Adherence to prophylaxis in adolescents and young adults with severe haemophilia: a qualitative study with healthcare professionals.

Aim: to examine healthcare professionals' (HP) perceptions and experiences in relation to adherence to prophylactic treatment among young people living with haemophilia (YPH). Methods: All HPs in four haemophilia centres across England and Wales were invited to participate, and all HPs who agreed to take part (n = 6) were interviewed. Interviews were audio-recorded, transcribed and then analysed using Interpretative Phenomenological Analysis (IPA). Results: HPs estimate that generally young people with haemophilia keep to their treatment regimen well, although they also recognise that adherence may fluctuate with many patients going through shorter periods of non-adherence. The increasingly personalised or flexible approach to prophylaxis makes it harder to assess adherence. The main themes identified through IPA included (1) HPs' suggest that adherence fluctuates (2) Non-adherence is mainly driven by lifestyle and developmental, social and family factors, and (3) Education, HPs' sensitivity to individual needs, and psychological and peer support are key facilitators of good adherence. Conclusion: The increasingly flexible approach to prophylaxis requires a new way of thinking about, and assessment of, adherence. More personalised treatment regimen can be more complicated and may, therefore, lead to accidental non-adherence. The results of this study with HPs complement those of a previous qualitative study with patients but place greater emphasis on a broader perspective on understanding drivers of non-adherence as well as understanding strategies to improve adherence in the minority of patients who appear to struggle.

Adherence to prophylaxis in adolescents and young adults with severe haemophilia A, a qualitative study with patients.

Introduction: Reported levels of adherence to prophylaxis among young people with haemophilia (YPH) vary widely and are predominately based on estimations made by healthcare professionals and parents. Reasons for (non)adherence among YPH in particular have not been evidenced. Aim: to examine experiences in relation to prophylaxis with YPH themselves, and barriers and facilitators to their adherence. Methods: 11 Participants were recruited in five haemophilia centres across England and Wales. All patients who met the inclusion criteria (aged 12-25, diagnosed with haemophilia, on prophylaxis) were approached during a routine check-up appointment, and all participants who agreed to take part were interviewed. Interviews were audio recorded, transcribed and analysed using Interpretative Phenomenological Analysis. Results: Self-reported adherence to prophylaxis was good. Few participants admitted to intentionally skipping injections although they reported sometimes forgetting. However, due to the increasingly personalised and flexible approach to prophylaxis, adherence is not straightforward to define. Barriers to adherence included a busy lifestyle, dislike of the intravenous injection, venous access issues, anxiety or stress and being out of one's normal routine. Support was an important facilitator to adherence, including support from health professionals at the haemophilia centre as well as friends. Parents appear to be very involved with their child's haemophilia management, even after they leave home. Conclusion: What this study adds is that the increasingly flexible and personalised approach to managing prophylaxis in haemophilia may sometimes lead to confusion around treatment frequency and dosing. This may lead to accidental non-adherence, which is distinct from both skipping and forgetting. Advice from haemophilia teams may not always be consistent and is likely to be interpreted differently by different individuals. Some additional training and education of patients and their families to increase their knowledge and skills around prophylaxis may reduce this confusion and therefore is likely to improve adherence further.

Safety of tibolone in the treatment of vasomotor symptoms in breast cancer patients--design and baseline data 'LIBERATE' trial.

Many patients with a history of breast cancer (BC) will suffer from vasomotor symptoms, which can be induced or exacerbated by treatment with tamoxifen or aromatase inhibitors. The LIBERATE trial was designed as a randomized, double-blind, multicenter trial to demonstrate that tibolone 2.5mg/day (Livial) is non-inferior to placebo regarding BC recurrence in women with vasomotor symptoms surgically treated for primary BC within the last 5 years. Secondary objectives are effects on vasomotor symptoms as well as overall survival, bone mineral density and health-related quality of life. Mean age at randomization was 52.6 years, and the mean time since surgery was 2.1 years. The mean daily number of hot flushes and sweating episodes was 7.3 and 6.1, respectively. For the primary tumor, Stage IIA or higher was reported for >70% of the patients. In subjects whose receptor status was known, 78.2% of the tumors were estrogen receptors positive. At randomization, tamoxifen was given to 66.2% of all patients and aromatase inhibitors to 7%. Chemotherapy was reported by 5% at randomization. The adjuvant tamoxifen use in LIBERATE allows a comparison with the Stockholm trial (showing no risk of BC recurrence associated with hormone therapy), which was stopped prematurely subsequent to HABITS. The LIBERATE trial is the largest, ongoing, well-controlled study for treatment of vasomotor symptoms in BC patients.

Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets.

UNLABELLED: Risperidone is an atypical anti-psychotic, available in various formulations. OBJECTIVE: The objective of the study was to compare the bioavailability of a generic oral solution of risperidone (Test formulation) and Risperdal tablets (Reference formulation). Both formulations contained 1 mg risperidone per dosing unit. METHODS: The study was carried out in 32 healthy volunteers under fasting conditions. Risperidone and 9-hydroxyrisperidone concentrations in plasma were determined using HPLC/MS/MS. RESULTS: The results show that the 90% confidence intervals for the geometric mean ratios of the solution and the tablet formulations were not within the acceptance range of 80 125% for risperidone, whereas the confidence intervals for 9-hydroxyrisperidone were within the acceptance range of 80 - 125%. CONCLUSION: Bioequivalence between the generic 1 mg/ml risperidone solution and the originator tablet formulation was not proven in this study.

Assessment of endotracheal tube placement in newborn infants: a randomized controlled trial.

OBJECTIVE: International resuscitation guidelines recommend clinical assessment and exhaled CO2 to confirm tube placement immediately after intubation. However, exhaled CO2 devices can display false negative results. In comparison, any respiratory function monitor can be used to measure and display gas flow in and out of an endotracheal tube. However, neither method has been examined in detail. We hypothesized that a flow sensor would improve the assessment of tracheal vs esophageal tube placement in neonates with a higher success rate and a shorter time to tube placement confirmation when compared with the use of a quantitative end-tidal CO2 (ETCO2) detector. STUDY DESIGN: Between December 2013 and September 2014, preterm and term infants requiring endotracheal intubation were eligible for inclusion and randomly allocated to either ETCO2 ('ETCO2 group') or flow sensor ('flow sensor group'). All infants were analyzed according to their group at randomization (that is, analysis was by intention-to-treat). RESULT: During the study period, a total of 110 infants (n=55 for each group) were randomized. Successful endotracheal tube placements were correctly identified in 100% of cases by the flow sensor compared with 72% of cases with the ETCO2 detector within 10 inflations (P<0.05). The median (interquartile range) number of inflations needed to identify successful tube placement was significantly lower in the flow sensor group with 2 (1 to 3) inflations vs 8 (6 to 10) inflations with the ETCO2 detector (P<0.001). CONCLUSION: A flow sensor would improve the assessment of successful endotracheal tube placement with a higher success rate and a shorter time compared with an ETCO2 detector.

Mask ventilation with two different face masks in the delivery room for preterm infants: a randomized controlled trial.

BACKGROUND: If an infant fails to initiate spontaneous breathing after birth, international guidelines recommend a positive pressure ventilation (PPV). However, PPV by face mask is frequently inadequate because of leak between the face and mask. Despite a variety of available face masks, none have been prospectively compared in a randomized fashion. We aimed to evaluate and compare leak between two commercially available round face masks (Fisher & Paykel (F&P) and Laerdal) in preterm infants <33 weeks gestational age in the delivery room. METHODS: Infants born at the Royal Alexandra Hospital from April to September 2013 at <33 weeks gestational age who received mask PPV in the delivery room routinely had a flow sensor placed between the mask and T-piece resuscitator. Infants were randomly assigned to receive PPV with either a F&P or Laerdal face mask. All resuscitators were trained in the use of both face masks. We compared mask leak, airway pressures, tidal volume and ventilation rate between the two groups. RESULTS: Fifty-six preterm infants (n=28 in each group) were enrolled; mean±s.d. gestational age 28±3 weeks; birth weight 1210±448 g; and 30 (52%) were male. Apgar scores at 1 and 5 min were 5±3 and 7±2, respectively. Infants randomized to the F&P face mask and Laerdal face mask had similar mask leak (30 (25-38) versus 35 (24-46)%, median (interquartile range), respectively, P=0.40) and tidal volume (7.1 (4.9-8.9) versus 6.6 (5.2-8.9) ml kg(-1), P=0.69) during PPV. There were no significant differences in ventilation rate, inflation time or airway pressures between groups. CONCLUSION: The use of either face mask during PPV in the delivery room yields similar mask leak in preterm infants <33 weeks gestational age.

Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations.

PURPOSE: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). METHODS: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. RESULTS: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). CONCLUSIONS: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

Probenecid interferes with renal oxidative metabolism: a potential pitfall in its use as an inhibitor of drug transport.

The anionic drug probenecid has been traditionally used as an inhibitor of renal organic anion transport. More recently the drug was found to inhibit organic cation transport as well, and it is used to retain intracellularly loaded fluorophores. In these investigations it is implicitly assumed that probenecid performs its activity through competition for transport. Here we studied the possibility that probenecid provokes its effect through inhibition of cellular oxidative metabolism. Oxygen consumption was measured in isolated rat kidney cortex mitochondria. At concentrations of 1 mM or higher, probenecid increased the resting state (state 4) and decreased the ADP-stimulated respiration (state 3). A complete loss in respiratory control was observed at 10 mM probenecid. After incubating isolated rat kidney proximal tubular cells (PTC) for 30 min with probenecid a concentration-dependent reduction in ATP content was observed, which was significant at concentrations of 1 mM and higher. Using digital image fluorescence microscopy the membrane potential in PTC was measured with bisoxonol. The mitochondrial effects of probenecid were paralleled by a depolarization of the plasma membrane, immediately after drug addition. All events are likely to be a result of membrane disordering due to the lipophilic character of probenecid, and may explain, at least in part, the various inhibitory effects found for the drug. We recommend to be cautious with applying probenecid in cellular research.

Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women.

UNLABELLED: A randomized trial was conducted in osteopenic postmenopausal women to compare the efficacy of tibolone versus raloxifene on BMD of the lumbar spine and hip. Tibolone increased lumbar spine and total hip BMD to a statistically significantly greater extent than raloxifene after two years of treatment. INTRODUCTION: Both tibolone, a selective tissue estrogenic activity regulator (STEAR), and raloxifene, a selective estrogen receptor modulator (SERM), are known to prevent postmenopausal bone loss. However, no head-to-head studies to compare the efficacy on bone have been performed. METHODS: A double-blind, randomized trial was conducted in osteopenic postmenopausal women aged 60-79 years to compare the effects of tibolone 1.25 mg/day to raloxifene 60 mg/day on bone mineral density (BMD). Serum osteocalcin and serum type I collagen C-telopeptides were measured as biochemical markers of bone metabolism. RESULTS: Three hundred and eight subjects were allocated to treatment. Both treatments significantly increased lumbar spine BMD, however the increase was significantly larger after tibolone treatment than after raloxifene treatment (at year 1: 2.2% versus 1.2%, p<0.01 and at year 2: 3.8% versus 2.1%, p<0.001). After 2 years of treatment, the increase in total hip BMD in the tibolone group was significantly larger than in the raloxifene group (p<0.05). Both treatments significantly reduced type I collagen C-telopeptides and osteocalcin levels when compared to baseline. CONCLUSIONS: Tibolone 1.25 mg/day for 2 years prevents postmenopausal bone loss in older women and results in a larger increase of BMD both at the lumbar spine and hip than raloxifene.