Intravenous oxycodone for pain relief in the first stage of labour--maternal pharmacokinetics and neonatal exposure

Physiological changes during pregnancy may change pharmacokinetics of compounds. Oxycodone is an increasingly used opioid agonist in acute pain management but its pharmacokinetics in labouring women has not been established. We studied the maternal pharmacokinetics and neonatal exposure of intravenous oxycodone for pain relief in the first stage of labour. The study was prospective, open‐labelled and with a control group. After informed consent, 15 nulliparous parturients and newborns, and newborns in a control group were studied. In the study group, oxycodone boluses of 1 mg i.v., up to a cumulative dose of 5 mg, was administered when labour pain score was 5/10 or higher. As the control group, 30 other newborns after uncomplicated deliveries with no systemic opioids were assessed for the neonatal outcome. In the study group, maternal pharmacokinetics of oxycodone was measured from plasma concentrations during labour, and neonatal exposure was assessed from umbilical plasma samples using population pharmacokinetic methods. Maternal plasma oxycodone concentration decreased with a median half‐life of 2.6 hr (range, 1.8–2.8). Oxycodone concentrations in the umbilical plasma 2.7 μg/l (0.3–14.5) were similar as in maternal plasma 2.4 (0.1–14.8) μg/l at the time of birth. No severe or unexpected adverse effects were noted. To conclude, firstly, maternal elimination half‐life of i.v. oxycodone was significantly shorter than that reported in non‐pregnant women, and secondly, maternal plasma oxycodone at the birth correlated well with neonatal umbilical concentrations and may, thus, be used as an estimate of neonatal exposure.     

Psychotic boys performing well in school are at increased risk of suicidal ideation

Aim:  This study investigated how the level of school performance is associated with suicidal behavior and psychiatric disorders among adolescent psychiatric inpatients aged 12–17 years.
Methods:  Data were collected from 508 adolescents (300 girls, 208 boys; age 12–17 years) admitted to inpatient psychiatric hospitalization between April 2001 and March 2006. Information on the adolescents' school performance, suicidal ideation, suicide attempts and self-mutilation as well as psychiatric DSM-IV diagnoses was obtained using the Schedule for Affective Disorder and Schizophrenia for School-Age Children.
Results:  An elevated risk of suicidal ideation (OR = 3.6, 95% CI 1.3–10.2, P  = 0.017) and of psychotic disorders (OR = 3.2, 95% CI 1.0–10.0, P  = 0.048) was observed among male adolescents performing well in school. In addition, adolescents with poor school performance had an increased likelihood of substance-related disorder both in boys (OR = 2.6, 95% CI 1.1–6.1, P  = 0.027) and girls (OR = 2.5, 95% CI 1.2–5.1, P  = 0.011).
Conclusions:  Our findings indicate that psychotic inpatient male adolescents performing well in school are at an elevated risk of suicidal ideation. Although good school performance is often considered a marker of high intelligence and good general ability, symptoms of major psychiatric disorders and suicidality need to be taken very seriously among adolescents performing well in school.     

The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland

Several putative schizophrenia susceptibility genes have recently been identified. Significant associations between schizophrenia and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were first reported in 2002 and studies in several populations have since independently reported positive associations to these gene regions. Further, both tentative functional and genetic data have implicated the role of AKT1 in the genetic background of this disorder. However, findings have not been consistent in all populations. We investigated the allelic diversity of these three genes NRG1, DTNBP1 and AKT1 in a representative nation-wide study sample of 441 Finnish schizophrenia families consisting of 865 affected individuals, in order to assess their role in one of the largest population-based study samples. DTNBP1 and AKT1 failed to show evidence of association, whereas two SNPs in the 3' region of the NRG1 gene yielded suggestive evidence of association (p=0.012 and p=0.048) in family-based association analyses. Thus, our study does not indicate that AKT1 or DTNBP1 play a role in the etiology of schizophrenia in the Finnish population. Furthermore, results do not support a major role for NRG1, but we cannot completely exclude a minor role of this gene in the Finnish population.     

Increasing process understanding by analyzing complex interactions in experimental data

There is a recognized need for new approaches to understand unit operations with pharmaceutical relevance. A method for analyzing complex interactions in experimental data is introduced. Higher-order interactions do exist between process parameters, which complicate the interpretation of experimental results. In this study, experiments based on mixed factorial design of coating process were performed. Drug release was analyzed by traditional analysis of variance (ANOVA) and generalized multiplicative ANOVA (GEMANOVA). GEMANOVA modeling is introduced in this study as a new tool for increased understanding of a coating process. It was possible to model the response, that is, the amount of drug released, using both mentioned techniques. However, the ANOVA model was difficult to interpret as several interactions between process parameters existed. In contrast to ANOVA, GEMANOVA is especially suited for modeling complex interactions and making easily understandable models of these. GEMANOVA modeling allowed a simple visualization of the entire experimental space. Furthermore, information was obtained on how relative changes in the settings of process parameters influence the film quality and thereby drug release.     

Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction

Isolated systolic hypertension is associated with increased cardiovascular risk. It is thought to result from large artery stiffening, which is determined by structural components within the vasculature but also by functional factors including NO and endothelin-1. We hypothesized that endothelial dysfunction would account for increased arterial stiffness in patients with isolated systolic hypertension. The aim of this study was to investigate the relationship between endothelial function and arterial stiffness in these patients along with control subjects. We studied 113 subjects: 35 patients with isolated systolic hypertension (mean age+/-SD: 68+/-6 years), 30 age-matched control subjects (65+/-5 years), and 48 young control subjects (37+/-9 years). Aortic pulse wave velocity (PWV) was derived by sequential carotid/femoral waveform recordings. Conduit artery endothelial function was determined by flow-mediated dilatation. Aortic PWV was higher (9.65+/-2.56 m/s versus 8.26+/-0.85 m/s; P=0.009), and flow-mediated dilatation was lower (2.67+/-1.64% versus 4.79+/-3.1%; P=0.03) in patients with isolated systolic hypertension compared with age-matched control subjects. Similarly, aortic PWV was also higher, and flow-mediated dilatation lower, in older versus young control subjects (8.26+/-0.85 m/s versus 7.09+/-1.01 m/s and 4.79+/-3.1% versus 6.94+/-2.7%; P=0.004 for both). Overall, aortic PWV correlated inversely with flow-mediated dilatation (r=-0.3; P=0.001), which remained significant after adjustment for confounding factors (P=0.01). Patients with isolated systolic hypertension have higher aortic PWV and decreased endothelial function compared with age-matched control subjects. Our results suggest that endothelial function contributes significantly to increased arterial stiffness in patients with isolated systolic hypertension and with age.     

Validation of surgical site infection surveillance in orthopedic procedures

BACKGROUND: Valid data are essential for a national surveillance system of nosocomial infections. METHODS: In 8 hospitals conducting surgical site infection (SSI) surveillance for orthopedic procedures, a validation team performed a blinded retrospective chart review (10 operations with reported infections, 40 without) and interviewed infection control nurses. RESULTS: In total, 397 patient charts were reviewed. Positive and negative predictive values for routine surveillance were 94% (95% CI: 89%-99%) and 99% (95% CI: 99%-100%), respectively. When these results were applied to the aggregated surveillance data (403 infections, 10,068 noninfections), sensitivity was 75% (95% CI: 56%-93%) and specificity 100% (95% CI: 97%-100%). The following case finding methods were used: ward visits (in 7/8 hospitals), microbiology reports (5/8), ward notifications by link nurses (8/8), and other nursing (7/8) and medical (5/8) staff. The wound culture rate ranged from 9 to 67 per 1000 patient-days. All hospitals carried out postdischarge surveillance on readmission and all but 1 at follow-up visits and by an additional questionnaire. CONCLUSION: Most SSIs reported by the hospitals were true infections, showing that, when an SSI was reported, the definitions were correctly implemented. Some SSIs were missed, which might be due to weaknesses in case finding. Variation in diagnostic practices may also affect SSI rates.     

Anticitrulline antibodies can be caused by homocitrulline‐containing proteins in rabbits

Objective

To clarify the possible roles of protein‐bound homocitrulline in causing an antibody response to citrulline and as a confounding factor in citrulline detection assays.

Methods

Native, carbamoylated, and citrullinated albumins were used for testing the specificity of commercial antibodies against modified citrulline by Western blot. Rabbits were immunized with human albumin and/or bone type I collagen, both of which were treated with cyanate to produce homocitrulline, or with citrullinated synthetic telopeptide of type I collagen. These antisera were tested for binding to cyclic citrullinated peptide 2 (CCP‐2), mutated citrullinated vimentin, and type I or II collagen telopeptides containing either citrulline or homocitrulline.

Results

Commercial antibodies that had been considered to be specific for chemically modified citrulline were found to recognize both homocitrulline‐ and citrulline‐containing albumins. The rabbits immunized with proteins containing homocitrulline produced high‐affinity antibodies against CCP‐2 and, to a lesser extent, against mutated citrullinated vimentin. The antisera also bound homocitrulline‐containing collagen telopeptides and, less strongly, citrulline‐containing telopeptides.

Conclusion

Our findings demonstrate that homocitrulline, which is a structural analog of citrulline (longer by 1 carbon, and readily formed in the body), can be involved in raising citrulline‐recognizing antibodies in experimental animals and can cause false‐positive reactions in assays for citrulline.

     

Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.     

Clinical Assessment and Improved Diagnosis of Bocavirus-induced Wheezing in Children, Finland

Human bocavirus (HBoV) is a widespread respiratory virus. To improve diagnostic methods, we conducted immunoglobulin (Ig) G and IgM enzyme immunoassays with recombinant virus–like particles of HBoV as antigen. Acute-phase and follow-up serum samples from 258 wheezing children and single serum samples from 115 healthy adults in Finland were examined. Our assays had a sensitivity of 97% and a specificity of 99.5%. Of adults, 96% had immunity; none had an acute infection. Of 48 children with serologically diagnosed acute HBoV infections, 45 were viremic and 35 had virus in nasopharyngeal aspirates (NPAs). Of 39 HBoV NPA PCR–positive children co-infected with another virus, 64% had a serologically verified HBoV infection. HBoV caused illness of longer duration than rhinovirus and of equal severity to that of respiratory syncytial virus. Among children with bronchiolitis, >25% had acute HBoV infections. Accurate HBoV diagnosis requires serologic analysis or PCR of serum; PCR of NPAs alone is insufficient.