Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug–drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3–4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4–4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.     

Relationship Between Calcium Intake and Impaired Activities of Daily Living in a Japanese Population: NIPPON DATA90

BackgroundMajor reasons for long-term care insurance certification in Japan are stroke, dementia, and fracture. These diseases are reported to be associated with calcium intake. This study examined the association between calcium intake and impaired activities of daily living (ADL) using the data from NIPPON DATA90, consisting of representative sample of the Japanese population.MethodsA population-based nested case-control study was performed. A baseline survey was conducted in 1990, followed by ADL surveys of individuals ≥65 years old in 2000. Individuals with impaired ADL and selected age- and sex-matched controls were then identified. We obtained 132 pairs. Calcium intake was energy-adjusted using the residual method. The association between calcium intake and impaired ADL was examined using conditional logistic regression models. To assess the accuracy of the estimates, we conducted bootstrap analyses.ResultsThe adjusted odds ratios (ORs) for impaired ADL compared with the group with a calcium intake of <476 mg/day were 0.72 (95% confidence interval [CI], 0.37–1.40) for the 476–606 mg/day group and 0.44 (95% CI, 0.21–0.94) for the ≥607 mg/day group in 2000 (P for linear trend = 0.03). After the bootstrap analyses, the inverse relationship unchanged (median OR per 100-mg rise in calcium intake, 0.87 [1,000 resamplings]; 95% CI, 0.76–0.97).ConclusionsAfter bootstrap analyses, calcium intake was inversely associated with impaired ADL 10 years after the baseline survey.Key words: bootstrap analyses, calcium intake, impaired activities of daily living, nested case-control study, NIPPON DATA90     

Non–clinical efficacy,safety and stable clinical cell processing of induced pluripotent stem cell‐derived anti–glypican‐3 chimeric antigen receptor‐expressing natural killer/innate lymphoid cells

The use of allogeneic, pluripotent stem‐cell‐derived immune cells for cancer immunotherapy has been the subject of recent clinical trials. In Japan, investigator‐initiated clinical trials will soon begin for ovarian cancer treatment using human leukocyte antigen (HLA)‐homozygous‐induced pluripotent stem cell (iPSC)‐derived anti–glypican‐3 (GPC3) chimeric antigen receptor (CAR)‐expressing natural killer/innate lymphoid cells (NK/ILC). Using pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, in terms of efficacy, safety and producibility. In this paper, we describe our methods for the stable, feeder‐free production of CAR‐expressing NK/ILC cells from CAR‐transduced iPSC with clinically relevant scale and materials. The average number of cells that could be differentiated from 1.8‐3.6 × 10⁶ iPSC within 7 weeks was 1.8‐4.0 × 10⁹. These cells showed stable CD45/CD7/CAR expression, effector functions of cytotoxicity and interferon gamma (IFN‐γ) production against GPC3‐expressing tumor cells. When the CAR‐NK/ILC cells were injected into a GPC3‐positive, ovarian‐tumor‐bearing, immunodeficient mouse model, we observed a significant therapeutic effect that prolonged the survival of the animals. When the cells were injected into immunodeficient mice during non–clinical safety tests, no acute systemic toxicity or tumorigenicity of the final product or residual iPSC was observed. In addition, our test results for the CAR‐NK/ILC cells generated with clinical manufacturing standards are encouraging, and these methods should accelerate the development of allogeneic pluripotent stem cell‐based immune cell cancer therapies.     

Evaluating a single dental anxiety question in Finnish adults

OBJECTIVE: To evaluate the psychometric properties (criterion validity, construct validity, sensitivity, and specificity) of a single-item question screening for dental anxiety in a Finnish adult population. MATERIAL AND METHODS: A total of 823 subjects, ranging in age from 18 to 87 years, answered a questionnaire comprising sections assessing the respondents' demographic profile and dental attendance patterns. A single dental anxiety question and the Modified Dental Anxiety Scale (MDAS) were included. The final response rate was 85%. RESULTS: Eight percent of the sample was highly dentally anxious using the MDAS cut-off point of 19 or above. Twelve percent of the respondents rated themselves as "very scared" on the single-item question. The percentage agreement between the single-item question and the MDAS was 93; the Kappa coefficient was 0.63. Specificity of the single question was 0.95 while sensitivity was 0.80 using the MDAS dichotomous classification. The single-item question related to age (p<0.001), gender (p<0.001), and dental attendance (p<0.001), as predicted. CONCLUSIONS: The single question has good validity, specificity, and sensitivity and may be used with confidence to assess dental fear in such situations as national health surveys or in routine dental practice where a multi-item dental anxiety questionnaire is not feasible.     

Resistance of core materials against torsional forces on differently conditioned titanium posts

STATEMENT OF THE PROBLEM: The separation of core materials from titanium posts, which have a low modulus of elasticity, has been identified as a problem in restorative dentistry. PURPOSE: This study evaluated the resistance to torsional forces of various core materials adapted to differently conditioned titanium posts. MATERIAL AND METHODS: Seven hundred and twenty specimens were tested consisting of: 6 core materials and 5 surface conditioning techniques for 2 kinds of opaquers with 10 specimens in each group (6 x 5 x 2 x 10=600) plus 6 core materials and 2 opaquers were tested and considered as control groups on nonconditioned titanium posts, each group containing 10 specimens (6 x 2 x 10=120). The custom-made pure titanium posts were conditioned with the following products: Silicoater Classical, Silicoater MD, Rocatec, Kevloc, and Siloc surface-conditioning systems. Subsequently, 6 core materials with different compositions (Durafill, Adaptic, Coradent, Ti-Core, Hytac Aplitip, and Photac-Fil Aplitip) were applied to titanium posts that were previously coated with 2 types of light-polymerized opaquers, either Artglass or Dentacolor. Sixty air-abraded titanium posts (250 microm, 30 seconds) were used as controls for each core material. Following thermocycling (5 degrees -55 degrees C, 30 seconds, 5,000 cycles), maximum torsional forces were determined with an electronic torque movement key. Data were statistically analyzed by 1-way analysis of variance followed by 2-way analysis of variance (P<.05). RESULTS: Significantly higher mean torsional forces were observed with respect to Siloc (20.4 Newton decimeter [dNm]), Silicoater Classical (18.6 dNm), Silicoater MD (18.2 dNm), and Rocatec (17.0 dNm) systems compared with the mean for the untreated control group (14.6 dNm) (P<.001). The Kevloc system (10.4 dNm) demonstrated no significant difference compared with the control group (P>.001). The Kevloc system in combination with the Artglass opaquer and Photac-Fil Aplitip (0.00 dNm) core material showed no resistance against torsional forces. Significant differences were observed between hybrid core materials and microfilled composite, compomer, or resin-modified glass ionomer core materials (P<.001). CONCLUSION:Within the limitations of this study, the resistance to torsional forces for the core materials on titanium posts increased with the use of chemical surface-conditioning techniques and varied in accordance with the opaquer type. Type of core material also significantly influenced the resistance after thermocycling.     

Neutral zone approach for denture fabrication for a partial glossectomy patient: a clinical report

According to the neutral zone concept, an appropriate denture form can be molded into a physiologic tooth arrangement by using a narrow rim bar occlusion, tissue conditioner, and a direct relining technique for both intaglio and cameo surfaces by using VLC reline resin. Denture stability can be obtained with this "border molding" technique, not only for edentulous patients but also for those with oral deformities.     

Investigation of trends and characteristics in patients with obstructive sleep apnea

Background

Oral appliance (OA) therapy for obstructive sleep apnea (OSA) has only been part of Japan’s National Health care coverage plan since 2004. Subsequently, not enough time has passed to establish the medical trends and characteristics of OSA patients in Japanese Dental Hospitals.

Aim

The aim of this study was to investigate the medical trends and the characteristics in patients with OSA who visited our clinic, and to compare our findings with previous studies.

Setting and design

Epidemiological survey (retrospective study).

Materials and methods

Two hundred and one patients were recruited at the Internal Medicine Division in the Tsurumi University Dental Hospital from February 2006 to December 2008, consecutively. Patients received a medical interview, and a detailed sleep analysis that included a polysomnography (PSG) to verify the exact nature of their condition. The efficacy of OA was assessed in 49 patients who wore an OA and underwent PSG.

Results

Of all subjects, 141 patients visited the Prosthodontic Division to receive OA therapy, 38 patients were treated or received a follow up examination in the Internal Medicine Division. The dropout rate was 10.4% in the all subjects, 17.0% in patients who visited the Prosthodontic Division. The male-to-female ratio was 3.3:1, 3.0:1 in patients who visited the Prosthodontic Division. In addition, females had a lower rate of OAS severity than males. In our patients, the major complication was hypertension and cardiac disease. The success rate of OA was 75.5%.

Conclusion

This approach allowed us to reveal some of the trends and characteristics in our patients.