A randomized, controlled trial to assess the efficacy and safety of a transdermal delivery system of nicotine/mecamylamine in cigarette smokers

AIMS: To determine the efficacy and safety of nicotine transdermal therapy co-administered with the nicotine antagonist, mecamylamine, compared to a nicotine transdermal patch alone (21 mg nicotine + 6 mg mecamylamine, 21 mg nicotine + 3 mg mecamylamine, and 21 mg nicotine + 0 mg mecamylamine). DESIGN: Multi-center (n = 4), double-blind, randomized, parallel group, repeat-dose study. SETTING: Clinical laboratory. PARTICIPANTS: A total of 540 subjects were enrolled into the study-135 from each of four sites; 180 patients in each of three treatment arms. INTERVENTION: Treatment was administered for the first 6 weeks of the 8-week study. Patients were instructed to continue smoking for the first 2 weeks of treatment. MEASUREMENTS: The primary efficacy parameter was 4-week continuous abstinence after the quit date, confirmed with an expired carbon monoxide of < 10 parts per million. FINDINGS: Analysis of the 4-week continuous abstinence for the intent-to-treat population showed overall rates of 29% (nicotine + 6 mg mecamylamine), 29% (nicotine + 3 mg mecamylamine) and 23% (nicotine only) using the slip definition which allows smoking in the first 2 weeks after the quit date. Statistical analyses revealed no significant treatment differences. Analyses using the strict definition (no smoking after the quit date) yielded similar non-significant group differences (29%, 27%, 26%). CONCLUSION: If adding mecamylamine to nicotine replacement therapy (NRT) improves the chances of success at stopping smoking, the results of this study suggest that the effect is very small.     

Hepatic activation of IKK/NFκB signaling induces liver fibrosis via macrophage-mediated chronic inflammation

Liver damage in humans is induced by various insults including alcohol abuse, hepatitis B/C virus infection, autoimmune or metabolic disorders and, when persistent, leads to development of liver fibrosis. Because the nuclear factor-κB (NF-κB) system is activated in response to several of these stresses, we hypothesized that NF-κB activation in hepatocytes may contribute to fibrosis development. To activate the NF-κB signaling pathway in a time- and cell-type-specific manner in the liver, we crossed transgenic mice carrying the tetracycline-responsive transactivator under the control of the liver activator protein promotor with transgenic mice carrying a constitutively active form of the Ikbkb gene (IKK2 protein [CAIKK2]). Double-transgenic mice displayed doxycycline-regulated CAIKK2 expression in hepatocytes. Removal of doxycycline at birth led to activation of NF-κB signaling, moderate liver damage, recruitment of inflammatory cells, hepatocyte proliferation, and ultimately to spontaneous liver fibrosis development. Microarray analysis revealed prominent up-regulation of chemokines and chemokine receptors and this induction was rapidly reversed after switching off the CAIKK2 expression. Turning off the transgene expression for 3 weeks reversed stellate cell activation but did not diminish liver fibrosis. The elimination of macrophages by clodronate-liposomes attenuated NF-κB-induced liver fibrosis in a liver-injury-independent manner. Conclusion: Our results revealed that hepatic activation of IKK/NF-κB is sufficient to induce liver fibrosis by way of macrophage-mediated chronic inflammation. Therefore, agents controlling the hepatic NF-κB system represent attractive therapeutic tools to prevent fibrosis development in multiple chronic liver diseases. (HEPATOLOGY 2012;56:1117-1128).     

Early phosphatemia changes in acute cardiac care patients

IntroductionThe significance of inorganic serum phosphate levels (Pi) in patients with acute coronary syndromes (ACS) in the reperfusion era is unknown, as well as its relation to biomarkers of myocardial necrosis. Our aim was to assess admission Pi and its dynamics in patients admitted to the intensive cardiac care unit (ICCU), with emphasis on patients with ST segment elevation myocardial infarction (STEMI).MethodsWe studied 192 patients admitted to the ICCU during a 4-month period. The first group included 92 patients with STEMI (STEMI group) treated by primary percutaneous coronary intervention (PCI). The second group consisted of 100 patients without ACS (non-ACS group). Normophosphatemia was defined as Pi 0.7–1.6 mmol/l. Phosphatemia was measured at admission and then 6 h and 12 h later as well as troponin I.ResultsAdmission phosphatemia was lower in the STEMI group as compared to the non-ACS group (Pi 0.95 mmol/l vs. 1.18 mmol/l, p<0.001). Admission hypophosphatemia (Pi<0.7 mmol/l) was more often present in the STEMI group than in the non-ACS group (21% vs. 4%, p=0.001). In all hypophosphatemic STEMI patients, serum Pi normalized itself within 6 h without substitution. Admission hyperphosphatemia (Pi>1.6 mmol/l) was more frequent in non-ACS group (6.5% STEMI pts. vs. 13% non-ACS pts.). In the STEMI group, admission phosphatemia did not correlate with peak troponin I.ConclusionWe conclude that patients with STEMI treated by primary PCI have lower Pi and more frequent transient hypophosphatemia at admission than acute cardiac care patients without acute coronary syndrome.