Effect of Switching to the Tobacco Heating System Versus Continued Cigarette Smoking on Chronic Generalized Periodontitis Treatment Outcome: Protocol for a Randomized Controlled Multicenter Study.

BACKGROUND: Smoking is a significant risk factor for periodontal disease and tooth loss, as shown in several clinical studies comparing smokers and nonsmokers. Although only a few longitudinal studies have assessed the outcome of periodontal disease after smoking cessation, they indicated that recovery after nonsurgical treatment was more successful in those who had quit smoking. As part of tobacco harm reduction strategies, substituting cigarettes with alternative, less harmful tobacco products is an approach complementary to cessation for smokers who would otherwise continue to smoke. The Tobacco Heating System (THS), developed by Philip Morris International (commercialized as IQOS), is part of the heat-not-burn product category. The IQOS device electrically heats tobacco instead of burning it, at much lower temperatures than cigarettes, thereby producing substantially lower levels of harmful and potentially harmful constituents, while providing the nicotine, taste, ritual, and a sensory experience that closely parallel those of cigarettes. Phillip Morris International has published the results from a broad clinical assessment program, which was established to scientifically substantiate the harm reduction potential of the THS among adult healthy smokers switching to the THS. The program is now progressing toward including adult smokers with smoking-related diseases. OBJECTIVE: The goal of this study is to demonstrate favorable changes of periodontal endpoints in response to mechanical periodontal therapy in patients with generalized chronic periodontitis who completely switched to THS use compared with continued cigarette smoking. METHODS: This is a randomized controlled two-arm parallel-group multicenter Japanese study conducted in patients with chronic generalized periodontitis who switch from cigarettes to THS compared with smokers continuing to smoke cigarettes for 6 months. The patients were treated with mechanical periodontal therapy as per standard of care in Japan. The primary objective of the study is to demonstrate the beneficial effect of switching to THS use compared with continued cigarette smoking on pocket depth (PD) reduction in all sites with an initial PD≥4 mm. The secondary objectives include evaluation of other periodontal parameters (eg, clinical attachment level or gingival inflammation) and overall oral health status upon switching to THS. Safety was monitored throughout the study. RESULTS: In total, 172 subjects were randomized to the cigarette (n=86) or THS (n=86) groups, and all 172 completed the study. The conduct phase of the study is completed, while data cleaning and analyses are ongoing. CONCLUSIONS: This study is the first to test a heat-not-burn tobacco product in smokers with an already established disease. The results should further strengthen the evidence that switching to THS can significantly reduce the risk of smoking-related diseases if favorable changes in the evolution of chronic generalized periodontitis after mechanical therapy are found when compared with continued cigarette smoking. TRIAL REGISTRATION: ClinicalTrials.gov NCT03364751; https://clinicaltrials.gov/ct2/show/NCT03364751. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15350.

Influence of smoking and smoking cessation on levels of urinary 11-dehydro thromboxane B2.

BACKGROUND: Thromboxane is a key clinical risk endpoint of smoking-induced inflammation which has been associated in the pathogenesis of cardiovascular disease. The goal of this review is to quantify the effect of smoking and smoking cessation on one of its urinary metabolites, 11-dehydrothromboxaneB2. METHODS: PubMed and SCOPUS were searched to identify publications which report urinary 11-dehydrothromboxaneB2 levels in smokers and non-smokers, as well as articles reporting the effect of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. RESULTS: We found ten studies assessing urinary 11-dehydrothroboxaneB2 levels in smokers and non-smokers. Four papers reported the amount of urinary 11-dehydrothromboxaneB2 excreted in 24 h while six reported the amount excreted adjusted for creatinine. The meta-analyses comparing the excretion of urinary 11-dehydrothromboxane in current smokers to non-smokers report increased levels in current smokers (mean difference = 0.31 µg/24-h [95%CI: 0.27-0.34] and 166.45 pg/mg creatinine [95%CI: 120.51-212.40]). There were not enough publications to perform meta-analyses on the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. CONCLUSIONS: Urinary 11-dehydrothromboxaneB2 levels are increased in cigarette smokers, however, more data are needed to elucidate the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion.

Physiologically Based Pharmacokinetic Modelling of Cytochrome P450 2C9-Related Tolbutamide Drug Interactions with Sulfaphenazole and Tasisulam.

BACKGROUND AND OBJECTIVES: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80-90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug-drug interactions (DDIs). This paper describes the development and verification of SimCYP®-based PBPK models that accurately describe the human pharmacokinetics of tolbutamide when dosed alone or in combination with the CYP2C9 inhibitors sulfaphenazole and tasisulam. METHODS: A PBPK model was optimized in SimCYP® for tolbutamide as a CYP2C9 substrate, based on published in vitro and clinical data. This model was verified to replicate the magnitude of DDI reported with sulfaphenazole and was further applied to simulate the DDI with tasisulam, a small molecule investigated for the treatment of cancer. A clinical study (CT registration # NCT01185548) was conducted in patients with cancer to assess the pharmacokinetic interaction of tasisulum with tolbutamide. A PBPK model was built for tasisulam, and the clinical study design was replicated using the optimized tolbutamide model. RESULTS: The optimized tolbutamide model accurately predicted the magnitude of tolbutamide AUC increase (5.3-6.2-fold) reported for sulfaphenazole. Furthermore, the PBPK simulations in a healthy volunteer population adequately predicted the increase in plasma exposure of tolbutamide in patients with cancer (predicted AUC ratio = 4.7-5.4; measured mean AUC ratio = 5.7). CONCLUSIONS: This optimized tolbutamide PBPK model was verified with two strong CYP2C9 inhibitors and can be applied to the prediction of CYP2C9 interactions for novel inhibitors. Furthermore, this work highlights the utility of mechanistic models in navigating the challenges in conducting clinical pharmacology studies in cancer patients.

Factors associated with stroke, myocardial infarction, ischemic heart disease, unstable angina, or mortality in patients from real world clinical practice with newly-diagnosed type 2 diabetes and early glycemic control.

OBJECTIVES: The objective of this study was to identify factors associated with stroke, myocardial infarction (MI), all-cause mortality, or a diagnosis of ischemic heart disease (IHD) or unstable angina (UA), among patients newly-diagnosed with type 2 diabetes (T2DM) with no recent history of cardiovascular (CV) events who rapidly achieve and maintain HbA1c ≤8.0%. METHODS: Data were obtained from the Clinical Practice Research Datalink (CPRD) from January 1990 to December 2012. A nested case-control design was used with Cox proportional hazards analysis. Cases were identified by the first occurrence of stroke, MI, IHD, UA, or death within 5 years after HbA1c ≤ 8.0% was first reached (index date) following T2DM diagnosis. Controls were selected using a risk-set sampling approach and were matched 4:1 to cases using index date, exposure time, age, gender, and HbA1c at index date. RESULTS: A total of 11,426 T2DM patients met the inclusion criteria for cases. Of these, 5,261 experienced a CV event. Stroke was the most frequent CV event (40%), followed by IHD (29%), MI (22%), and UA (9%). Mean HbA1c ≥7.0% over the length of exposure (vs 6.5 to <7.0%) was associated with an increased risk of stroke, MI, and IHD. The use of anti-platelet medications at baseline was also associated with increased risk of stroke (HR = 1.82 [CI = 1.60-2.06]), MI (HR = 1.67 [CI = 1.38-2.03]), and IHD (HR = 1.85 [CI = 1.57-2.17]). Mean HbA1c < 6.0% was associated with increased risk of stroke (HR = 1.29 [CI = 1.02-1.63]) and IHD (HR = 1.65 [CI = 1.25-2.19]). Use of nitrate medications at baseline was associated with increased risk of MI (HR = 2.83 [CI = 2.24-3.57]), IHD (HR = 4.32 [CI = 3.57-5.22]), and UA (HR = 10.38 [CI = 7.67-14.03]). CONCLUSIONS: Early and sustained HbA1c control between 6.5 and <7.0% appears to be an important modifiable factor that helps reduce CV risk in patients with newly-diagnosed T2DM in real-world clinical practice.

Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors.

PURPOSE: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors. METHODS: Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations. RESULTS: Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration-QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation. CONCLUSIONS: The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.

Effects of enzastaurin and its metabolites on the QT interval in cancer patients.

Preclinical and interim results from a clinical pharmacology study in patients with cancer indicated that enzastaurin might have the potential to prolong the QT. Rather than undertake a formal thorough QT study, the effect of enzastaurin on the QT was assessed by combining the QT corrected for heart rate (QTc) intervals from 3 clinical pharmacology studies totaling 85 patients with cancer receiving multiple therapeutic or supratherapeutic doses of enzastaurin. Neither a placebo nor an active control was used. Serial, replicate, time-matched electrocardiograms were collected during a no-drug baseline day and when enzastaurin and its major active metabolite, LSN326020, had achieved steady state. Plasma concentrations of enzastaurin and LSN326020 were determined at each electrocardiogram point to enable concentration-QT analyses. The cross-study analysis showed that enzastaurin resulted in a statistically significant prolongation of the QTc at therapeutic and supratherapeutic doses. At an enzastaurin maximum plasma concentration (Cmax ) of 3660 nmol/L, the predicted QTc using Fridericia's formula (QTcF) interval and its 90% confidence interval was 17.72 milliseconds (16.52-18.92 milliseconds). Likewise, at an LSN326020 Cmax value of 1718 nmol/L, the predicted QTcF interval was 20.23 milliseconds (18.72-21.74 milliseconds). The concentration-QTcF slopes for enzastaurin and LSN326020 were positive and statistically significantly different from zero (all P < .05).