Delmopinol - adsorption to and absorption through the oral mucosa.

OBJECTIVES: To investigate the surface chemical changes in dynamic interactions of delmopinol on salivary films on oral mucosa in healthy participants after rinsing with an unbuffered water solution of delmopinol, and to examine the oral tissue disposition of delmopinol in rats after local administration. MATERIAL AND METHODS: The contact angle technique was used to monitor the interaction of delmopinol with the salivary film coating the upper labial mucosa of 10 healthy participants through a 4 h period. The tissue disposition of 14C-labelled delmopinol was examined in rats by autoradiography. RESULTS: Rinsing with delmopinol increased the polarity of the saliva coated mucosa during the time of observation. The binding of delmopinol was verified in the autoradiograms showing that radioactivity remained in the rat oral mucosa after 24 h. Delmopinol was however not irreversibly bound. CONCLUSIONS: The findings indicate that delmopinol interacts with the salivary film of the upper labial mucosa and affects its polarity. It appears that delmopinol assists in the maintenance of the hydrophilicity of the mucosal pellicle and thereby also reinforcing hydration of the mucosa. The rat autoradiograms, showed that radioactivity remains in the oral mucosa after 24 h, but diffuses through the mucosal membranes into the systemic circulation.

Survival outcomes in myelofibrosis patients treated with ruxolitinib: A population-based cohort study in Sweden and Norway.

OBJECTIVE: To estimate survival in Swedish and Norwegian myelofibrosis (MF) patients who received ruxolitinib. METHODS: Swedish and Norwegian patients with MF diagnosis in the National Cancer Registries (Sweden: 2001-2015; Norway: 2002-2016) and ≥1 record of ruxolitinib in the Prescribed Drug Registries (2013-2017) were included. Patients were followed from ruxolitinib initiation until death or end of follow-up; those who discontinued ruxolitinib were followed from ruxolitinib discontinuation. Relative survival (RS) and excess mortality rate ratios (EMRRs) were calculated vs a matched general population. Average loss in life expectancy (LEL) was predicted using flexible parametric models. RESULTS: Among patients who initiated ruxolitinib (n = 190), 1- and 4-year RS were 0.80 (95% confidence interval [CI]: 0.74, 0.86) and 0.52 (95% CI: 0.42, 0.64), respectively, and LEL was 11 years. EMRR was greater in patients aged >70 vs <60 years (3.16; 95% CI: 1.34-7.40). Among patients who discontinued ruxolitinib (n = 71), median RS was 16.0 months (95% CI: 6.3, NE), and LEL was 12 years. After ruxolitinib treatment discontinuation, Swedish patients (n = 37) received glucocorticoids, hydroxyurea, busulfan, danazol and lenalidomide. CONCLUSION: Swedish and Norwegian MF patients who discontinued ruxolitinib had dismal survival outcomes and limited subsequent treatment options, highlighting the need for improved therapies.

Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges.

BCR-ABL inhibitors for treating chronic myeloid leukemia in chronic phase have transformed a previously incurable malignancy into a manageable condition. However, suboptimal medication adherence has been observed with these agents affecting clinical outcomes and healthcare costs. In order to raise awareness of the problem of adherence, and before developing pragmatic strategies to enhance medication adherence, a deep understanding of the best approaches for measuring adherence in chronic myeloid leukemia patients and identifying non-adherence is required. A systematic literature review on the prevalence, measurement methods, consequences and risk factors for non-adherence to BCR-ABL inhibitors and adherence-enhancing interventions was performed and critically appraised. Of the 19 included articles, 9 were retrospective. Average adherence varied from 19% to almost 100% of the proportion of prescribed drug taken, but it was measured through various different methods and within different study groups. Suboptimal adherence was associated with a negative impact on both clinical and economic outcomes. There is a lack of supportive evidence demonstrating a difference in adherence across BCR-ABL inhibitors and even contradictory results between the 2(nd) generation inhibitors. Drug-related adverse events and forgetfulness were common reasons for intentional and unintentional non-adherence, respectively, but further research is required to identify additional reasons behind non-adherence or patients at risk of non-adherence. Non-adherence in chronic myeloid leukemia patients treated with BCR-ABL inhibitors is common and associated with critical outcomes. However, this review highlights important existing gaps, reveals inconsistent definitions, and a lack of standardized methods for measuring adherence in chronic myeloid leukemia. All require further investigation.

A systematic review of methods to diagnose oral dryness and salivary gland function.

BACKGROUND: The most advocated clinical method for diagnosing salivary dysfunction is to quantitate unstimulated and stimulated whole saliva (sialometry). Since there is an expected and wide variation in salivary flow rates among individuals, the assessment of dysfunction can be difficult. The aim of this systematic review is to evaluate the quality of the evidence for the efficacy of diagnostic methods used to identify oral dryness. METHODS: A literature search, with specific indexing terms and a hand search, was conducted for publications that described a method to diagnose oral dryness. The electronic databases of PubMed, Cochrane Library, and Web of Science were used as data sources. Four reviewers selected publications on the basis of predetermined inclusion and exclusion criteria. Data were extracted from the selected publications using a protocol. Original studies were interpreted with the aid of Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. RESULTS: The database searches resulted in 224 titles and abstracts. Of these abstracts, 80 publications were judged to meet the inclusion criteria and read in full. A total of 18 original studies were judged relevant and interpreted for this review. In all studies, the results of the test method were compared to those of a reference method.Based on the interpretation (with the aid of the QUADAS tool) it can be reported that the patient selection criteria were not clearly described and the test or reference methods were not described in sufficient detail for it to be reproduced. None of the included studies reported information on uninterpretable/intermediate results nor data on observer or instrument variation. Seven of the studies presented their results as a percentage of correct diagnoses. CONCLUSIONS: The evidence for the efficacy of clinical methods to assess oral dryness is sparse and it can be stated that improved standards for the reporting of diagnostic accuracy are needed in order to assure the methodological quality of studies. There is need for effective diagnostic criteria and functional tests in order to detect those individuals with oral dryness who may require oral treatment, such as alleviation of discomfort and/or prevention of diseases.

Screening for oral dryness in relation to salivary flow rate addresses the need for functional tests of saliva.

PURPOSE: The aim of the present study was to assess the occurrence of reported subjective oral dryness in relation to objective sialometric values in a randomly selected group and a dental care-seeking group. MATERIALS AND METHODS: A questionnaire assessing subjective oral dryness was sent out to a randomly selected sample of 200 individuals. The dental care-seeking group was recruited from among patients attending the Department of Oral Diagnostics, Malmö University. A total of 200 patients were asked to participate in the present study. In total, 312 individuals (78%) completed the survey and 157 individuals agreed to participate in the complementary clinical examination that included measures of salivary flow rate. RESULTS: The reported subjective oral dryness was 20% and 28.6% for the randomly selected group and the dental care-seeking group, respectively. No statistically significant differences were found between the two study populations with regard to percentage of reported subjective oral dryness, and stimulated and unstimulated salivary flow rates (P > 0.05). In the dental care-seeking group, individuals reporting subjective oral dryness presented 'a small degree of abrasion in the dentine in the incisor region' to a greater extent (P < 0.05). No statistically significant association between subjective oral dryness and unstimulated and stimulated salivary flow rates was found in either of the studied populations (P > 0.05). Individuals identified with subjective or objective oral dryness presented to a greater extent a history of oral rehabilitation compared to individuals who showed no indication of oral dryness. CONCLUSIONS: No association between sialometric measures and subjective report of oral dryness was found in the present study.

The effect of laser therapy as an adjunct to non-surgical periodontal treatment in subjects with chronic periodontitis: a systematic review.

BACKGROUND: The objective of this study was to systematically review the evidence on the effectiveness of laser therapy as an adjunct to non-surgical periodontal treatment in adults with chronic periodontitis. METHODS: A search was conducted for randomized controlled trials comparing the outcome of periodontitis with laser as an adjunct to scaling and root planing in the treatment of chronic periodontal disease. The electronic databases, PubMed and Cochrane Central Register of Controlled Trials, were used as data sources. Screening, data abstraction, and quality assessment were conducted independently by three reviewers (MK, HJ, and CDL). The primary outcome measures evaluated were changes in clinical attachment level, probing depth, and bleeding on probing. RESULTS: The search resulted in 25 abstracts; four randomized controlled clinical trials were included. Four different laser methods were used; consequently, it was impossible to conduct a quantitative data synthesis leading to a meta-analysis. All studies included a limited number of subjects. CONCLUSIONS: No consistent evidence supports the efficacy of laser treatment as an adjunct to non-surgical periodontal treatment in adults with chronic periodontitis. More randomized controlled clinical trials are needed.

Higher plasma but not intracellular concentrations after infusion with liposomal daunorubicin compared with conventional daunorubicin in adult acute myeloid leukemia.

To investigate the plasma and intracellular pharmacokinetics of liposomal daunorubicin (DaunoXome) in comparison with conventional daunorubicin, 14 patients aged 28 to 60 years with newly diagnosed acute myeloid leukemia were treated for 1 day with DaunoXome (50 mg/m) and for 2 days with daunorubicin (50 mg/m) with concomitant Ara-C (7 days, 200 mg/m, continuous IV). Eleven of the 14 patients entered complete remission; 9 are still alive. Pharmacokinetic profiles were obtained by blood sampling at appropriate intervals on days 1 to 4. Daunorubicin and daunorubicinol concentrations in plasma and in peripheral leukemic blast cells were measured by high-performance liquid chromatography. Following liposomal daunorubicin administration, the peak values and plasma area under the curve (AUC) were more than 100 times higher than after administration of conventional daunorubicin (AUC, 176 vs. 0.98 micromol/L x hour), but the intracellular AUCs were comparable (759 vs. 715 micromol/L x hour). Intracellular concentrations after DaunoXome peaked later and half as high as after daunorubicin. After DaunoXome versus daunorubicin, plasma clearance was 0.001 versus 0.4 micromol/h, respectively. The volume of distribution was 5.5 L for DaunoXome, versus 3640 L for daunorubicin, indicating low tissue affinity for the liposomal formulation. The authors conclude that liposomal daunorubicin, DaunoXome, yields 2-log higher plasma concentrations but similar intracellular concentrations of daunorubicin and its metabolite daunorubicinol than does free daunorubicin.

Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells.

The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (NAs) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside)-induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5'-nucleotidases (50-100%). The ratio 5'-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5'-nucleotidase/deoxycytidine kinase ratio might be an important factor in predicting resistance to NAs. Implications of this finding for combining anthracyclines or vinca alkaloids with NAs toward leukemic cells are discussed.

Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study.

Cladribine has single-drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara-CTP) of cytosine arabinoside (ara-C). To evaluate the feasibility of adding intermittent cladribine to intermediate-dose ara-C (1 g/m2/2 h) b.i.d. for 4 d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60 years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty-three patients (median 71 years, range 60-84 years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17 d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8 d with fever over 38 degrees C, and 17 d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two-drug therapy (P = 0.014). The median survival with a 2-year follow-up was 14 months, and the 2-year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population-based approach, the overall results are encouraging.