Shoshana Zevin

Drug interactions with tobacco smoking : An update

Cigarette smoking remains highly prevalent in most countries. It can affect drug therapy by both pharmacokinetic and pharmacodynamic mechanisms. Enzymes induced by tobacco smoking may also increase the risk of cancer by enhancing the metabolic activation of carcinogens.Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1. CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta. There are genetic polymorphisms in the inducibility of CYP1A1, with some evidence that high inducibility is more common in patients with lung cancer. CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of drugs and activation of some procarcinogens. Caffeine demethylation, using blood clearance or urine metabolite data, has been used as an in vivo marker of CYP1A2 activity, clearly demonstrating an effect of cigarette smoking. CYP2E1 metabolises a number of drugs as well as activating some carcinogens. Our laboratory has found in an intraindividual study that cigarette smoking significantly enhances CYP2E1 activity as measured by the clearance of chlorzoxazone.In animal studies, nicotine induces the activity of several enzymes, including CYP2E1, CYP2A1/2A2 and CYP2B1/2B2, in the brain, but whether this effect is clinically significant is unknown. Similarly, although inhibitory effects of the smoke constituents carbon monoxide and cadmium on CYP enzymes have been observed in vitro and in animal studies, the relevance of this inhibition to humans has not yet been established.The mechanism involved in most interactions between cigarette smoking and drugs involves the induction of metabolism. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis with enhanced heparin binding to antithrombin III. Cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration.Pharmacodynamic interactions have also been described. Cigarette smoking is associated with a lesser magnitude of blood pressure and heart rate lowering during treatment with β-blockers, less sedation from benzodiazepines and less analgesia from some opioids, most likely reflecting the effects of the stimulant actions of nicotine.The impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy. Cigarette smoking should be specifically studied in clinical trials of new drugs.

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.

Low-dose enzyme replacement therapy for Gaucher's disease: Effects of age, sex, genotype, and clinical features on response to treatment☆

Although alglucerase therapy has become the treatment of choice for symptomatic patients with Gauchers disease, the low-dose/high-frequency regimen introduced as a means to reduce the high cost of treatment has raised major controversy. We evaluated the efficacy and safety of low-dose alglucerase in 29 patients with Gauchers disease who completed 6 to 28 months of therapy. All received intravenous alglucerase at a monthly dose of 30 units/kg, given usually in equal doses 3 times a week. All patients responded well to treatment. The hematological improvement and the reduction in organomegaly were satisfactory. No correlation was found between age, sex, genotype, previous splenectomy, or severity score index and the response to treatment. Patients with a greater degree of hepatomegaly tended to have a more pronounced decrease in liver size, although this reduction did not reach statistical significance. We confirmed that a low-dose/high-frequency regimen of alglucerase was as effective as a high-dose/low-frequency protocol in the treatment of Gauchers disease, even in the severely ill. Whenever cost is an issue, we recommend using this low-dose regimen.

Clinical pharmacology of nicotine

Nicotine is the primary reason why people consume tobacco products and it may contribute to causation of tobacco-related diseases. This chapter reviews the human pharmacology of nicotine, the evidence for a role of nicotine in human disease, and the use of nicotine (gum) as a therapeutic agent in smoking cessation therapy.

Dose-related cardiovascular and endocrine effects of transdermal nicotine

Transdermal nicotine in doses up to 21 mg/24 hr is used to facilitate smoking cessation. However, this dose does not achieve the nicotine plasma levels seen among heavy smokers, and underdosing may be one of the reasons for the limited efficacy of transdermal nicotine. There are some concerns about the adverse cardiovascular effects of nicotine, especially with concomitant smoking. Treatment with higher doses of transdermal nicotine has been proposed for highly dependent smokers, but the effects of such treatment on the cardiovascular system have not been determined. The objective of this study was to determine the cardiovascular effects of high‐dose transdermal nicotine with concomitant smoking.

Cotinine effects on nicotine metabolism

Nicotine clearance and half‐life are known to be significantly reduced in smokers compared to nonsmokers. Cotinine is the major primary metabolite of nicotine, and it accumulates in the body with regular smoking. Nicotine and cotinine appear to be metabolized by the same liver enzyme. Therefore we hypothesized that cotinine inhibits nicotine metabolism, resulting in slower nicotine clearance in smokers compared with nonsmokers.

A safety trial of high dose glyceryl triacetate for Canavan disease.

Canavan disease (CD MIM#271900) is a rare autosomal recessive neurodegenerative disorder presenting in early infancy. The course of the disease is variable, but it is always fatal. CD is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA), which breaks down N-acetylaspartate (NAA) to acetate and aspartic acid. The lack of NAA-degrading enzyme activity leads to excess accumulation of NAA in the brain and deficiency of acetate, which is necessary for myelin lipid synthesis. Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone and has proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (up to 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We present for the first time the safety profile of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infants with CD at ages 8 months and 1 year with high dose GTA, for 4.5 and 6 months respectively. No significant side effects and no toxicity were observed. Although the treatment resulted in no motor improvement, it was well tolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, when significant brain damage was already present. Further larger studies of CD patients below age 3 months are required in order to test the long-term efficacy of this drug.

Transient Expression of a Purine-Selective Nucleoside Transporter (SPNTint) in a Human Cell Line (HeLa)

AbstractPurpose. The goal of this study was to develop a mammalian expression system for the cloned rat intestinal, Na+-dependent, purine-selective nucleoside transporter (SPNTint) and to study the interactions of nucleosides and nucleoside analogs with this transporter. Methods. Lipofection was used to transfect HeLa cells with a mammalian expression vector (pcDNA3) containing the cDNA insert encoding SPNTint. Nucleoside transport activity was measured using [3H] inosine, [3H]uridine, [3H]-dideoxyinosine (ddl), and [3H]-2-chloro-2′-deoxyadenosine (2CdA) as model substrates. Results. Expression of SPNTint was observed between 36 and 90 h post-transfection, with maximal expression at 66 h. At 66 h, Na+-stimulated uptake of [3H]inosine in cells transiently transfected with SPNTint was approximately threefold greater than that in cells transfected with empty vector (p < 0.05). The Na+-stimulated uptake of both inosine and uridine was saturable (Km = 28.1 ± 7.1 μM and 20.6 ± 5.6 μM, respectively) in the transfected cells and was significantly inhibited by the naturally occurring nucleosides (1 mM) inosine and uridine and to a lesser extent by thymidine. The nucleoside analogs ddl (IC50 = 46 μM) and 2CdA (IC50 =.13 μM) also significantly inhibited the Na+-stimulated uptake of [3H]inosine. A Na+-stimulated uptake of [3H]2CdA was observed suggesting that 2CdA is also a permeant of SPNTint. Conclusions. HeLa cells transiently transfected with SPNTint represent a useful tool to study the kinetics and interactions of drugs with SPNTint.

Clinical pharmacology of oral cotinine.

Cotinine is the major proximate metabolite of nicotine. The aims of our study were to assess the pharmacokinetics of oral cotinine comparing the use of saliva and plasma concentrations, and to characterize the subjective and cardiovascular effects of oral cotinine in nonsmokers. The clearance and half-life of cotinine measured using plasma or saliva concentrations were similar. There was no change in heart rate or blood pressure, and no differences in subjective response with cotinine compared to placebo. We conclude that administration of oral cotinine with measurement in saliva samples is easy, safe, and provides an accurate estimate of systemic clearance and half-life of cotinine.

Nicotine‐mecamylamine interactions

Mecamylamine blocks nicotinic cholinergic receptors and has been proposed, in combination with nicotine, as a novel therapy to aid smoking cessation. The objective of this study was to characterize the pharmacokinetic and pharmacodynamic interactions between transdermal mecamylamine and intravenous nicotine.