Advertisements suggest that smokers of cigarettes low in nicotine are exposed to less nicotine and tar. Nicotine yields are measured with smoking machines, but machines do not smoke cigarettes as people do. We therefore measured the actual nicotine content of commercial cigarettes with different nicotine and tar yields as determined with smoking machines, and also measured actual nicotine intake as indicated by blood concentrations of its metabolite, cotinine, in 272 subjects smoking various brands of cigarettes. We found that low-yield cigarette tobacco did not contain less nicotine; in fact, the nicotine concentration in tobacco inversely correlated (r = -0.53, P less than 0.05) with the concentration measured by smoking machines. Blood cotinine concentrations correlated with the number of cigarettes smoked per day but not with the nicotine yield measured by smoking machines. Only 3.8 to 5.0 per cent of total variance in blood cotinine was contributed by nicotine yield. We conclude that smokers of low-nicotine cigarettes do not consume less nicotine.

Our findings suggest that maternal cigarette smoking may be the major predictor of tone abnormalities reported in cocaine-exposed infants.

No abstract

Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.

While naproxen pharmacokinetics appear to be altered in the presence of both diminished renal and hepatic function, the degree to which naproxen disposition might be influenced in the elderly by concurrent alteration in these functions is not obvious. Total plasma clearance/bioavailability (CL/F) of naproxen after a single 375 mg oral dose was found to be less in a group of 10 healthy men between 66 and 81 years of age than in 10 healthy men between 22 and 39 years (0.318 +/‐ 0.078, 0.416 +/‐ 0.061 l/h). At steady state (375 mg, 12 hourly), however, CL/F was statistically indistinguishable between the two groups. The fraction of naproxen unbound to plasma protein was doubled in elderly subjects, both at peak and trough drug concentrations. The lowered protein binding tended to obscure a 50% decrement in the intrinsic clearance of naproxen in the elderly as estimated by unbound clearance/bioavailability (213 +/‐ 64, 396 +/‐ 155 l/h). As a result, mean steady‐state plasma concentrations of naproxen were indistinguishable between the elderly and young (64.2 +/‐ 8.5, 58.2 +/‐ 8.1 mg/l) but the elderly generated twice the mean steady‐state unbound plasma drug concentration (0.157 +/‐ 0.039, 0.0859 +/‐ 0.0212 mg/l). Since it is the unbound drug concentration which appears in general to relate more closely to pharmacological and toxic effect, it may be advisable to reduce naproxen doses by half in the elderly, pending plasma drug concentration‐response studies in this age group. If a similar perturbation with age occurs in benoxaprofen protein binding as was observed with naproxen, benoxaprofen intrinsic clearance in the elderly might be only one quarter of that in younger individuals; a factor which may contribute to the toxicity of this drug in the elderly.

When six normal men took probenecid with ketoprofen in a two-treatment crossover study, steady-state plasma concentrations of ketoprofen and ketoprofen conjugates rose, but plasma protein binding of ketoprofen and urinary excretion of ketoprofen conjugates decreased. Probenecid decreased protein binding of ketoprofen by 28 +/- 7%, total ketoprofen clearance by 67 +/- 11%, clearance of unbound ketoprofen by 74 +/- 10%, clearance of unbound ketoprofen by conjugation by 91 +/- 5%, and renal clearance of ketoprofen conjugates by 93 +/- 4%. An apparent decrease (22 +/- 29%) in unbound ketoprofen clearance by mechanisms other than conjugation might have been established in a study of more than six subjects. Probenecid, which reaches plasma concentrations that approach 100 times those of ketoprofen or its conjugates, appears to inhibit both the conjugation of ketoprofen and the renal excretion of ketoprofen conjugates. An alternative explanation to inhibition of conjugation involves cumulation and subsequent hydrolysis of ketoprofen conjugates as a result of the renal action of probenecid. In addition to the advantages of obtaining simultaneous uricosuric and anti-inflammatory effects, there may be clinical kinetic advantages of administration of probenecid with ketoprofen, because the large interdose concentration swings of ketoprofen are then substantially reduced.

No abstract

The administration of epinephrine to humans increases natural killer (NK) cell activity and numbers. If endogenous catecholamines regulate NK cells, then their activity should be increased by cocaine, an agent that potentiates endogenous catechoamines. We investigated the in vivo effect of cocaine on NK cell activity and on the distribution of lymphocyte subsets, including NK cells. Intravenous cocaine (0.6 mg/kg) produced a three-to fourfold increase in NK cell activity in peripheral blood. The increase was accompanied by a marked and selective increase in circulating NK cells, as identified by the Fc receptor (Leu-il). Normal saline and benzoylecgonine, a major metabolite of cocaine, had little effect on NK cell activity or on levels of Leu-ll+ cells.Other lymphocyte subpopulations were not increased by cocaine. The time course of the alterations in NK cell numbers and activity paralleled plasma levels of cocaine. In vitro cocaine did not increase NK cell activity. Our results indicate that cocaine selectively alters the activity and distribution of the NK lymphocyte subset. Because cocaine increases the activity of endogenous catecholamines, these findings suggest that human NK cells are selectively regulated by the sympathetic nervous system.