A phase I/IIa study with succinylated human serum albumin (Suc-HSA), a candidate HIV-1 fusion inhibitor

BACKGROUND: Succinylated human serum albumin (Suc-HAS) is a negatively charged neo-glycoprotein that binds to the positively charged V3-loop of HIV-1 gp120, acting as HIV-1-fusion inhibitor in vitro (IC50: 0.5-5.0 microg/ml). Suc-HSA was safe in rats and monkeys, and showed antiretroviral effect in a human-to-mouse model. We evaluated safety and pharmacokinetics of single and multiple doses of Suc-HSA in HIV-1-infected individuals. METHODS: First, six untreated, chronically HIV-1-infected patients were randomized to a single dose of 1 or 10 mg/kg Suc-HSA intravenously. Second, five consecutive daily doses (10 mg/kg, based on the results of the single dose study) were given to four patients. Safety laboratory assessments, Suc-HSA plasma levels, plasma HIV-1 RNA (pVL), and CD4+ T-cell counts were determined. RESULTS: Increase of liver transaminases (grade 1/2) occurred in one of six patients in the single-dose phase and in three of four patients in the multiple-dosing phase. Suc-HSA plasma levels were undetectable 4 h after a single dose of 1 mg/kg. After a dose of 10 mg/kg, plasma levels were more sustained, but declined under the target plasma concentration (10 microg/ml) 12-24 h post-dosing. After multiple dosing, plasma levels reached peak values 2h post-dosing as predicted by our kinetic model. However, trough levels were below the target concentrations. There was no change in pVL or CD4+ T-cell count in either the single- or multiple-dosing phase. CONCLUSIONS: At the chosen dosing regimens, adequate antiviral plasma levels were not maintained, probably because the hepatic clearance was more rapid than expected. This may partially explain the lack of effect on pVL and CD4+ T-cell count. The observed liver transaminase increases prohibit further dose escalation.     

Use of platelet rich plasma to treat plantar fasciitis: design of a multi centre randomized controlled trial

Background

If conservative treatment for chronic plantar fasciitis fails, often a corticosteroid injection is given. Corticosteroid injection gives temporarily pain reduction, but no healing. Blood platelets initiate the natural healing rate. GPS^® gives an eightfold concentrate platelets of patients own blood. Injection of these platelets in the attachment of the fascia to the os calcis might induce a healing rate.

Methods and design

A randomized controlled multi centre trial will be performed. The study population consists of 120 patients of 18 years and older. Patients with chronic plantar fasciitis will be allocated randomly to have a steroid injection or an autologous platelet concentrate injections. Data will be collected before the procedure, 4,8,12,26 weeks and 1 year after the procedure.The main outcome measures of this study are pain and function measured with questionnaires.

Conclusion

Recent literature show positive effects for the treatment of tendinosis with autologous platelet injections. The forthcoming trial will compare treatment for chronic plantar fasciitis with a steroid injection versus an autologous platelet injection. Our results will be published as soon as they become available.

Trial Registration

Trial registration number: http://www.clinicaltrials.gov NCT00758641.

     

Glucose tolerance testing in patients scheduled for cardiovascular surgery

Diabetes and impaired glucose tolerance are largely underdiagnosed in patients with acute atherosclerotic events. This glucose-unawareness is an obstacle for aggressive treatment in these patients. It is suggested to check fasting glucose levels in patients scheduled for cardiovascular surgery and to give intensive insulin therapy perioperatively if fasting glucose levels are greater than 7.0 mmol/L (126 mg/dL). If fasting glucose levels are not elevated an oral glucose tolerance test should be considered so that unknown diabetes can be detected and treated.     

Profound differences in spontaneous long-term functional recovery after defined spinal tract lesions in the rat

The purpose of this study was to compare spontaneous functional recovery after different spinal motor tract lesions in the rat spinal cord using three methods of analysis, the BBB, the rope test, and the CatWalk. We transected the dorsal corticospinal tract (CSTx) or the rubrospinal tract (RSTx) or the complete dorsal half of the spinal cord (Hx) at thoracic level T8. Functional recovery was monitored for 31 weeks. We found no recovery of consistent inter limb coordination in any experimental group over time using the BBB locomotor rating scale. Quantitative CatWalk analysis revealed significant differences between experimental groups for inter limb coordination (RI). RSTx and Hx animals showed a significant decrease in the RI, and only in the RSTx group did the RI improve from 6 weeks post-lesion onward. Significant differences between experimental groups in step sequence patterns and base of support were also observed. In the rope test all experimental groups had significantly higher error percentages compared to control animals. Tracing of the CST revealed enhanced collateral formation rostral to the lesion in the CSTx group, not in other groups. The results presented here show that locomotor function in all, but CSTx groups gradually improved over time. This is important for studies that employ pharmacological, cell-, and/or gene therapy- based interventions to improve axonal regeneration and functional recovery after spinal cord injury.     

Folinic acid-responsive seizures initially responsive to pyridoxine

This report presents a male who developed clonic seizures on the day he was born. The next day, the diagnosis of pyridoxine-dependent seizures was made. However, contradictory to this diagnosis, seizures reappeared despite treatment with pyridoxine. Seizures ceased after folinic acid was initiated. The clinical and biochemical characteristics of folinic acid-responsive seizures are reviewed. Treatment with folinic acid should be considered in neonatal seizures of unknown origin that do not respond to pyridoxine, or manifest a transient response to pyridoxine.     

Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery

BACKGROUND: To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described. METHODS: After craniofacial surgery, 22 of the 44 evaluated infants (aged 3-17 months) in the pediatric intensive care unit received propofol (2-4 mg . kg-1 . h-1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 . (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index. CONCLUSIONS: Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12-14 on the COMFORT-Behavior scale and 70-75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.     

Clinical heterogeneity was a common problem in Cochrane reviews of physiotherapy and occupational therapy

BACKGROUND AND OBJECTIVE: To identify the strategies used to deal with the clinical heterogeneity of interventions and multiple outcome measures used in Cochrane reviews on physiotherapy and occupational therapy. METHODS: A search for systematic reviews on physiotherapy and occupational therapy in the Cochrane Library was performed. Data on the method of categorization of interventions, on measures, and on the method of data synthesis were systematically extracted. RESULTS: 52 reviews were identified. In 22 (42%) reviews only one index intervention was evaluated, in the other 30 reviews index interventions were categorized. A large diversity in the number and type of outcome measures was found (median 6.5, range 1-23). In 48% of the reviews one or more primary outcome measures were defined. In 52% of the reviews no quantitative data synthesis was performed, whereas five different methods for qualitative data synthesis were applied in 11 reviews. CONCLUSIONS: Limitation to a few outcome measures and explicit procedures for the categorization of interventions might increase the transparency and reproducibility of systematic reviews on physiotherapy and occupational therapy. Qualitative data synthesis is not often applied, although it is a useful tool to summarize results if a quantitative synthesis is not appropriate. International consensus on a method for qualitative synthesis is clearly needed.