Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT)

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide ( average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mgm(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mgm(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mgm(-2). The half-lives of both MAG-CPT and released CPT were prolonged (46 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development

The effectiveness of self-management interventions in adults with chronic orofacial pain: A systematic review, Meta-analysis and Meta-regression

Background: Psychosocial risk factors associated with chronic orofacial pain are amenable to self‐management. However, current management involves invasive therapies which lack an evidence base and have the potential to cause iatrogenic harm. Objectives: To determine: 1) whether self‐management is more effective than usual care in improving pain intensity and psychosocial well‐being 2) optimal components of self‐management interventions. Databases and Data treatment: Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, WHO International Clinical Trials Registry Platform and Clinical Trialsgov were searched. Meta‐analysis was used to determine effectiveness and GRADE was used to rate quality, certainty and applicability of evidence. Results: Fourteen trials were included. Meta‐analyses showed self‐management was effective for long‐term pain intensity (standardised mean difference (SMD) ‐0.32, 95% confidence interval (CI) ‐0.47 to ‐0.17) and depression (SMD ‐0.32, 95% CI ‐0.50 to ‐0.15). GRADE analysis showed a high score for certainty of evidence for these outcomes and significant effects for additional outcomes of activity interference (‐0.29 95% CI ‐0.47 to ‐ 0.11) and muscle palpation pain (SMD ‐0.58 95% CI ‐0.92 to ‐0.24). Meta‐regression showed non‐significant effects for biofeedback on long‐term pain (‐0.16, 95% CI ‐0.48 to 0.17, P‐value = 0.360) and depression (‐0.13, 95% CI ‐0.50 to 0.23, P‐value = 0.475). Conclusions: Self‐management interventions are effective for patients with chronic orofacial pain. Packages of physical and psychosocial self‐regulation and education appear beneficial. Early self‐management of chronic orofacial pain should be a priority for future testing

Term elective induction of labour and perinatal outcomes in obese women: retrospective cohort study

ObjectiveTo compare perinatal outcomes between elective induction of labour (eIOL) and expectant management in obese women.DesignRetrospective cohort study.SettingDeliveries in California in 2007.PopulationTerm, singleton, vertex, nonanomalous deliveries among obese women (n = 74 725).MethodsWomen who underwent eIOL at 37 weeks were compared with women who were expectantly managed at that gestational age. Similar comparisons were made at 38, 39, and 40 weeks. Results were stratified by parity. Chi-square tests and multivariable logistic regression were used for statistical comparison.Main outcome measuresMethod of delivery, severe perineal lacerations, postpartum haemorrhage, chorioamnionitis, macrosomia, shoulder dystocia, brachial plexus injury, respiratory distress syndrome.ResultsThe odds of caesarean delivery were lower among nulliparous women with eIOL at 37 weeks [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.34-0.90] and 39 weeks (OR 0.77, 95% CI 0.63-0.95) compared to expectant management. Among multiparous women with a prior vaginal delivery, eIOL at 37 (OR 0.39, 95% CI 0.24-0.64), 38 (OR 0.65, 95% CI 0.51-0.82), and 39 weeks (OR 0.67, 95% CI 0.56-0.81) was associated with lower odds of caesarean. Additionally, eIOL at 38, 39, and 40 weeks was associated with lower odds of macrosomia. There were no differences in the odds of operative vaginal delivery, lacerations, brachial plexus injury or respiratory distress syndrome.ConclusionsIn obese women, term eIOL may decrease the risk of caesarean delivery, particularly in multiparas, without increasing the risks of other adverse outcomes when compared with expectant management

Self-reported assessment of disability and performance-based assessment of disability are influenced by different patient characteristics in acute low back pain

For an individual, the functional consequences of an episode of low back pain is a key measure of their clinical status. Self-reported disability measures are commonly used to capture this component of the back pain experience. In non-acute low back pain there is some uncertainty of the validity of this approach. It appears that self-reported assessment of disability and direct measurements of functional status are only moderately related. In this cross-sectional study, we investigated this relationship in a sample of 94 acute low back pain patients. Both self-reported disability and a performance-based assessment of disability were assessed, along with extensive profiling of patient characteristics. Scale consistency of the performance-based assessment was investigated using Cronbach’s alpha, the relationship between self-reported and performance-based assessment of disability was investigated using Pearson’s correlation. The relationship between clinical profile and each of the disability measures were examined using Pearson’s correlations and multivariate linear regression. Our results demonstrate that the battery of tests used are internally reliable (Cronbach’s alpha = 0.86). We found only moderate correlations between the two disability measures (r = 0.471, p < 0.001). Self-reported disability was significantly correlated with symptom distribution, medication use, physical well-being, pain intensity, depression, somatic distress and anxiety. The only significant correlations with the performance-based measure were symptom distribution, physical well-being and pain intensity. In the multivariate analyses no psychological measure made a significant unique contribution to the prediction of the performance-based measure, whereas depression made a unique contribution to the prediction of the self-reported measure. Our results suggest that self-reported and performance-based assessments of disability are influenced by different patient characteristics. In particular, it appears self-reported measures of disability are more influenced by the patient’s psychological status than performance-based measures of disability