Phase I/II tolerability/pharmacokinetic study with one-hour intravenous infusion of doxifluiridine (5′-dFUrd) 3 g/m2 VS 5 g/m2 QD x 5 per month

Summary Eighteen patients with advanced solid cancer were treated with daily 5-dFUrd infusions given over 1 h on days 1–5 of a 4-week cycle. Nine patients received 3 g/m² 5-dFUrd daily and another nine patients 5 g/m². One patient on 5 g/m² 5-dFUrd was not fully evaluable for tolerability due to early death (progressive disease) 4 weeks after the first cycle. A total of 48 cycles was given. The gastrointestinal and hematological toxicity was generally mild (grade 1–2). Central neurotoxicity (ataxia, unsteadiness, diplopia, dysarthria, sometimes confusion) was observed in 7 of 8 patients on 5 g/m² 5-dFUrd leading to premature discontinuation of treatment in 3 patients (after 2 cycles). Only 3 of the 9 patients in the 3 g/m² group had slight signs of cerebellopathy. Typically, the reversible neurological side effects started at the end of the 2nd week of a cycle. The serum elimination kinetics of 5-dEUrd and its metabolites 5-FU and 5-dFUH₂ have been investigated in the serum and showed very low intra- and interindividual variations. Peak concentrations of the 5-dFUrd at the end of the infusion approximated 500 mol/l and 1000 mol/l for the 3 g/m² and 5 g/m² group, respectively. The peak of the serum 5-FU was reached at the same time, the ratio 5-FU/5-dFUrd being around 10%. The elimination half-life time for 5-FU was protracted by a factor of 2–3 compared with the direct injection of 5-FU.Monthly infusion of 5-dFUrd 5 mg/m² per day on days 1–5 lead to an unacceptable frequency and degree of neurological toxicity. Similar infusions of 5-dFUrd 3 g/m² per day on days 1–5 were well tolerated.     

Dichotic listening performance predicts language comprehension

Dichotic listening performance is considered a reliable and valid procedure for the assessment of language lateralisation in the brain. However, the documentation of a relationship between language functions and dichotic listening performance is sparse, although it is accepted that dichotic listening measures language perception. In particular, language comprehension should show close correspondence to perception of language stimuli. In the present study, we tested samples of reading-impaired and normally achieving children between 10 and 13 years of age with tests of reading skills, language comprehension, and dichotic listening to consonant-vowel (CV) syllables. A high correlation between the language scores and the dichotic listening performance was expected. However, since the left ear score is believed to be an error when assessing language laterality, covariation was expected for the right ear scores only. In addition, directing attention to one ear input was believed to reduce the influence of random factors, and thus show a more concise estimate of left hemisphere language capacity. Thus, a stronger correlation between language comprehension skills and the dichotic listening performance when attending to the right ear was expected. The analyses yielded a positive correlation between the right ear score in DL and language comprehension, an effect that was stronger when attending to the right ear. The present results confirm the assumption that dichotic listening with CV syllables measures an aspect of language perception and language skills that is related to general language comprehension.     

Prediction of postoperative pain after percutaneous nephrolithotomy: can preoperative experimental pain assessment identify patients at risk?

Postoperative pain remains a significant problem and the individual variance in postoperative pain is not fully understood. In recent years, there has been focus on identifying risk factors predicting patients with high postoperative pain intensity or consumption of analgesics, which may facilitate an improvement in rehabilitation. This study evaluates the relationship between preoperative experimental pain assessment and postoperative pain and opioid consumption. Forty-four patients with uni- or bilateral kidney stone disease scheduled for percutaneous nephrolithotomy were included. The preoperative pain thresholds were measured using electrical (single and 5 repeated) and pressure pain stimulation over the flank bilaterally (stone-side = operation side and control-side = non-operation side). Postoperative pain scores were recorded on a numerical rating scale and analgesic consumption was registered. The responses to repeated electrical stimuli (temporal summation) were preoperatively increased on the stone-side compared to the control-side (P = 0.016). Preoperative electrical pain thresholds from the control-side correlated inversely with postoperative opioid consumption (single stimuli: ρ = ?0.43, P < 0.01; repeated stimuli: ρ = ?0.45, P < 0.005). This correlation was more pronounced for the 22 patients with unilateral renal calculi (single stimuli: ρ = ?0.54, P < 0.02; repeated stimuli: ρ = ?0.58, P < 0.01). There were no other correlations between the preoperative sensory tests and postoperative pain or opioid consumption. This study showed a correlation between the preoperative electrical pain thresholds on the control-side and postoperative opioid consumption after percutaneous nephrolithotomy. Preoperative measurement of the electrical pain thresholds may, therefore, be useful as a screening tool to identify patients at high risk of postoperative pain.     

The Effect of a Combination of Diclofenac and Methadone Applied as Gel in a Human Experimental Pain Model – A Randomized,Placebo‐controlled Trial

Pain involves responses in which both peripheral and central mechanisms contribute to the generation of pain. Pre‐clinical laboratory data have supported that a topical formulation of combined diclofenac and methadone (Diclometh) may alleviate local pain, and potentially, the side effect profile should be low. We hypothesized that antiallodynic and antihyperalgesic effects of Diclometh could be demonstrated in a human experimental pain model and that Diclometh would be safe to administer. Thus, the aims were as follows: (i) to compare two doses of Diclometh versus placebo; and (ii) to assess the safety profile of Diclometh. The study was a crossover, randomized, double‐blind, placebo‐controlled comparison of two doses of Diclometh gel (0.1% and 0.2%) administered topically in healthy participants. Nerve growth factor (NGF) and capsaicin intradermal injections were used as human pain models. Pressure stimulation, contact heat stimulation, hyperalgesia (pinprick stimulation) and allodynia (brush stimulation) to mechanical stimulation were performed in the area where capsaicin and NGF were injected. Side effects were recorded on a four‐point Likert scale. Twenty‐one men completed the study (mean age 26.14 ± 5.3). Diclometh 0.2% reduced the capsaicin‐induced dynamic mechanical allodynia compared to placebo (primary end‐point, p = 0.03). No other primary or secondary end‐points were found significantly different (all p > 0.05). All side effects were reported as mild with no differences between treatments (p = 0.15). Indication of antiallodynic effect of Diclometh 0.2% was found. Additionally, it was demonstrated that Diclometh was safe to use.     

Electroencephalography and analgesics

To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy. We searched PubMed with MeSH terms ‘analgesics’, ‘electroencephalography’ and ‘evoked potentials’ for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified. Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N-methyl-D-aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed. This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients.     

Aetiological risk factors are associated with distinct imaging findings in patients with chronic pancreatitis: A study of 959 cases from the Scandinavian Baltic Pancreatic Club (SBPC) imaging database

ObjectivesThe relation between aetiology and structural changes of the pancreas in patients with chronic pancreatitis (CP) is not fully understood. Earlier studies are limited by focusing on selected factors in studies of limited sample size. We aimed to use a large dataset to explore associations between aetiology and pancreatic morphology in CP.MethodsSubjects with definite or probable CP according to the M-ANNHEIM diagnostic criteria were included in this multicentre cross-sectional observational study and assessed using a standardized and validated CP imaging system. We performed multivariate logistic regression to analyse if aetiological factors adjusted for covariates were independently associated with morphological pancreatic features.ResultsWe included 959 patients (66% males). Mean (SD) age was 55 (14) years. Pancreatic structural changes were found in 94% of the subjects: 67% had calcifications, 59% main pancreatic duct dilatation, 33% pseudo-cysts and 22% pancreatic atrophy. Alcohol abuse was independently associated with pancreatic calcifications (odds ratio (OR, [95% CI]); 1.61, [1.09, 2.37]) and focal acute pancreatitis (OR; 2.13, [1.27, 3.56]), whereas smoking was independently associated with more severe calcifications (OR; 2.09, [1.34, 3.27]) and involvement of the whole gland (OR; 2.29, [1.61, 3.28]). Disease duration was positively associated with calcifications (OR; (per year) 1.05 [1.02, 1.08]) and pancreatic atrophy (OR; 1.05 [1.02, 1.08]) and negatively associated with focal acute pancreatitis (OR 0.91, [0.87, 0.95] and pseudo cysts (OR; 0.96, [0.93, 0.98]).ConclusionIn this large-scale study, etiological risk factors and disease duration in CP were independently associated with specific structural pancreatic imaging changes.