New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

Monthly bulletin ... Municipal health dept.

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A la Comisión Regia que entiende en el arreglo de las tres facultades de curar /

Incluye: Proyecto de ordenanzas generales para gobierno y regimen en el ejercicio de la Facultad de Farmacia.

Prolonged Duration of Sciatic Nerve Blockade in the Elderly after Foot and Ankle Surgery

1.1 Background and Objectives: Perioperative morbidity related to anesthesia renders elderly patients vulnerable because age related factors affect medication effects, clearance and metabolism. Regional anesthesia within a multimodal regimen reduces opioid adverse effects in the elderly and improves immediate analgesia but not long term recovery and prolonged nerve blockade has been reported. The purpose of this study was to assess analgesic effects of sciatic nerve blockade in the elderly. 1.2 Methods: Postoperative sciatic nerve blockade was administered for foot and ankle surgery to patients over age 18 years. Preoperative, post-anesthesia unit and 24 hour postoperative pain scores and opioid doses for these same intervals were recorded. 1.3 Results: 47 patients enrolled and 12 (25.5%) were over age 70. Preoperative, immediate and 24 post-operative pain scores and total intraoperative and immediate postoperative opioid doses were lower in the elderly. The total 24 hour postoperative opioid doses in the elderly were lower compared to the younger group. 1.4 Conclusions: Total 24 hour postoperative cumulative opioid doses after sciatic nerve blockade in patients over 70 are lower than in younger patients. Further observations in greater numbers of patients and improved ultrasound to assess sciatic nerve structure in the elderly are warranted to study this effect.

Periextubation caffeine in preterm neonates: A randomized dose response trial

Objective: To compare the effectiveness of three dosing regimens of caffeine for preterm infants in the periextubation period. Methods: A randomized double-blind clinical trial of three dosing regimens of caffeine citrate ( 3, 15 and 30 mg/kg) for periextubation management of ventilated preterm infants was undertaken. Infants born < 32 weeks gestation who were ventilated for > 48 h were eligible for the study. Caffeine citrate was given as a once daily dose for a period of 6 days commencing 24 h prior to a planned extubation, or within 6 h of an unplanned extubation. The primary outcome measure was extubation failure, defined as neonates who were unable to be extubated within 48 h of caffeine loading or who required reventilation or doxapram dose within 7 days of caffeine loading. Continuous recordings of oxygen saturation and heart rate were undertaken in a subgroup of enrolled infants. Results: A total of 127 babies were enrolled into the study ( 42, 40, 45, in the 3, 15, and 30 mg/kg groups, respectively). No statistically significant difference was demonstrated in the incidence of extubation failure between dosing groups ( 19, 10, and 11 infants in the 3, 15, and 30 mg/kg groups, respectively), however, infants in the two higher dose groups had statistically significantly less documented apnoea than the lowest dose group. Of the 37 neonates with continuous pulse oximetry recordings, those on higher doses of caffeine recorded a statistically significantly higher mean heart rate, oxygen saturations and less time with oxygen saturations < 85%. Conclusions: This trial indicated there were short-term benefits of decreased apnoea in the immediate periextubation period for ventilated infants born < 32 weeks gestation receiving higher doses of caffeine. Further studies with larger numbers of infants assessing longer-term outcomes are necessary to determine the optimal dosing regimen of caffeine in preterm infants.

Plasma concentrations of tafenoquine, a new long-acting antimalarial agent, in Thai soldiers receiving monthly prophylaxis

We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai- Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine ( 400 mg daily for 3 days), followed by tafenoquine monthly ( 400 mg every 4 weeks) for 5 months. Consecutive monthly mean ( +/- standard deviation) trough plasma tafenoquine concentrations were 223 +/- 41, 127 +/- 29, 157 +/- 51. 120 +/- 24, and 88 +/- ng/ mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/ mL, which was similar to 3- fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.

Single-subject research designs and data analyses for assessing elite athletes' conditioning

Research in conditioning (all the processes of preparation for competition) has used group research designs, where multiple athletes are observed at one or more points in time. However, empirical reports of large inter-individual differences in response to conditioning regimens suggest that applied conditioning research would greatly benefit from single-subject research designs. Single-subject research designs allow us to find out the extent to which a specific conditioning regimen works for a specific athlete, as opposed to the average athlete, who is the focal point of group research designs. The aim of the following review is to outline the strategies and procedures of single-subject research as they pertain to.. the assessment of conditioning for individual athletes. The four main experimental designs in single-subject research are: the AB design, reversal (withdrawal) designs and their extensions, multiple baseline designs and alternating treatment designs. Visual and statistical analyses commonly used to analyse single-subject data, and advantages and limitations are discussed. Modelling of multivariate single-subject data using techniques such as dynamic factor analysis and structural equation modelling may identify individualised models of conditioning leading to better prediction of performance. Despite problems associated with data analyses in single-subject research (e.g. serial dependency), sports scientists should use single-subject research designs in applied conditioning research to understand how well an intervention (e.g. a training method) works and to predict performance for a particular athlete.

Feeding strategies for grain-fed cattle in a hot environment

Six Bos taurus (Hereford) steers (body weight 324 22 kg) were used in a 45-day study with a replicated 3 x 3 Latin-square design. Three treatments [ad libitum feeding (ADLIB); limit feeding, 85% of ad libitum (LIMIT); bunk management feeding where steers were only given access to feed from 1600 to 0800 hours the following day (BUNK)] were imposed over 3 periods, with 2 steers assigned to each treatment in each period. Cattle were managed in a temperature-controlled metabolism unit and were exposed to both thermoneutral (17.7degreesC-26.1degreesC) and hot (16.7degreesC-32.9degreesC) environmental conditions. By design, during the thermoneutral period, the ADLIB cattle displayed greater intake (P < 0.05) than the LIMIT group, with the BUNK group being intermediate. However, during the hot period, both the LIMIT and BUNK treatment groups increased feed intake 4-5%, whereas feed intake of the ADLIB treatment group declined nearly 2%. During both periods respiration rate (RR, breath/min) followed the same pattern that was observed for feed intake, with the greatest (P < 0.05) RR found in the ADLIB treatment group (81.09 and 109.55, thermoneutral and hot, respectively) and lowest (P < 0.05) RR in the LIMIT treatment group (74.47 and 102.76, thermoneutral and hot, respectively). Rectal temperature (RT) did not differ among treatments during the thermoneutral period or the first hot day, although during the thermoneutral period the ADLIB treatment group did tend to display a lower RT, possibly as a result of other physiological processes (pulse rate and RR) aiding to keep RT lower. During the hot period, differences in RT were found on Day 5, with the LIMIT cattle having lower (P < 0.10) RT (38.92degreesC) than the ADLIB (39.18degreesC) cattle, with BUNK cattle RT (39.14degreesC) being intermediate. However, when hourly data were examined, the ADLIB cattle had greater(P < 0.05) RT than the BUNK and LIMIT at 1800 hours and greater RT (P < 0.05) than the LIMIT group at 1400, 1500, and 1600 hours. Clearly, a change in diurnal RT pattern was obtained by using the LIMIT and BUNK feeding regimen. Both of these groups displayed a peak RT during the hot conditions, between 2100 and 2200 hours, whereas the ADLIB group displayed a peak RT between 1400 and 1500 hours, a time very close to when peak climatic stress occurs. Based on these results it is apparent that feedlot managers could alleviate the effects of adverse hot weather on cattle by utilising either a limit-feeding regimen or altering bunk management practices to prevent feed from being consumed several hours prior to the hottest portion of the day.

Wetting and the physiological responses of grain-fed cattle in a heated environment

A controlled crossover experimental design was used to determine the effect of altered water sprinkling duration on heifers subjected to heat stress conditions. Heifers were subjected to 3 days of thermoneutral conditions followed by 3 days of hot conditions accompanied by water sprinkling between 1300 and 1500 h (HOT1-3). Then on the following 2 days (HOT4-5), environmental conditions remained similar, but 3 heifers were sprinkled between 1200 and 1600 h ( WET) and 3 were not sprinkled (NONWET). This was followed by a 1-day period (HOT6) in which environmental conditions and sprinkling regimen were similar to HOT1-3. Rectal temperature (RT) was collected hourly, and respiration rate (RR) was monitored every 2 h on HOT Days 2, 4, 5, and 6. Dry matter intake and rate of eating were also determined. Sprinkling reduced RR and RT (P < 0.01) of all heifers during HOT1-3. During HOT4-5, WET heifers had lower (P < 0.05) RT than NONWET from 1300 to 700 h and lower RR from 1400 to 2000 h. Dry matter intake of NONWET heifers was reduced by 30.6% (P < 0.05) during HOT4-5 and by 51.2% on HOT6. On HOT4-5 the dry matter intakes of WET heifers were similar to intakes under thermoneutral conditions. During HOT6, RT was again reduced following sprinkling in all heifers. Comparison of RT and RR of NONWET and WET heifers on HOT1-3 v. HOT6 revealed that under similar environmental conditions, NONWET heifers had increased RT, partially due to carry-over from HOT4-5. However, NONWET heifers had 40% lower feed intake but tended to have lower RR on HOT6 v. HOT1-3. Only RR of WET heifers was greater on HOT6, possibly a result of switching from a 4-h back to a 2-h sprinkling period, while maintaining a 62% greater intake (5.80 v. 3.58 kg/day) than NONWET heifers during this time. Results suggest that inconsistent cooling regimens may increase the susceptibility of cattle to heat stress and elicit different physiological and metabolic responses.

Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: A report from the EBMT and ABMTR

Objective. Since 1996, autologous hemopoietic stem cell transplantation (HSCT) has been used to treat severe rheumatoid arthritis (RA). To date, published reports have been individual cases or series containing small numbers. This study combined the worldwide experience in a single analysis. Methods. The Autoimmune Disease Databases of the European Group for Blood and Marrow Transplantation (EBMT) and the Autologous Blood and Marrow Transplant Registry (ABMTR) were used to identify patients with RA treated with autologous HSCT. Further information relating to patient and treatment-specific variables was obtained by questionnaire. Results. Seventy-six patients were registered from 15 centers. Seventy-three patients had received autologous HSCT, and in 3 patients hematopoietic stem cells (HSC) were mobilized but not transplanted. Transplanted patients (median age 42 yrs, 74% female, 86% rheumatoid factor positive) had been previously treated with a mean of 5 (range 2-9) disease modifying antirheumatic drugs (DMARD). Significant functional impairment was present, with a median Health Assessment Questionnaire (HAQ) score of 1.4 (range 1.1-2.0) and Steinbrocker score mean 2.39 (SD 0.58). The high dose treatment regimen was cyclophosphamide (CYC) alone in the majority of patients, mostly 200 mg/kg (n = 62). Seven patients received anti-thymocyte globulin (ATG) in addition to CYC, 2 patients busulfan and CYC (BuCYC), and one patient CYC with total body irradiation and ATG. One patient received fludarabine with ATG. Following treatment, one patient received bone marrow but the rest received chemotherapy and/or granulocyte colony-stimulating factor mobilized peripheral blood stem cells. The harvest was unmanipulated in 28 patients, the rest receiving some form of lymphocyte depletion, mostly through CD34+ selection. Median followup was 16 months (range 3-55). Responses were measured using the American College of Rheumatology (ACR) criteria. Forty-nine patients (67%) achieved at least ACR 50% response at some point following transplant. There was a significant reduction in the level of disability measured by the HAQ (p < 0.005). Most patients restarted DMARD within 6 months for persistent or recurrent disease activity, which provided disease control in about half the cases. Response was significantly related to seronegative RA (p = 0.02) but not to duration of disease, number of previous DMARD, presence of HLA-DR4, or removal of lymphocytes from the graft. There was no direct transplant related mortality, although one patient, treated with the BuCYC regimen, died 5 months post-transplant from infection and incidental non-small cell lung cancer. Conclusion. Autologous HSCT is a relatively safe form of salvage treatment in severe, resistant RA. In these open label studies significant responses were achieved in most patients, with over 50% achieving an ACR 50 or more response at 12 months. Although the procedure is not curative, recurrent or persistent disease activity may be subsequently controlled in some patients with DMARD. Clinical trials are necessary to develop this approach inpatients with aggressive disease who have failed conventional treatment including anti-tumor necrosis factor agents.

Promising results of a cooperative group phase II trial of preoperative chemoradiation for locally advanced rectal cancer (TROG 9801)

PURPOSE: This article reports the overall survival, failure-free survival, local failure, and late radiation toxicity of a phase II trial of preoperative radiotherapy with continuous infusion 5-fluorouracil for rectal cancer after a minimum 3.5 years of follow-up. METHODS: Eligible patients were those with newly diagnosed localized adenocarcinoma of the rectum, within 12 cm of the anal verge, staged T3-T4 and deemed suitable for curative resection. Radiotherapy (50.4 Gy in 28 fractions in five weeks and three days) was given with continuous infusion 5-fluorouracil throughout the course of radiotherapy. RESULTS: A total of 82 patients were accrued in 13 months. The median follow-up time was 4.1 (range, 2.3-4.5) years. There were 55 males (67 percent) and the median age was 59 (range, 27-87) years. Patients were staged pretreatment as T3 (89 percent) and resectable T4 (11 percent). Endorectal ultrasound was performed in 70 percent and magnetic resonance imaging in another 5 percent. The four-year overall and failure-free survival rates were 82 percent (95 percent Cl: 72-89) and 69 percent (95 percent Cl: 58-78), respectively. The cumulative incidence of local failure at four years was 3.9 percent (95 percent CI: 1.3-11). Risk of failures, local and distant, has not reached a plateau phase. CONCLUSION: This regimen can be delivered safely and without leading to a significant increase in late toxicity. It provides excellent local control and favorable overall survival. There is a need for longer follow-up than has commonly been used for the proper evaluation of failures after an effective regimen of preoperative chemoradiation.

Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial

Background Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer. Methods 128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m(2) cisplatin on day 1, 800 mg/m(2) fluorouracil on days 1-4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat. Findings Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0.82 [95% CI 0.61-1.101 and 0.89 [0.67-1.19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0.0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0.003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0.47 [0.25-0.86] vs 1.02 [0.72-1.44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup. Interpretation Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamouscell tumours.

Echinacea alkamide disposition and pharmacokinetics in humans after tablet ingestion

Echinacea is a widely used herbal remedy for the treatment of colds and other infections. However, almost nothing is known about the disposition and pharmacokinetics of any of its components, particularly the alkamides and caffeic acid conjugates which are thought to be the active phytochemicals. In this investigation, we have examined serial plasma samples from 9 healthy volunteers who ingested echinacea tablets manufactured from ethanolic liquid extracts of Echinacea angustifolia and Echinacea purpurea immediately after a standard high fat breakfast. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkamides were rapidly absorbed and were measurable in plasma 20 min after tablet ingestion and remained detectable for up to 12 h. Concentration-time curves for 2,4-diene and 2-ene alkamides were determined. The maximal concentrations for the sum of alkamides in human plasma were reached within 2.3 h post ingestion and averaged 336 +/- 131 ng eq/mL plasma. No obvious differences were observed in the pharmacokinetics of individual or total alkamides in 2 additional fasted subjects who took the same dose of the echinacea preparation. This single dose study provides evidence that alkamides are orally available and that their pharmacokinetics are in agreement with the one dose three times daily regimen already recommended for echinacea.

Bioavailability of Echinacea Constituents: Caco-2 Monolayers and Pharmacokinetics of the Alkylamides and Caffeic Acid Conjugates

Many studies have been done over the years to assess the effectiveness of Echinacea as an immunomodulator. We have assessed the potential bioavailability of alkylamides and caffeic acid conjugates using Caco-2 monolayers and compared it to their actual bioavailability in a Phase I clinical trial. The caffeic acid conjugates permeated poorly through the Caco-2 monolayers. Alkylamides were found to diffuse rapidly through Caco-2 monolayers. Differences in diffusion rates for each alkylamide correlated to structural variations, with saturation and N-terminal methylation contributing to decreases in diffusion rates. Alkylamide diffusion is not affected by the presence of other constituents and the results for a synthetic alkylamide were in line with those for alkylamides found in an ethanolic Echinacea preparation. We examined plasma from healthy volunteers for 12 hours after ingestion of Echinacea tablets manufactured from an ethanolic liquid extract. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkylamides were detected in plasma 20 minutes after tablet ingestion and for each alkylamide, pharmacokinetic profiles were devised. The data are consistent with the dosing regimen of one tablet three times daily and supports their usage as the primary markers for quality Echinacea preparations.

Polymorphisms in glutathione S-transferases and non-melanoma skin cancer risk in Australian renal transplant recipients

Caucasian renal transplant recipients from Queensland, Australia have the highest non-melanoma skin cancer (NMSC) risk worldwide. Although ultraviolet light (UVR) exposure is critical, genetic factors also appear important. We and others have shown that polymorphism in the glutathione S-transferases (GST) is associated with NMSC in UK recipients. However, the effect of high UVR exposure and differences in immunosuppressive regimen on these associations is unknown. In this study, we examined allelism in GSTM1, GSTM3, GSTT1 and GSTP1 in 361 Queensland renal transplant recipients. Data on squamous (SCC) and basal cell carcinoma (BCC), UVR/tobacco exposure and genotype were obtained. Associations with both NMSC risk and numbers were examined using logistic and negative binomial regression, respectively. In the total group, GSTM1 AB [P = 0.049, rate ratio (RR) = 0.23] and GSTM3 AA (P = 0.015, RR = 0.50) were associated with fewer SCC. Recipients were then stratified by prednisolone dose (less than or equal to7 versus >7 mg/day). In the low-dose group, GSTT1 null (P = 0.006, RR = 0.20) and GSTP1 Val/Val (P = 0.021, RR = 0.20) were associated with SCC numbers. In contrast, in the high-dose group, GSTM1 AB (P = 0.009, RR = 0.05), GSTM3 AB (P = 0.042, RR = 2.29) and BB (P = 0.014, RR = 5.31) and GSTP1 Val/Val (P = 0.036, RR = 2.98) were associated with SCC numbers. GSTM1 AB (P = 0.016) and GSTP1 Val/Val (P = 0.046) were also associated with fewer BCC in this group. GSTP1 associations were strongest in recipients with lower UVR/tobacco exposure. The data confirm our UK findings, suggesting that protection against UVR-induced oxidative stress is important in NMSC development in recipients, but that this effect depends on the immunosuppressant regimen.