Efficacy and Safety of a Nicotine Mouth Spray for Smoking Cessation: A Randomized, Multicenter, Controlled Study in a Naturalistic Setting.

BACKGROUND: Nicotine replacement therapy (NRT) has been demonstrated to be an effective pharmacological treatment for smoking cessation, and most types of NRT have been approved as over-the-counter (OTC) medications. In an effort to create a fast-acting, flexible, and discreet NRT, a nicotine mouth spray (NMS) has been developed. This study was designed to assess the efficacy and safety of NMS in a naturalistic setting in the United States. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 26-week study in 1198 smokers motivated to quit. The study was designed to resemble an OTC environment, and thus included limited intervention, limited motivational screening, and no behavioral support. The primary efficacy endpoint was carbon monoxide-verified, self-reported continuous abstinence from smoking from week 2 until week 6. The safety of NMS was assessed by measuring vital signs, visual mouth inspection, and collection of subject-reported adverse events (AEs). RESULTS: The percentage of subjects with carbon monoxide-verified continuous abstinence from week 2 to week 6 was statistically significantly greater in the NMS group compared with the placebo group (5.0% vs. 2.5%, p = .021). Statistically significant treatment effects for the NMS were maintained throughout the 26-week period. The study medications were generally well tolerated. The severity of AEs was similar for both treatment groups, and most AEs were of mild or moderate severity. CONCLUSIONS: These study results demonstrate that the NMS is an effective and safe smoking cessation option for smokers motivated to quit, even in a naturalistic setting and without behavioral support. IMPLICATIONS: This study demonstrated the safety, efficacy, and acceptability of an NMS in an OTC environment with no behavioral counseling or support. It provides an additional option for smokers motivated to quit. TRIAL REGISTRATION: ClinicalTrials.gov (number NCT02355665).

Effect of nicotine 6 mg gum on urges to smoke, a randomized clinical trial.

BACKGROUND: Ability to manage urges to smoke is fundamental to maximizing the chances of success in smoking cessation. Previous studies have linked a higher dose of nicotine in nicotine replacement therapy to a higher success rate for smoking cessation. Thus, this study was performed to compare relief of urges to smoke, up until 5 h following treatment with a new 6 mg nicotine gum versus currently marketed 4 mg nicotine gum. METHODS: This was a randomized crossover clinical study. Following 12 h of abstinence from smoking, either one 6 mg or one 4 mg nicotine gum was given to 240 healthy adult smokers. Thereafter, urges to smoke were scored on a 100 mm Visual Analogue Scale repeatedly over 5 h. RESULTS: The reductions in urges to smoke over the first 1 and 3 h after administration were statistically significantly greater with 6 mg than 4 mg gum, (p < 0.005). A 50% reduction in perceived urges to smoke was reached in 9.4 min with 6 mg gum compared to 16.2 min with 4 mg gum (median values). The median duration of a 50% or more reduction in VAS urges to smoke score was 111 min with the 6 mg gum, versus 74 min for the 4 mg gum. CONCLUSION: This study provides evidence that the 6 mg nicotine gum provided a greater reduction, faster and longer relief of urges to smoke than the 4 mg nicotine gum. TRIAL REGISTRATION: EudraCT Number: 2010-023268-42. Study was first entered in EudraCT 2011-02-23.

Potassium oxalate mouthrinse reduces dentinal hypersensitivity: A randomized controlled clinical study.

BACKGROUND: Dentinal hypersensitivity is a prevalent oral condition that can be treated with in-office application of potassium oxalate (KO), which has US Food and Drug Administration 510(k) clearance. In this study, the authors assessed a KO mouthrinse for home use. The authors evaluated clinically meaningful improvement by analyzing the proportions of participants who responded to treatment. METHODS: In this multicenter, double-blind, parallel-group controlled study, the authors randomly assigned 375 participants with dentinal hypersensitivity to 1 of 2 mouthrinse groups: KO (189 participants) and placebo (186 participants). Participants used their assigned mouthrinses for 4 weeks. Each participant's success (defined as a ≥ 30% reduction from baseline in mean cold air stimulus response) was the primary efficacy measurement. The authors further defined success, on the basis of 2012 criteria from the American Dental Association, as a statistically significant difference of 20% or more between experimental and placebo groups for 1 sensitivity index. RESULTS: KO mouthrinse had statistically significantly higher success rates (the primary efficacy measurement) than did placebo (69.3% versus 44.6%; estimated odds ratio [OR], 2.817; 95% confidence interval [CI], 1.843 to 4.307; P < .001). At week 4, KO had statistically significant improvements compared with placebo in cold air stimulus score (estimated difference, -14.27 millimeters; 95% CI, -18.68 to -9.87; 35.6% improvement; P < .001) and tactile sensitivity (estimated difference, 13.45 grams; 95% CI, 9.83 to 17.08; 88.0% improvement; P < .001). The authors also observed statistically significant improvements for KO at week 2. Cold air stimulus and tactile sensitivity scores at weeks 2 and 4 were secondary efficacy measurements. CONCLUSIONS: This study's results demonstrated that KO mouthrinse used as an adjunct to toothbrushing statistically and clinically significantly controlled and reduced dentinal hypersensitivity. PRACTICAL IMPLICATIONS: Clinicians can use these results when determining appropriate at-home care regimens for patients with hypersensitivity.

Comparison of Two Forms of Loperamide-Simeticone and a Probiotic Yeast (Saccharomyces boulardii) in the Treatment of Acute Diarrhoea in Adults: A Randomised Non-Inferiority Clinical Trial.

BACKGROUND: Acute diarrhoea is a frequent health problem in both travellers and residents that has a social and economic impact. This study compared the efficacy and tolerability of two loperamide-simeticone formulations and a Saccharomyces boulardii capsule as symptomatic treatment. METHODS: This was a prospective, randomised, single (investigator)-blind, three-arm, parallel group, non-inferiority clinical trial in adult subjects with acute diarrhoea at clinics in Mexico and India, with allocation to a loperamide-simeticone 2/125 mg caplet or chewable tablet (maximum eight in 48 h) or S. boulardii (250 mg twice daily for 5 days). OUTCOME MEASURES: The primary outcome measure was the number of unformed stools between 0 and 24 h following the initial dose of study medication (NUS 0-24). The secondary outcome measures were time to last unformed stool (TLUS), time to complete relief of diarrhoea (TCRD), time to complete relief of abdominal discomfort (TCRAD) and the subject's evaluation of treatment effectiveness. Follow-up endpoints at 7 days were feeling of complete wellness; stool passed since final study visit; and continued or recurrent diarrhoea. SUBJECTS: In this study, 415 subjects were randomised to either a loperamide-simeticone caplet (n = 139), loperamide-simeticone chewable tablet (n = 139) or S. boulardii capsule (n = 137) and were included in the intention-to-treat analysis. RESULTS: With regards to mean NUS 0-24, the loperamide-simeticone caplet was non-inferior to loperamide-simeticone tablets (3.4 vs. 3.3; one-sided 97.5 % confidence interval ≤0.5), with both significantly lower than S. boulardii (4.3; p < 0.001). The loperamide-simeticone groups had a shorter median TLUS [14.9 and 14.0 vs. 28.5 h (loperamide-simeticone caplet and chewable tablet groups, respectively, vs. S. boulardii); p < 0.001], TCRD (26.0 and 26.0 vs. 45.8 h; p < 0.001) and TCRAD (12.2 and 12.0 vs. 23.9 h; p < 0.005) than S. boulardii. Treatment effectiveness for overall illness, diarrhoea and abdominal discomfort relief was greater (p < 0.001) in the loperamide-simeticone groups than with S. boulardii. At 7-day follow-up most subjects reported passing stool at least once since the final study visit (loperamide-simeticone caplet 94.1 %, loperamide-simeticone chewable tablet 94.8 %, S. boulardii 97.0 %), did not experience continued or recurrent diarrhoea [loperamide-simeticone caplet 3.7 % (p < 0.03 vs. S. boulardii), loperamide-simeticone chewable tablet 3.7 %, S. boulardii 5.7 %] and felt completely well [loperamide-simeticone caplet 96.3 % (p < 0.02 vs. S. boulardii), loperamide-simeticone chewable tablet 96.3 % (p < 0.02 vs. S. boulardii), S. boulardii 88.6 %]. All treatments were well-tolerated with few adverse events. CONCLUSIONS: The loperamide-simeticone caplet was non-inferior to the original loperamide-simeticone chewable tablet formulation; both formulations can be expected to demonstrate similar clinical efficacy in the relief of symptoms of acute diarrhoea. Both loperamide-simeticone formulations were superior to the S. boulardii capsule in the primary and secondary endpoints. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00807326.

Nicotine gum or patch treatment for smoking cessation and smoking reduction: a multi-centre study in Chinese physicians.

In China, around 23% of physicians (41% male, 3% female) currently smoke. Pharmacotherapy for tobacco dependence is available, but is not widely used in China. The purpose of this study was to estimate the effectiveness and the safety on smoking cessation of nicotine gum and nicotine patch in Chinese healthcare professionals. Three hundred regular smokers motivated to quit were recruited from six hospitals in China. All subjects were accepted nicotine replacement therapy, and they could choose nicotine gum (2 mg or 4 mg, depending on baseline smoking level) or nicotine patch (15 mg/16 h) for 12 weeks, with a 12-week follow-up. Limited behavioural support was provided. At Week 24, the 2-24 weeks continuous abstinence rate (verified by expired carbon monoxide) was 17%, the point prevalence abstinence rate (no smoking since the previous visit) was 35%, and 38% of subjects had continuously reduced their daily cigarette consumption by at least 50% versus baseline. Compliance with treatment was good, particularly with patch. No serious adverse event was reported, and most adverse events were mild or moderate. The most common treatment-related adverse events were gastrointestinal (both gum and patch) and local irritation symptoms. Nicotine patch and gum were well tolerated in Chinese smokers. Abstinence rates were comparable to those previously reported with nicotine replacement therapy, and many smokers who did not quit substantially reduced their cigarette consumption.

Effects of nicotine mouth spray on urges to smoke, a randomised clinical trial.

OBJECTIVE: A new nicotine mouth spray was shown to be an effective stop-smoking treatment. This study was set up to examine the speed with which it relieves urges to smoke, and how it compares with nicotine lozenge in this respect. DESIGN: Randomised, cross-over trial that compared nicotine mouth spray 2 mg versus nicotine lozenge 2 or 4 mg. SETTING: Clinical pharmacology research unit. PARTICIPANTS: 200 Volunteer smokers who smoked their first cigarette of the day within 30 min of waking. INTERVENTIONS: Subjects abstained from smoking the night before the morning they attended the laboratory. Treatment was administered following 5 h of witnessed abstinence. PRIMARY AND SECONDARY OUTCOME MEASURES: Urge to smoke was rated before and at 1, 3, 5, 10, 15, 25, 30, 45 min and 1, 1.5, and 2 h after treatment administration. The primary outcome concerned change during the first 1, 3 and 5 min after treatment administration. RESULTS: Nicotine mouth spray achieved greater reductions in craving than either lozenge during the first 1, 3 and 5 min postadministration. After using mouth spray, half of the users experienced 50% reduction in craving within 3.40 min, while the same treatment effect was achieved within 9.92 and 9.20 min for the 2 and 4 mg lozenge, respectively. Adverse events with both mouth spray and lozenge were mostly mild. Hiccups, local irritation, nausea and dyspepsia were more frequent with spray than lozenge. CONCLUSIONS: Nicotine mouth spray provides a faster relief of cravings than nicotine lozenge.

Efficacy of a nicotine mouth spray in smoking cessation: a randomised, double-blind trial.

A nicotine mouth spray has advantages over other acute forms of nicotine replacement therapy, such as a faster uptake of nicotine and faster relief of craving. This multicentre, randomised (2:1), double-blind, placebo-controlled efficacy and safety study evaluated self-reported, carbon monoxide-verified continuous abstinence from smoking from week 2 until weeks 6, 24, and 52 in 479 smokers (≥ 1 cigarette per day) who were treated with either active (n=318) or placebo (n=161) spray for 12 weeks and low-intensity counselling at three smoking cessation clinics in Denmark and Germany. Active treatment yielded significantly higher continuous abstinence rates than placebo from week 2 until week 6 (26.1% versus 16.1%; relative success rate (RR) 1.62, 95% CI 1.09-2.41), week 24 (15.7% versus 6.8%; RR 2.30, 95% CI 1.23-4.30), and week 52 (13.8% versus 5.6%; RR 2.48, 95% CI 1.24-4.94). Most adverse events were mild to moderate, and 9.1% of subjects on active spray withdrew due to adverse events, compared to 7.5% on placebo. The overall rate of treatment-related adverse events was 87.4% with active spray versus 71.4% with placebo spray. Nicotine mouth spray delivered significantly higher 6-, 24- and 52-week continuous abstinence rates than placebo.

Single-dose pharmacokinetics of nicotine when given with a novel mouth spray for nicotine replacement therapy.

INTRODUCTION: As the efficacy of nicotine replacement therapy might be improved by faster systemic nicotine uptake, a new nicotine mouth spray has been developed. The current study was performed to evaluate the single-dose pharmacokinetics of nicotine at 3 doses of the mouth spray and to compare the speed of nicotine uptake from the spray versus nicotine lozenge and gum. METHODS: In a randomized crossover study, 45 healthy adult smokers received single doses of nicotine mouth spray 1, 2, and 4 mg, nicotine lozenge 4 mg, and nicotine gum 4 mg on separate occasions. Blood samples were collected for 12 hr to determine pharmacokinetic variables. RESULTS: Mean plasma nicotine concentrations during the first 10 min, measured using area under the curve (AUC(10 min)), were 3 times as high with spray 4 mg as with lozenge or gum. The AUC(10 min) with 2 and 1 mg doses of spray, respectively, was twice and 1.5 times as high as the AUC(10 min) with lozenge or gum. The maximum baseline-corrected plasma nicotine concentration (cC(max)) with 4 mg spray exceeded that for lozenge and gum by 34% and 20%; the median time to reach C(max) was 10-12.5 min for the 3 doses of spray, 45 min for lozenge, and 30 min for gum. The mean baseline-corrected area under the plasma nicotine concentration-versus-time curve (cAUC(∞)) with 4 mg spray was 15% higher than that with gum but did not differ significantly from that with lozenge. CONCLUSION: Nicotine delivered via the mouth spray is absorbed considerably faster than nicotine given via gum or lozenge.

Predicting the outcome of optic neuritis: evaluation of risk factors after 30 years of follow-up.

BACKGROUND: Multiple sclerosis (MS) is a common disease with considerable risk for disability. Optic neuritis (ON) is a common first symptom of MS but it can also remain an isolated episode. Therefore, predicting the outcome of ON has gained in importance, particularly in light of current discussions of early disease modifying treatments in individuals at risk of developing MS. We reported previously on our cohort of 86 patients with acute monosymptomatic unilateral ON of whom 33 had progressed to MS after up to 18 years. Three patients had died. The present study extends the observation period to 31 years. METHODS: Patients were followed for up to 31 years or until a diagnosis of MS was made. Cerebrospinal fluid (CSF) was examined at onset. HLA class I and II antigens were determined. Magnetic Resonance Imaging (MRI) was performed during follow up. FINDINGS: Only one of 50 patients at risk developed clinical manifestations of MS during the extended follow up period. The estimated 15-year-risk of MS was 40 % (confidence interval [CI] 31%-52%). Most cases, 20 of 34 or 60%, occurred within three years. Among factors present at onset, CSF with mononuclear pleocytosis and/or oligoclonal Ig increased the risk for subsequent MS significantly, 49% (CI 38%-65%) compared with 23 % (CI 12%-44%) for those with normal CSF, p=0.02. Younger patients and those with winter onset also had greater risk. Recurrence of ON similarly elevated the risk significantly, p<0.001. After 19-31 years MRI lesions suggestive of demyelinating disease were detected in 20 of 30 individuals although no clinical manifestations of MS had occurred. CONCLUSION: The risk of MS in this large population-based prospective ON patient series was 40% and significantly higher in those with inflammatory CSF abnormalities at onset. Clinically silent MRI lesions suggestive of MS were detected in a majority of those with "ON-only". This finding should be taken into account when discussing prognosis and early intervention in patients with clinically isolated ON.

Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes.

Identification of individuals at high risk of developing type 2 diabetes is a prerequisite for prevention of the disease. We therefore studied risk factors predicting type 2 diabetes in the Botnia Study in Western Finland. A total of 2,115 nondiabetic individuals were prospectively followed with repeated oral glucose tolerance tests. After a median follow-up of 6 years, 127 (6%) subjects developed diabetes. A family history of diabetes (hazard ratio [HR] 2.2, P = 0.008), BMI (HR for comparison of values below or above the median 2.1, P < 0.001), waist-to-height index (2.3, P < 0.001), insulin resistance (2.1, P = 0.0004), and beta-cell function adjusted for insulin resistance (2.7, P < 0.0001) predicted diabetes. Marked deterioration in beta-cell function with modest changes in insulin sensitivity was observed during the transition to diabetes. The combination of FPG > or =5.6 mmol/l, BMI > or =30 kg/m(2), and family history of diabetes was a strong predictor of diabetes (3.7, P < 0.0001). Of note, using FPG > or =6.1 mmol/l or 2-h glucose > or =7.8 mmol/l did not significantly improve prediction of type 2 diabetes. In conclusion, a marked deterioration in beta-cell function precedes the onset of type 2 diabetes. These individuals can be identified early by knowledge of FPG, BMI, and family history of diabetes.

[Strongly increasing incidence of adenocarcinoma of the esophagus and gastric cardia]. / Adenocancer i esofagus och ventrikelns kardiaregion ökar kraftigt.

The objective of this retrospective study was to see whether there was an increasing incidence of adenocarcinoma of the oesophagus and gastric cardia in the Swedish population 1970-1997. If there was, could it be explained as a period or cohort phenomenon? The data were compared with the incidence of squamous cell carcinoma and gastric adenocarcinoma with the gastric cardia excluded. Age standardised incidence for each sex was calculated using the age distribution of the world population as a reference. For the combined group of adenocarcinoma in the oesophagus and gastric cardia incidence gradually increased during the study period. The median increase between adjacent five-year intervals was 14% in men and 20% in women. Previously described risk factors are gastro-oesophageal reflux, obesity and smoking. This study suggests that the increasing incidence also can be explained as a shift in classification from squamous cell carcinoma to adenocarcinoma after 1985.

Late mortality among five-year survivors of cancer in childhood and adolescence.

The present study was aimed at assessing differences between the Nordic countries, if any, in late mortality among five-year survivors of childhood cancer. All cases diagnosed before the age of 20 years, between 1960 and 1989, were collected from all Nordic cancer registries. In total, 13,689 patients were identified as five-year survivors and during the extended follow-up 12.3% of them died. Mortality was analysed by decade of diagnosis, for all sites, and for leukaemia, Hodgkin's lymphoma, and central nervous system tumours separately. Analyses were done within a Cox proportional hazards regression framework with adjustments made for gender and age at diagnosis. Hazard ratios were calculated in relation to a weighted Nordic mean based on the proportion of five-year survivors in each country. Overall late mortality was significantly higher in Denmark and Finland than in Norway and Sweden. This could not be explained by inverse differences in five-year survival. The differences diminished over time and had disappeared in the last period. The pattern was similar for both genders. The disappearance of the differences was most probably the effect of a closer collaboration between Nordic paediatric oncologists with development and implementation of common protocols for treatment of childhood cancers in all countries.

A prospective survey of radiotherapy practice 2001 in Sweden.

A prospective survey of radiotherapy practice in Sweden was conducted during 12 weeks in the autumn of 2001. All hospitals that provided radiotherapy participated, and all patients who started radiotherapy during the study period were included. The final patient sample comprised 5,105 treatments given to 4,171 patients. The results were compared with those of a similar survey conducted in 1992, and the following conclusions were drawn: A substantial increase in the use of radiotherapy was noted; The estimated proportion of cancer cases receiving radiotherapy (compared to the incident number of cases) had increased from 32% in 1992 to 47%; The proportion of cancer patients receiving radiotherapy was estimated at between 37 and 46%; 54% of treatments were given with curative intent, a small increase since 1992; The difference between regional and county departments for proportion of treatments with curative intent had diminished; Treatments with curative intent used a higher proportion of resources measured in terms of fractions; The proportion of palliative treatment was slightly lower than in 1992, but the absolute number of treatments had increased by more than 20%; No improvement in participation in clinical trials was noted; Treatments given with curative intent were more complex with more fields; Hyperfractionation was used, mainly in treatments of cancers of the head and neck, lung, and bladder; The use of brachytherapy for non-gynaecological malignancies had increased dramatically; Treatment of bone metastases with a single or few fractions was used much more frequently; Dose planning and patient set-up showed a high standard but quality control of dosimetry of given treatment did not fully comply with Swedish and European recommendations; The treatment devices seem to be used more efficiently.

FDG PET studies during treatment: prediction of therapy outcome in head and neck squamous cell carcinoma.

BACKGROUND: Positron emission tomography (PET) provides metabolic information of tissues in vivo. The purpose of this study was to assess the value of PET with 2-[(18) F] fluoro-2-deoxy-D-glucose (FDG) in prediction of therapy outcome (tumor response, survival, and locoregional control) in locally advanced HNSCC. METHODS: Between 1993 and 1999 47 patients underwent PET before (PET(1)) and after (PET(2)) 1 to 3 weeks of radical treatment with evaluation of metabolic rate (MR) and standardized uptake value (SUV) of FDG. All patients received radiotherapy, and 10 also received neoadjuvant chemotherapy. Median follow-up time was 3.3 years. RESULTS: Low and high MR FDG at PET(2), with median value as cutoff, was associated with complete remission in 96% and 62% (p =.007), with 5-year overall survival in 72% and 35% (p =.0042) and with local control in 96% and 55% (p =.002), respectively. CONCLUSIONS: FDG PET in the early phase of treatment of HNSCC is associated with tumor response, survival, and local control.