Venous Irritation Related to Intravenous Administration of Phenytoin versus Fosphenytoin

Study Objective . To compare the frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin with an equimolar dose of fosphenytoin, a water-soluble phenytoin prodrug. Design . Randomized, double-blind, two-period, crossover study. Setting . University hospital clinical research unit. Patients . Twelve healthy volunteers within 15% of ideal body weight and with no clinically significant abnormalities on physical examination, medical history, or laboratory assessment. Interventions . Volunteers randomly received a 30-minute infusion of phenytoin sodium 250 mg (250 mg/5 ml) or an equimolar dose of fosphenytoin 375 mg (375 mg/5 ml). Subjects returned for the crossover treatment 14–21 days later. Measurements and Main Results . Subjects assessed venous irritation (pain, burning, itching), and investigators evaluated phlebitis (erythema, swelling, tenderness), induration, exudation, and cording. Phenytoin was associated with a significantly higher degree of pain at the infusion site in all subjects and a significant degree of phlebitis in eight subjects (p<0.05); cording occurred in six subjects. The time course of phenytoin-induced phlebitis was bimodal. Erythema and tenderness were prominent at the end of the infusion and again at 24 hours. Cording was first noted between 24 hours and 1 week after infusion. In contrast, fosphenytoin was associated with mild pain in two subjects, one incident of phlebitis, and no erythema or cording. Conclusions . Fosphenytoin administration resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin. The clinical use of this water-soluble phenytoin prodrug should minimize the frequency and severity of infusion-site reactions and should allow convenient, rapid, intravenous administration of drug, undiluted or admixed with intravenous solutions.     

Peritoneal morphology in children treated by continuous ambulatory peritoneal dialysis

Fifty peritoneal biopsies (PB) from 35 patients with end-stage renal disease, treated by continuous ambulatory peritoneal dialysis (CAPD) and aged 2 months to 18 years, were examined by light microscopy (n=50) and/or scanning electron microscopy. PB were performed during surgical procedures immediately before the start of, during, or after the cessation of CAPD treatment. PB from 15 children without renal disease undergoing laparatomy were examined similarly. Before the start of CAPD, a scarcity and shortening of the mesothelial microvilli was observed by scanning electron microscopy. During and after CAPD, variable alterations of mesothelium, interstitium and capillaries were found. The mesothelial layer was absent in all 5 PB obtained during episodes of active peritonitis. In patients treated by CAPD for longer than 6 months, mesothelial denudation was observed more frequently (6/11) than in children treated for shorter periods (1/7) (P<0.08). Fibrosis of the peritoneal membrane was present in about 50% of patients during or after the cessation of CAPD without impairment of peritoneal function. No correlation was found between the presence of fibrosis and the frequency of peritonitis or the duration of CAPD treatment.     

Improvement of Decreased Critical Flicker Frequency (CFF) in Headache Patients With Drug Abuse After Successful Withdrawal

A considerable proportion of headache patients fulfill the criteria of "drug abuse" (definition according to the International Headache Society [IHS] criteria). These patients exhibit markedly reduced vigilance and continuous performance, as shown by the results of critical flicker frequency (CFF) analysis.
The present study deals with the question whether this impairment of vigilance and continuous performance is reversible. Forty-eight headache patients with drug abuse were investigated three times by means of CFF analysis: immediately before (A), immediately after (B), and 3 weeks after having finished (C) inpatient drug withdrawal.
Immediately after withdrawal, a significant decrease of headache intensity was observed. The CFF values, however, remained unchanged at a depressed level, probably due to withdrawal medication and the initial sedative side effects of thymoleptic agents (given as prophylaxis).
Three weeks after withdrawal, however, the CFF values were significantly improved, and were now within a range not far from the normal values known from a healthy general population. Thus, even after many years of drug abuse, headache patients have a good chance to improve their vigilance and continuous performance and to reach normal or close to normal levels.     

Prefrontal cortex dysfunction and depression in atypical parkinsonian syndromes.

Depressive symptoms are common in patients with neurodegenerative disorders. Imaging studies suggest that a disruption of frontal-subcortical pathways may underlie depression associated with basal ganglia disease. This pilot study tested the hypothesis that frontal dysfunction contributes to depression associated with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Depressed patients with MSA (n = 11), PSP (n = 9), and age-matched controls (n = 25) underwent measures of cerebral glucose metabolism applying positron emission tomography with (18)F-fluorodeoxyglucose. Regional metabolism in the patient groups was compared to the normal subjects using the voxel-based statistical parametric mapping. Depressive symptom severity (Hamilton Depression Rating) and degree of locomotor disability (Hoehn & Yahr) were assessed in the patient groups. The association between prefrontal metabolism and the occurrence of depressive symptoms and the degree of locomotor disability was investigated. When compared to controls, MSA patients revealed significant metabolic decreases in bilateral frontal, parietal, and cerebellar cortex and in the left putamen. In PSP patients, significant hypometabolism was demonstrated in bilateral frontal cortex, right thalamus, and midbrain. Depression severity but not the patients' functional condition was significantly associated with dorsolateral prefrontal glucose metabolism in both patient groups. The findings of this pilot study support the hypothesis that depressive symptoms in MSA and PSP are associated with prefrontal dysfunction.     

Establishing the Cost-Effectiveness of New Pharmaceuticals under Conditions of Uncertainty—When Is There Sufficient Evidence?

Decisions about which health-care interventions represent adequate value to collectively funded health-care systems are as widespread as they are unavoidable. In the case of new pharmaceuticals, many countries now require formal cost-effectiveness analysis to inform this decision-making process. This requires evidence on parameters associated with health-related utilities, treatment effects, resource use, and costs, for which data from available regulatory trials are invariably absent or highly uncertain. This uncertainty results from a number of factors including the predominance of intermediate end points in the clinical evidence-base and the limited period of follow-up of patients in clinical studies. Despite these imperfections in the evidence base, decisions about whether new pharmaceuticals are sufficiently cost-effective for reimbursement cannot be side-stepped. Data limitations do, however, require the use of rigorous analytical methods to support decision making. Probabilistic decision models and value of information analysis offer a means of structuring decision problems, synthesizing all available data, characterizing the uncertainty in the decision, quantifying the cost of uncertainty, and establishing the expected value of perfect information. This analytical framework is important because it addresses two fundamental questions about new pharmaceuticals. First, is the product expected to be cost-effective on the basis of existing evidence? Second, is additional research concerning the product itself cost-effective? In addressing these questions, the analytical framework can establish when sufficient evidence exists to sustain a claim for a new pharmaceutical to be cost-effective.     

The effects of literacy and education on the quantitative and qualitative aspects of semantic verbal fluency.

Semantic verbal fluency tasks are commonly used in neuropsychological assessment. Investigations of the influence of level of literacy have not yielded consistent results in the literature. This prompted us to investigate the ecological relevance of task specifics, in particular, the choice of semantic criteria used. Two groups of literate and illiterate subjects were compared on two verbal fluency tasks using different semantic criteria. The performance on a food criterion (supermarket fluency task), considered more ecologically relevant for the two literacy groups, and an animal criterion (animal fluency task) were compared. The data were analysed using both quantitative and qualitative measures. The quantitative analysis indicated that the two literacy groups performed equally well on the supermarket fluency task. In contrast, results differed significantly during the animal fluency task. The qualitative analyses indicated differences between groups related to the strategies used, especially with respect to the animal fluency task. The overall results suggest that there is not a substantial difference between literate and illiterate subjects related to the fundamental workings of semantic memory. However, there is indication that the content of semantic memory reflects differences in shared cultural background--in other words, formal education--, as indicated by the significant interaction between level of literacy and semantic criterion.     

High-resolution imaging of progressive articular cartilage degeneration.

The objective of this study was to develop and verify a new technique for monitoring the progression of osteoarthritis (OA) by combining a rat model with the imaging modality optical coherence tomography (OCT). Time-sequential, in vivo, OCT imaging was performed on the left femoral condyles of 12 Wistar rats following sodium-iodoacetic acid-induced OA progression. The right femoral condyles (untreated) were also imaged and served as controls. Imaging was performed on days 0, 10, 20, 30, and 60 with an OCT system capable of acquiring images at four frames per second and an axial resolution of 5 microm. Progressive changes were analyzed using an OA scoring system. OCT successfully identified progressive cartilage degeneration as well as alteration of the cartilage/bone interface. Significant changes to both of these structures were observed in the sodium-iodoacetic acid-injected condyles. Structural changes detected with OCT were confirmed histologically. OCT in combination with a well-known model used in arthritis research represents a powerful tool for following degenerative joint disease progression in a given animal by detecting changes to the cartilage/bone interface and articular cartilage.     

Local induction of an insulin-like growth factor binding protein-3 degrading protease activity in the course of wound healing

Proteases that reduce insulin-like growth factor binding protein-3 affinity for insulin-like growth factor-I have been found in various biological fluids from human beings and rats. The aim of this study was to assess the local and systemic role of insulin-like growth factor binding protein-3 proteases in the course of wound healing. Six rats had polyvinyl alcohol sponges implanted subcutaneously. Wound fluid and serum were collected 3 days after wounding. Gel filtration experiments showed that insulin-like growth factor-I was present as a 150 kDa complex in both serum and wound fluid. However, insulin-like growth factor binding protein-3 measured by Western ligand blotting was virtually absent in wound fluid. Co-incubation of serum and wound fluid resulted in an ethylenediamine tetraacetic acid-inhibitable degradation of serum insulin-like growth factor binding protein-3, suggesting the presence of an insulin-like growth factor binding protein-3 degrading activity in wound fluid. Incubation of ((125)I)-labeled insulin-like growth factor binding protein-3 in wound fluid and serum showed a rapid and time-dependent proteolysis of insulin-like growth factor binding protein-3 in wound fluid with metabolites similar to those generated by human term pregnant serum. No sign of insulin-like growth factor binding protein-3 degrading activity was observed in rat-serum. In conclusion, there is an insulin-like growth factor binding protein-3 proteolytic activity in wound fluid, and it is hypothesized that this activity results in a localized increase in insulin-like growth factor-I bioactivity.     

Demonstration of extrachromosmal DNA fromBabesia equi merozoites

An extrachromosomal nucleic acid element was detected in high-molecular-weight DNA preparations formBabesia equi merozoites. This extrachromosomal element was shown to be DNA rather than RNA and had an apparent fragment size of about 9 kilobasepairs (kb). Hybridization experiments using purified 9-kb DNA as a probe revealed sequence homologies with extrachromosomal DNA from two otherBabesia species.