up, these values had reduced to mean BASDAI of 3.12, BASFI 4.16 and CRP of 7 g/dl. Improvements were sustained for 24 months and beyond with no loss of effect. Only nine patients (8%) suffered side-effects leading to cessation or switching of first-line therapy and non-response occurred in 15 patients (13%) in the long term. Fifteen patients (13%) switched to a second drug and 14 of these (93%) had a significant and sustained response. Outcomes were similar regardless of drug used, duration of disease and HLA-B27 status. CONCLUSION: Treatment of active AS with TNF blockers according to the British Society of Rheumatology guidelines leads to a sustained response for over 2 yrs with most patients tolerating the drugs well. The rate of non-response is significantly lower than that seen in RA and nearly all of these patients respond well to a second-line agent.

The suppression of Antarctic bottom water formation by melting ice shelves in Prydz Bay.

A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. Here we show new observations from CTD-instrumented elephant seals in 2011-2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf water (salinity 34.65-34.7) is exported through Prydz Channel. This provides a distinct, relatively fresh contribution to Cape Darnley bottom water. Elsewhere, dense water formation is hindered by the freshwater input from the Amery and West Ice Shelves into the Prydz Bay Gyre. This study highlights the susceptibility of Antarctic bottom water to increased freshwater input from the enhanced melting of ice shelves, and ultimately the potential collapse of Antarctic bottom water formation in a warming climate.

Clinical valproate toxicity induced by acetylsalicylic acid.

We report three patients with serious clinical valproate (VPA) toxicity induced by interaction with acetylsalicylic acid (ASA). Two patients had a documented rise in VPA free level, and the third showed only clinical signs of toxicity. Symptoms resolved in all three when the ASA was stopped. This interaction has been previously documented under experimental conditions, and is due to displacement of VPA from plasma protein binding sites and a probable interference in metabolism. This is the first report of the clinical significance of this interaction.

New drugs for the treatment of epilepsy.

OBJECTIVES: This article will review current data on the metabolism, interactions, methods of analysis, and adverse effects observed with the use of new anticonvulsant drugs. The role of the laboratory in the provision of therapeutic drug monitoring for these drugs is discussed. CONCLUSION: Certain of the newer anticonvulsant drugs require therapeutic drug monitoring for their optimal use in the treatment of epileptic seizures. The requirement for therapeutic drug monitoring has not been established for some of these drugs. Many of the newer anticonvulsant drugs, including lamotrigine, felbamate, vigabatrin, and zonisamide, interact clinically with established drugs, such as phenytoin, phenobarbital, carbamazepine, and valproic acid. Introduction of these new drugs will result in the need for more frequent monitoring of the established drugs during polytherapy. The need for a drug-monitoring service for anticonvulsant drugs overall will continue, due to the frequency of drug interactions, the incidence of adverse effects, and concerns about compliance with the dosing regimen in these patients.

Clinical toxicology of drugs used in the treatment of opiate dependency.

Many aspects of the pharmacokinetics of methadone have been evaluated since 1970. Analytic techniques used to monitor urine and serum or plasma concentrations of methadone and its metabolites have improved with advances in chromatography and development of immunoassay techniques. On reviewing the literature on methadone since 1970, however, there were several recurring limitations of the experimental design in a large number of the studies reported. These include: 1. No appreciation for the effect of urinary pH on excretion of methadone 2. Small number of patients enrolled with inadequate control subjects 3. The effect of smoking cigarettes was not evaluated or adequately controlled 4. Urine collections were often obtained without supervision and correcting results to creatinine excretion 5. Blood specimens were generally not collected from 0-15 minutes after intravenous dosing 6. Incomplete excretion data (nonhydrolysis of glucuronide conjugates) in the urine 7. Most studies did not evaluate protein binding of methadone when attempting to correlate therapeutic control or failure with serum concentrations of methadone. In general, the literature supporting the use of naltrexone was more favorable than for methadone, buprenorphine, LAAM, and clonidine. The major limitation on the use of naltrexone, however, is the lack of incentive for the patient to keep taking the medication. If the use of naltrexone, LAAM, buprenorphine, or clonidine becomes widely available, robust analytic techniques must be developed for monitoring of these drugs, their metabolites, or both in the urine to verify patient compliance.

Urine drug testing for social service agencies. A Canadian experience.

The introduction of urine drug testing for this program has been considered a success by the social services agencies in Nova Scotia for the following reasons: 1. The results of urine drug testing have been accepted by the Family Courts of Nova Scotia because the urine collection and testing are performed with chain of custody procedures from collection to reporting and the analysis includes confirmation of all positive immunoassay screening tests. 2. Urine drug testing (with established screening and confirmation cut-offs) provides an objective indication of recent drug use compared with relying on self-reporting of drug use. 3. Urine drug testing is believed to be a deterrent to drug use because several individuals with a history of drug use have consistently tested negative for 6 to 12 months (30% of the clients). 4. Some clients with a history of substance abuse are successful in becoming drug free with the support of the social workers and the deterrent effect of random drug testing.

Modes of inhibition of foodborne non-Salmonella bacteria by selenite cystine selective broth.

Various cell densities of six common foodborne non-Salmonella bacteria were exposed to selenite cystine (SC) Salmonella selective medium. The insensitivity of Pseudomonas aeruginosa and Proteus vulgaris to SC was confirmed. Selenite cystine selective medium was effective against the sensitive bacteria up to certain cell densities, beyond which the bacteria survived. As judged from the minimum cell number required for survival in SC, Staphylococcus aureus was the most sensitive to SC, followed by Bacillus cereus, Escherichia coli and Citrobacter freundii. When sensitive bacteria were grown in SC, they enriched resistant variants which exhibited no or reduced sensitivity to SC. The change in density of sensitive cells after exposure to SC suggested that bacterial sensitivity to SC depended on the efficiency of killing and growth inhibition by SC as well as the fraction of resistant variants in the bacterial population. Since Salmonella samples generally contain unknown numbers and types of sensitive bacteria, it is difficult to predict the effectiveness of their selective inhibition by SC.

Evaluation of the toxicity of Salmonella selective media for shortening the enrichment period.

Five Salmonella serotypes recovering from heat injury exhibited different kinetics of resuscitation and growth. Exponential growth was reached before full resuscitation. Fully resuscitated cells and uninjured cells at low cell densities exhibited sensitivity when transferred from non-selective media to selective media, Rappaport-Vassiliadis (RV) and tetrathionate-brilliant green (TBG). The minimum number of cells required to survive in RV and TBG was determined and ranged from 10(2) to 10(5) CFU depending on the serotype. Salmonella grown in RV produced cell populations which exhibited no sensitivity when transferred to fresh RV even at low cell densities. Thus, toxic selective media enriched a resistant population. Selenite cystine exhibited no toxicity to resuscitated or uninjured Salmonella. The significance of these findings was discussed for the purpose of shortening the Salmonella enrichment period.

Simple extraction of Campylobacter lipopolysaccharide and protein antigens and production of their antibodies in egg yolk.

Antigens were heat extracted from Campylobacter jejuni (LI04) and C. coli (LI020) in the presence of ethylenediaminetetraacetate (EDTA) and were recovered in the supernatant of a low-speed centrifugation. The method is simpler, safer and more efficient in extracting lipopolysaccharide (LPS) antigens than the hot phenol method. The extracted antigens (LPS plus several proteins) elicited production of antigen-specific antibodies in the egg yolk of immunized hens. Antibodies purified by polyethyleneglycol fractionation were used to detect antigens fractionated on SDS polyacrylamide gel electrophoresis.

Rapid detection and enumeration of Salmonella in chicken carcass rinses using filtration, enrichment and colony blot immunoassay.

A strategy was developed for 24-h detection and enumeration of Salmonella spp. on processed chicken carcasses. Carcasses were rinsed with saline and the rinses spiked with known numbers of serogroup B, C, D or E Salmonella. The total rinse volume was passed through two filter units of decreasing pore size. These removed most of the extraneous material while permitting rapid passage of more than 77% of the Salmonella. At least 100 ml of the filtrate was passed through a third filter unit containing a nitrocellulose capture membrane. Captured bacteria were selectively enriched by incubating the nitrocellulose membrane on filter pads soaked in Rappaport-Vassiliadis broth and then on pads soaked in brilliant green broth containing sulfadiazine and novobiocin. A colony blot immunoassay using two anti-Salmonella monoclonal antibodies was used to identify and enumerate the captured Salmonella. As few as five Salmonella colony forming units per carcass rinse could be detected. An evaluation of this system with 24 field samples indicated that the specificity was comparable to and the sensitivity higher than that of standard culture procedures.

Simple and economical culture of Campylobacter jejuni and Campylobacter coli in CO2 in moist air.

Strains of Campylobacter jejuni and C. coli representing the 18 serogroups (Lior) most commonly isolated from humans in Canada were grown on solid media in an atmosphere of 10% CO2 in moist air, 99% relative humidity. When the growth of all 18 serogroups on Mueller Hinton agar in a microaerobic atmosphere (5% O2, 10% CO2 and 85% N2) was compared with the growth of all 18 serogroups on the same media in 10% CO2 in moist air, colony sizes were significantly larger (p less than 0.05) for strains grown in 10% CO2 in moist air. No significant difference in colony numbers was seen between the two atmospheres. The addition of blood to the media significantly enhanced the growth of the campylobacters in both types of atmospheres (p less than 0.05). This simple CO2 atmosphere permitted the use of a common CO2 incubator thereby reducing the cost and difficulty of culturing these organisms.

Molecular discrimination of Campylobacter coli serogroup 20 biotype I (Lior) strains.

Plasmid, protein and restriction endonuclease analysis (REA) profiles and multilocus enzyme electrophoresis were used to effect a molecular discrimination of twenty-seven Campylobacter coli serogroup 20, biotype 1 (Lior) strains. These strains were not outbreak-associated but were isolated from a number of different countries and different animal and environmental sources. Each of the techniques was able to discriminate, to various degrees, between the serogroup 20, biotype 1 strains. The choice of a particular technique depends to a large extent on the level of discrimination desired, the previous experiences of the investigator and on the laboratory facilities at hand. REA profiles demonstrated the greatest degree of discrimination between these strains. Plasmid and protein profiles could discriminate reasonably well. Multilocus enzyme electrophoresis (allozyme typing) and protein profiles may prove effective in subgrouping serogroup 20, biotype 1 strains.

The use of antiepileptic drug levels in children: a survey of Canadian pediatric neurologists.

There are 60 pediatric neurologists in Canada. Replies were received from 56 in response to a survey regarding the use and perceived value of antiepileptic drug (AED) levels. AED levels are frequently ordered and influence clinical care. There were, however, discrepancies among pediatric neurologists regarding the upper and lower limits of the "therapeutic ranges" and the clinical application of levels. We suggest that both the value and use of AED levels needs further study.

Changes in serum anticonvulsant levels with febrile illness in children with epilepsy.

Changes in anticonvulsant serum levels during intercurrent illness may cause toxicity or decreased seizure control in children with epilepsy. We studied prospectively the effect of intercurrent illness and its treatment in 111 children being treated with AC monotherapy. Free fraction and total serum AC levels were determined when the child was well, on the fifth day of any illness with fever and one month after recovery. There were 55 episodes of febrile illness in 39 children during the study period. Twelve illnesses were associated with significant increases or decreases in serum AC levels; 7 children became clinically toxic; 1 child had increased seizures during illness. The mechanisms of AC level changes appeared to include interaction with antibiotics, with antipyretics or with viral illness. Amoxycillin and acetaminophen did not appear to interact with the AC's used. Physicians caring for children with epilepsy should be aware of the frequency and complexity of potential interactions between intercurrent febrile illness and anticonvulsant medication.

Once-daily ethosuximide in the treatment of absence epilepsy.

Once-daily ethosuximide was used to treat 10 consecutive children with typical absence seizures. Three patients had gastrointestinal side effects which resolved when the same total daily dose was divided into 2 doses. Two other patients continued to have seizures on ethosuximide, whether given once or twice daily. Five patients had complete seizure control without adverse effects on once-daily ethosuximide.

A 6-year experience with urine drug testing by family service agencies in Nova Scotia, Canada.

The objective of this study is to describe a urine drug-testing program implemented for parents with a history of substance abuse by family service agencies in the province of Nova Scotia, Canada. Nurse collectors went to the parents' home to obtain urine specimens under direct observation and then delivered the specimens to the toxicology laboratory or arranged shipment by courier under chain of custody. Each urine specimen was screened for cannabinoids, cocaine metabolite, opiates, amphetamines and benzodiazepines, ethyl alcohol and creatinine. All positive screening tests were confirmed by another method such as gas chromatography-mass spectrometry (GC-MS). In 15,979 urine specimens collected from 1994 to 1999, the percent positive rate for one (or more) drugs/metabolites ranged from 45.6% (1994-1996) to 30.0% (1998, 1999). A total of 575 specimens (3.7%) were dilute (urine creatinine <25mg/dl). Positive rates in 15,404 non-dilute specimens from 1994 to 1999 were as follows: cannabinoids - 11.7%, benzodiazepines - 11.3%, cocaine metabolite - 3.7%, and ethyl alcohol - 2.6%. Most clients provided less than 20 urine specimens for testing but some individuals submitted urine specimens more than 100 times in a 12-15-month period. Urine drug screening in parents with a history of substance abuse provided an objective and reliable indication of recent drug use in this population.

Experience with urine drug testing by the Correctional Service of Canada.

The Correctional Service of Canada implemented a urine drug-screening program over 10 years ago. The objective of this report is to describe the program and drug test results in this program for 1999. Offenders in Canadian federal correctional institutions and those living in the community on conditional release were subject to urine drug testing. Urine specimens were collected at correctional facilities and shipped by courier to MAXXAM Analytics Inc. laboratory. All urine specimens were analyzed for amphetamines, cannabinoids, cocaine metabolite (benzoylecgonine), opiates, phencyclidine, benzodiazepines, methyl phenidate, meperidine, pentazocine and fluoxetine by immunoassay screening (homogeneous EIA and ELISA assays) followed by GC-MS confirmation. Ethyl alcohol was analyzed when specifically requested. Alternative screening and confirmation methods with lower cut-off values were used, whenever urine specimens were dilute (creatinine <20mg/dl and specific gravity

Urinary screening for alprazolam, triazolam, and their metabolites with the EMIT d.a.u. benzodiazepine metabolite assay.

Alprazolam (Xanax) and triazolam (Halcion) are relatively new triazolobenzodiazepines that are anxiolytic and hypnotic. This study assesses the reactivity of these drugs and their major metabolites in the EMIT d.a.u. benzodiazepine metabolite assay. Analytical standards of drugs and metabolites and urine specimens from patients receiving these drugs were analyzed by EMIT. Alprazolam and alpha-OH alprazolam gave an equivalent response to the EMIT low calibrator between 0.2 and 0.3 microgram/mL. Triazolam and alpha-OH triazolam were reactive between 0.3 and 0.5 microgram/mL. The assay was positive in 24 out of 27 random urine specimens from alprazolam-treated patients and in 8 out of 19 urine specimens from triazolam-treated patients. Positive urine results were confirmed by measuring the major urinary metabolites alpha-OH alprazolam and alpha-OH triazolam by HPLC. The study demonstrates that the EMIT assay can detect significant amounts of alprazolam and metabolites in the urine. The assay was negative in 58% of the specimens from individuals receiving triazolam, however.

Evaluation of the Abbott ADx and TDx serum benzodiazepine immunoassays for analysis of alprazolam.

This study evaluated the Abbott ADx and TDx serum benzodiazepine assays for the analysis of alprazolam in serum. These systems were compared to the EMIT tox serum benzodiazepine assay and a gas chromatographic (GC) method. Six-point calibration curves (nordiazepam concentrations from 50-1,000 ng/mL) were stable on both instruments for at least 14 days. The precision of these assays was determined using three control serums containing 75,300, and 700 ng/mL of nordiazepam. On the ADx, within-run coefficients of variation (CV) for the three controls were 3.9, 3.1, and 2.8%, respectively. Between-run CVs were 2.8, 1.4, and 1.2% on the ADx. For the TDx, within-run CVs were 1.9, 1.4, and 2.6, and between-run CVs were 4.1, 1.3, and 1.9% for the three controls. Percent cross-reactivity of serum alprazolam calibrators (25-100 ng/mL) ranged from 77-88% on the ADx and 60-79% on the TDx. 99 serum specimens containing alprazolam were analyzed with the ADx, TDx, EMIT, and by gas chromatography-electron capture detection (sensitivity of 5 ng/mL). Overall, 48 of 99 specimens on the TDx, 43 of 99 on the ADx (both with a cutoff of 12 ng/mL), and 0 of 99 by EMIT (cutoff of 300 ng/mL) were positive. Of the specimens reading negative on the Abbott systems, 43 of 51 TDx results and 44 of 56 ADx results were obtained in specimens containing less than 25 ng/mL of alprazolam. For specimens with more than 25 ng/mL of alprazolam in serum (by GC), 8 specimens were negative on the TDx and 12 on the ADx.