Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study.

BACKGROUND: Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. OBJECTIVES: To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. METHODS: Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. RESULTS: In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. CONCLUSIONS: Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.

Clonidine for smoking cessation.

BACKGROUND: Clonidine was originally used to lower blood pressure. It acts on the central nervous system and may reduce withdrawal symptoms in various addictive behaviours, including tobacco use. OBJECTIVES: The aim of this review is to determine clonidine's effectiveness in helping smokers to quit. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register for trials of clonidine. Date of the most recent search: May 2004. SELECTION CRITERIA: We considered randomized trials of clonidine versus placebo with a smoking cessation endpoint assessed at least 12 weeks following the end of treatment. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the dose and duration of clonidine therapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least 12 weeks follow up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effect model. MAIN RESULTS: Six trials met the inclusion criteria. There were three trials of oral, and three of transdermal clonidine. Some form of behavioural counselling was offered to all participants in five of the six trials. There was a statistically significant effect of clonidine in one of these trials. The pooled odds ratio for success with clonidine versus placebo was 1.89 (95% confidence interval 1.30 to 2.74). There was a high incidence of dose-dependent side-effects, particularly dry mouth and sedation. REVIEWERS' CONCLUSIONS: Based on a small number of trials, in which there are potential sources of bias, clonidine is effective in promoting smoking cessation. Prominent side-effects limit the usefulness of clonidine for smoking cessation.

Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study.

BACKGROUND: Inhibition of leukocyte adhesion can reduce myocardial infarct size in animals. This study was designed to define the safety and efficacy of a recombinant, humanized, monoclonal antibody to the CD18 subunit of the beta2 integrin adhesion receptors (rhuMAb CD18), in reducing infarct size in patients treated with a thrombolytic agent. METHODS AND RESULTS: The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study (LIMIT AMI) was a randomized, double-blind, placebo-controlled, multicenter study conducted in 60 centers in the United States and Canada. A total of 394 subjects who presented within 12 hours of symptom onset with ECG findings (ST-segment elevation) consistent with AMI were treated with recombinant tissue plasminogen activator and were also given an intravenous bolus of 0.5 or 2.0 mg/kg rhuMAb CD18 or placebo. Coronary angiography was performed at 90 minutes, 12-lead ECGs were obtained at baseline, 90, and 180 minutes, and resting sestamibi scans were performed at >/=120 hours. Adjunctive angioplasty and use of glycoprotein IIb/IIIa antiplatelet agents at the time of angiography were discretionary. There were no treatment effects on coronary blood flow, infarct size, or the rate of ECG ST-segment elevation resolution, despite the expected induction of peripheral leukocytosis. A slight trend toward an increase in bacterial infections was observed with rhuMAb CD18 (P=0.33). CONCLUSIONS: RhuMAb CD18 was well tolerated but not effective in modifying cardiac end points.

Cardiovascular effects of carbon monoxide and cigarette smoking.

OBJECTIVES: This study was designed to compare the effects of inhaled carbon monoxide (CO), administered to achieve concentrations similar to those found in cigarette smoking, with the effects of cigarette smoking and air inhalation on heart rate and blood pressure, catecholamine release, platelet activation and C-reactive protein (CRP), a marker of inflammation. BACKGROUND: Carbon monoxide may contribute to smoking-induced cardiovascular disease. Exposure to environmental CO has been associated with increased cardiovascular morbidity and mortality. Animal and in vitro studies suggest that CO may contribute to atherosclerosis and endothelial injury. There is conflicting evidence about the hemodynamic consequences of exposure to CO and its role in platelet activation. METHODS: In a single-blind, crossover design, 12 healthy smokers inhaled CO at 1,200 ppm to 1,500 ppm to simulate CO intake from cigarette smoking, inhaled air on a similar schedule and smoked 20 cigarettes per day, each for seven days. Mean carboxyhemoglobin was 5 +/- 1% on CO treatment, 6 +/- 1% while smoking and 0.4 +/- 0.2% on air inhalations. RESULTS: There was no difference in blood pressure between the treatments. Mean heart rate was higher during cigarette smoking compared with CO and air inhalations (75 beats/min vs. 66 beats/min; p < 0.05). Plasma levels of platelet factor 4 and CRP and urine epinephrine and norepinephrine were higher while smoking, with no effect of CO compared with air. CONCLUSIONS: Carbon monoxide administered under conditions similar to those of cigarette smoking had no significant effect on blood pressure, heart rate, plasma catecholamines, platelet aggregation or CRP. The short-term chronotropic effect, adrenergic-activating, platelet-activating and CRP-increasing effects of smoking in healthy smokers are probably due to components of cigarette smoke other than CO.

Clonidine for smoking cessation.

BACKGROUND: Clonidine was originally used to lower blood pressure. It acts on the central nervous system and may reduce withdrawal symptoms in various addictive behaviours, including tobacco use. OBJECTIVES: The aim of this review is to determine clonidine's effectiveness in helping smokers to quit. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register. Date of the most recent search: October 1998. SELECTION CRITERIA: We considered randomised trials of clonidine versus placebo with a smoking cessation endpoint assessed at least 12 weeks following the end of treatment. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the dose and duration of clonidine therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least twelve weeks follow-up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effects model. MAIN RESULTS: Six trials met the inclusion criteria. There were three trials of oral, and three of transdermal clonidine. Some form of behavioural counselling was offered to all participants in five of the six trials. There was a statistically significant effect of clonidine in one of these trials. The pooled odds ratio for success with clonidine vs placebo was 1.89 (95% confidence interval 1.30 to 2.74). There was a high incidence of dose-dependent side-effects, particularly dry mouth and sedation. REVIEWER'S CONCLUSIONS: Based on a small number of trials, in which there are potential sources of bias, clonidine is effective in promoting smoking cessation. Prominent side-effects limit the usefulness of clonidine for smoking cessation.

Predictors and timing of adverse experiences during trandsdermal nicotine therapy.

OBJECTIVES: Difficulty sleeping is a recognised tobacco withdrawal symptom, but sleep problems, like application site reactions, are commonly reported as adverse reactions to transdermal nicotine therapy. However, no studies have examined potential predictive factors associated with the occurrence of expected adverse experiences during transdermal nicotine therapy. The subject of skin tolerability among patients with a history of eczema, psoriasis or other skin disorders is of particular interest, as are the relationships between plasma concentrations of nicotine, concurrent smoking, sleep problems and nausea. METHODS: The cohort study involving 1392 participants was designed to assess the timing, severity and predictive factors of adverse experiences reported during 24-hour transdermal nicotine therapy. Data were collected on patients aged 18 to 70 years old who were smokers and who had expressed a strong desire to stop smoking. The intervention consisted of brief behavioural counselling, a booklet containing smoking cessation advice and instructions for use of the patches, and a 12-week course of decreasing transdermal nicotine doses. RESULTS: Follow-up was available on 1392 out of 1481 study participants. The majority of adverse experiences were mild. Sleep problems occurred in 669 out of 1392 (48%) participants and most often commenced on the day of smoking cessation. Application site reactions occurred in 478 out of 1392 (34%) participants and most often occurred after 6 days of therapy. No predictor had an adjusted hazard ratio above 2. Statistically significant (p < 0.05) predictors of sleep problems were successfully quitting smoking and female gender. Predictors of application site reactions were psoriasis or eczema, other skin conditions, age <40 years, female gender, place of birth outside Australasia, and trade or university education level. Substantially increased nicotine intake during therapy compared with baseline smoking occurred in 8% of participants who smoked concurrently, and 4% of participants who did not (p = 0.1). Increased nicotine intake was associated with a modest increase in the overall rate of adverse experiences (89% vs 63%, p = 0.04) and dizziness/lightheadedness (17% vs 3%, p = 0.03), but not with sleep problems or cardiovascular events. CONCLUSIONS: Transdermal nicotine therapy appears to be well tolerated, even if the user smokes concurrently. Sleep disturbance during therapy appeared to be primarily associated with tobacco withdrawal rather than with nicotine excess from treatment with transdermal nicotine. Study participants with pre-existing skin disorders were somewhat more likely to report mild application site reactions than other participants.

Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray, and intravenous nicotine.

BACKGROUND AND OBJECTIVES: Delivery of a high concentration bolus of nicotine through the arterial circulation is believed to be an important determinant of the addictive, behavioral, and physiologic effects of nicotine. To better understand the pharmacologic features of nicotine with different routes of administration, we measured arterial and venous plasma concentrations of nicotine, cotinine, epinephrine, and norepinephrine after tobacco smoking, intravenous nicotine infusion, and use of a nicotine nasal spray. SUBJECTS AND METHODS: Arterial and venous blood samples were drawn simultaneously from 12 male smokers. Six subjects received a single dose of 1 mg nicotine nasal spray, and six subjects smoked cigarettes, one puff per minute for 10 minutes. All 12 subjects were administered nicotine as a 30-minute infusion beginning 70 minutes after administration of the nicotine nasal spray or commencement of smoking. RESULTS: The mean peak arterial plasma concentrations of nicotine (Cmax) after smoking or administration of nicotine nasal spray, or intravenous nicotine averaged twofold those of venous plasma. For nicotine nasal spray, the time to Cmax was much faster for arterial than for venous plasma (median, 5 versus 18 minutes, p < 0.01). Intravenous nicotine produced the greatest increase in plasma epinephrine concentration, although smoking had a greater chronotropic effect. Acute tolerance to the chronotropic effects of nicotine was suggested at pharmacodynamic analysis with venous nicotine concentrations, whereas analysis of arterial concentrations found the opposite--a time lag between plasma concentration and effect. CONCLUSION: Nicotine is rapidly absorbed from nicotine nasal spray. The Cmax of nicotine after smoking or administration of nicotine nasal spray, or intravenous nicotine is substantially higher in arterial than venous plasma. Acute tolerance to the chronotropic effects of nicotine is not apparent if arterial plasma concentrations are measured.

Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy.

This review discusses the known cardiovascular effects of smoking and the effects of nicotine without tobacco smoke and interprets the available data on cardiovascular risk during nicotine replacement therapy (NRT). Nicotine gum and patches are now approved for over the counter sale in the United States. Smokers with cardiovascular disease are advised to seek physician counseling before using nicotine products, but information regarding the safety of these products in such patients is not readily available to most physicians. Nicotine may contribute to cardiovascular disease, presumably by hemodynamic consequences of sympathetic neural stimulation and systemic catecholamine release. However, there are many potential cardiovascular toxins in cigarette smoke other than nicotine. The doses of nicotine obtained by regular cigarette smoking generally exceed those delivered by NRTs, and the cardiovascular effects of nicotine are, in general, more intense when delivered rapidly by cigarette smoking than the slower delivery by transdermal nicotine or nicotine gum. Because the dose-cardiovascular response relation for nicotine is flat, the effects of cigarette smoking in conjunction with NRT are similar to those of cigarette smoking alone. Cigarette smoking increases blood coagulability, a major risk factor for acute cardiovascular events, whereas transdermal nicotine does not appear to do so. Clinical trials of NRT in patients with underlying, stable coronary disease suggest that nicotine does not increase cardiovascular risk. At worst, the risks of NRT are no more than those of cigarette smoking. The risks of NRT for smokers, even for those with underlying cardiovascular disease, are small and are substantially outweighed by the potential benefits of smoking cessation.

Determinants of plasma concentrations of nicotine and cotinine during cigarette smoking and transdermal nicotine treatment.

OBJECTIVE: Interindividual variability in plasma concentrations of nicotine and its proximate metabolite, cotinine, is considerable during smoking and transdermal nicotine treatment, even among individuals taking in nominally similar doses of nicotine. This report explores the determinants of this variability and the utility of baseline (smoking) plasma concentrations to predict concentrations during transdermal nicotine treatment. METHODS: Data were analysed from a smoking cessation study (n = 466), and from a pharmacokinetic study (n = 12). Multiple regression models examined the relationships of plasma concentrations to individual characteristics such as smoking pattern, absorbed dose of nicotine, and pharmacokinetic parameters. RESULTS: Plasma concentrations of nicotine and cotinine were highly variable in both studies. Indirect estimates of plasma clearance (baseline plasma concentration divided by cigarettes per day) together with other factors could account for 18 to 33% of the variability during transdermal nicotine treatment in the smoking cessation study. In contrast, 75 to 99% was accounted for by direct measurements of plasma clearances and systemic dose of nicotine in the pharmacokinetic study. CONCLUSION: Plasma concentrations of nicotine and cotinine during transdermal nicotine treatment are poorly predicted by clinical history or baseline plasma concentrations. This is a result of inadequate characterisation of highly variable individual pharmacokinetic parameters and absorbed dose of nicotine. Considering the interindividual variability of plasma nicotine and cotinine concentrations together with the lack of clinical end-points for transdermal nicotine dosing, it seems logical to investigate the utility of a therapeutic drug monitoring approach for transdermal nicotine treatment-particularly for high dose regimens (> 22 mg per 24 hours).

The benefits of stopping smoking and the role of nicotine replacement therapy in older patients.

Considerable benefits accrue from stopping smoking in older patients. Reversal of the short term cardiovascular adverse effects of smoking is rapid. Long term risk reduction appears to occur as a result of decreased life-time exposure to tobacco smoke. The pharmacology of nicotine has not been studied in older patients but is unlikely to change in clinically important ways with advancing age. Nicotine replacement doubles long term success rates, compared with placebo, among younger smokers of > or = cigarettes per day. There is no reason to believe its efficacy should be less among older smokers. Transdermal nicotine is the replacement therapy of choice in older patients because of once-daily administration and good tolerability. Approximately half of the users of transdermal nicotine smoke concurrently with treatment. It is unlikely that concurrent smoking or high doses of nicotine replacement therapy will adversely effect healthy patients. While it is generally believed that patients with unstable coronary heart disease may be at risk from concurrent smoking during nicotine replacement therapy, it is unclear whether this risk is greater than the risk of smoking alone. Nicotine replacement therapy is a logical approach for motivated, older smokers who are unable to stop smoking by simpler means. Results can be augmented by including other interventions, such as counselling and follow-up support.

Double blind trial of repeated treatment with transdermal nicotine for relapsed smokers.

OBJECTIVE: To assess the efficacy and safety of a repeat course of treatment with transdermal nicotine for cessation of smoking in a brief intervention setting. STUDY DESIGN: Randomised, double blind, placebo controlled trial with follow up for 26 weeks. SUBJECTS: 629 smokers who had unsuccessfully attempted to stop smoking by using active transdermal nicotine and brief behavioural counselling. Smokers were motivated to quit smoking for a second time and smoked > or = 15 cigarettes a day. INTERVENTIONS: Twelve weeks' treatment with active transdermal nicotine patches or placebo and brief counselling at monthly visits. MAIN OUTCOME MEASURE: Sustained smoking cessation for the 28 days before the visit at week 12 verified by expired carbon monoxide concentrations. RESULTS: At 12 weeks 21/315 (6.7%) subjects allocated to active treatment had stopped smoking compared with 6/314 (1.9%) allocated to placebo (absolute difference 4.7%; 95% confidence interval 1.6% to 7.9%; P = 0.003). At 26 weeks the rates were 20/315 (6.4%) and 8/314 (2.6%) (3.8%; 0.6% to 7.0%; P = 0.021). Difficulty in sleeping was reported by 43/179 (24.0%) on active treatment and 19/143 (13.3%) on placebo (P = 0.015). Severe reactions at the site of application were rare (6/322; 1.9%). CONCLUSIONS: Repeated treatment with transdermal nicotine together with brief counselling can improve the low success rates of smoking cessation in recently relapsed, moderate to heavy smokers. Questions remain about whether more intensive interventions or higher doses of nicotine could be more effective. The likelihood of severe reactions at the site of application with repeated treatment is low.

A cohort study comparing the detection of HPV DNA from women who stop and continue to smoke.

The objective of this study was to compare the detection of human papillomavirus (HPV) DNA in women who stopped smoking, and those who continued to smoke. Women entering a smoking cessation programme had tampon specimens collected and analyzed for HPV DNA using polymerase chain reaction (PCR) (L1 consensus primers). Women with HPV DNA in their initial specimens had follow-up specimens collected 1 year later. The stored initial specimens were reanalyzed in the same experiment with the follow-up specimen. In addition, Hybrid Capture and quantitative PCR were used to determine if the change in HPV DNA over the year of follow-up was greater in either group. Of 197 women who were recruited into the study, 57 (29%) were positive for HPV DNA. Second specimens were obtained from 49 of these 57 women. Of these 49 women, 13 had stopped smoking and 36 continued to smoke. The detection of HPV DNA in follow-up specimens was not significantly different in the women who stopped smoking (54%) compared to those who continued to smoke (50%, p = 0.81). Furthermore, the change in the amount of HPV DNA during follow-up was not different in women who stopped smoking compared to women who continued to smoke (p > 0.25). This study suggests that smoking cessation does not affect the detection of genital HPV DNA. On the basis of these findings it is likely that smoking does not increase the risk of invasive cervical cancer by prolonging the detection of HPV DNA.

Prospective study of factors predicting outcome of transdermal nicotine treatment in smoking cessation.

OBJECTIVE: To assess the factors associated with cessation of smoking with transdermal nicotine and brief behavioural counselling. DESIGN: Interviews, treatment, and follow up for 26 weeks. SUBJECTS: 1481 subjects recruited by mass media publicity who smoked > or = 15 cigarettes a day and were motivated to stop smoking. INTERVENTIONS: Twelve weeks' treatment with transdermal nicotine and brief behavioural counselling at monthly visits. MAIN OUTCOME MEASURE: Sustained smoking cessation for the 28 days before the visit at week 26 verified by expired carbon monoxide concentrations. The logistic regression analysis included all subjects. RESULTS: Most subjects were dependent on nicotine, and the mean (SD) number of cigarettes smoked a day was 32 (12). Overall, 316/1481 subjects (21.3%) stopped smoking. Factors associated with stopping were being male (adjusted odds ratio 2.0; 95% confidence interval 1.5 to 2.7), age > or = 40 years (1.5; 1.1 to 2.0), living with a spouse or partner (1.5; 1.1 to 2.1), motivation ("want to quit" 1.7; 1.2 to 2.3), and concern about weight gain (1.7; 1.3 to 2.2). Negative associations were smoking marijuana (0.4; 0.2 to 0.8) and the presence of other smokers in the household (0.8; 0.6 to 0.9). Almost all subjects who smoked three or more cigarettes in the first four weeks of treatment resumed smoking in the long term (525/547, 96%). CONCLUSIONS: Age, sex, marital status (living with a spouse or partner), motivation, concern about weight gain, recent marijuana smoking, and other smokers in the household were baseline factors associated with differences in outcome of smoking cessation attempts. Smoking three or more cigarettes in the first few weeks after stopping strongly predicted long term relapse.

Discordance of mercury sphygmomanometer and ambulatory blood pressure measurements for the detection of untreated hypertension in a population study.

To evaluate the extent to which ambulatory blood pressure (ABP) measurements could redefine the prevalence of untreated hypertension in the general population, we studied a randomly selected subgroup of the National Heart Foundation of Australia's Risk Factor Prevalence Study 1989. Subjects taking blood pressure (BP) lowering medications were excluded, leaving 66 patients with 24h ABP recordings for analysis. Mean awake ABPs were generally lower than survey BPs and diminished with reduced activity (away from work and during sleep). The correlation of survey BP and daytime ABP (10.00-20.00 h) classification of untreated hypertension was moderate (Cohen's correlation coefficient 0.49-0.56). Untreated hypertension was identified in 20 subjects by the mercury sphygmomanometer technique (BP > or = 150/90 mmHg). Six (30%) of those subjects had a mean ABP < 135/85 mmHg suggesting 'normotension' on ambulatory criteria. Conversely, 19 subjects had a mean ABP of > or = 135/85 mmHg, five (26%) of whom had 'normal' survey BPs. We conclude that ambulatory and mercury sphygmomanometer methods of BP measurement in this population study defined a similar prevalence of untreated hypertension but were discordant for a substantial percentage of individuals. The prognostic significance of ABP levels and any discordance with survey or office mercury sphygmomanometer BP readings will remain uncertain until prospective studies using both forms of measurement are completed.

Antismoking products.

Nicotine is the addictive substance in tobacco and its withdrawal is responsible for a range of unpleasant symptoms after smoking cessation. Although it produces acute physiological effects, nicotine alone is not carcinogenic and does not appear to cause the vascular disease associated with smoking. Nicotine replacement has been shown to be a safe and effective pharmacological treatment for tobacco dependence in certain smokers. Its efficacy is greatest when prescribed for those who are motivated and highly nicotine-dependent. It is probably not indicated for smokers with a low degree of nicotine dependence. Studies of nicotine chewing gum conducted in special referral clinics have generally produced positive results, whereas those conducted in community practice settings have shown a smaller benefit when compared with placebo. When the results of all published placebo-controlled trials are pooled the typical improvement in smoking cessation rate is 40% (odds ratio continued smoking 0.6; 95% confidence interval 0.5-0.71; P less than 0.00001). The best results with nicotine chewing gum have been obtained with multicomponent programmes which have included some counselling and ongoing follow up and support. Early reports of success with a transdermal nicotine preparation suggest that it may have similar efficacy to nicotine gum. Clonidine administered orally or transdermally has also been shown to reduce tobacco withdrawal symptoms but requires more convincing evidence of long-term efficacy before it can be recommended for routine use. Currently available over-the-counter products, apart from nicotine chewing gum, have not been shown to be effective.