As part of a clinical trial investigating the level of nicotine replacement with different doses of transdermal therapy for smoking cessation, peak and trough serum nicotine and plasma cotinine concentrations were measured in 70 subjects while they were actively smoking (baseline) and daily for 6 consecutive inpatient days while they were receiving transdermal nicotine. Subjects were randomly assigned to a daily 24-hour patch delivering a transdermal nicotine dose of 0, 11, 22, or 44 mg and stratified by self-reported smoking rate as either light (10-15 cigarettes per day), moderate (16-30 cigarettes per day), or heavy (>30 cigarettes per day). Steady-state concentrations of nicotine and cotinine were attained in 1 and 3 days, respectively, at all doses and were independent of baseline smoking rate. Mean percentage replacement of nicotine was calculated by dividing steady-state peak nicotine or cotinine concentrations by their respective baseline concentrations. Significant underreplacement occurred in subjects receiving the 11 mg/day patch regardless of baseline smoking rate. Underreplacement also occurred in moderate and heavy smokers receiving 22 mg/day and in light smokers at this same dose. Complete replacement occurred only in subjects receiving the 44 mg/day patch. These results have several implications for transdermal nicotine therapy. First, with the higher nicotine and cotinine levels observed with heavier smoking, it is inherent that one size does not fit all, and there is a need to consider more individualization of dosage for nicotine patch therapy. Second, there is substantial underreplacement with the 22 mg/day dose in moderate to heavy smokers and in some light smokers. Third, even with twice the usual dose (i.e., 44 mg/day), there was no accumulation of either nicotine or cotinine. Plasma cotinine levels after achievement of steady state (i.e., after 3 days of patch therapy) can be collected at any time and used to calculate percent replacement using baseline levels.

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We studied 62 consecutive patients with progressive autonomic failure (PAF) or multiple system atrophy (MSA) (26 PAF; 36 MSA). Patients were well matched in age (67 vs 66 years), duration (39 vs 36 months), and severity of autonomic failure (median values for PAF and MSA). Peripheral somatic neuropathy occurred in 2 patients with PAF and 7 patients with MSA. Postganglionic sudomotor and vasomotor functions were studied using the quantitative sudomotor axon reflex test and supine plasma norepinephrine. The extent and severity of autonomic failure were assessed by the thermoregulatory sweat test, by heart rate responses to deep breathing and the Valsalva maneuver, and by blood pressure recordings. Severe and widespread anhidrosis was found in both PAF and MSA patients. Postganglionic sudomotor failure occurred at the forearm in 50% each of PAF and MSA patients and at the foot in 69% and 66% of PAF and MSA patients, respectively. However, postganglionic sudomotor function was preserved in some patients with anhidrosis on thermoregulatory sweat test, indicating a preganglionic lesion. Vagal abnormalities were found in 77% and 81% of PAF and MSA patients. Supine plasma free norepinephrine values were significantly reduced in PAF (p less than 0.001), but not in MSA, patients. Standing plasma norepinephrine values were reduced in both PAF (p less than 0.001) and MSA (p less than 0.001) patients. We conclude the following: (1) PAF is characterized by combined postganglionic sudomotor and adrenergic failure. (2) MSA is associated with a similar frequency of postganglionic sudomotor failure, but postganglionic adrenergic denervation was uncommon. (3) Preganglionic neuron is also involved in both disorders, but more severely in MSA. (4) Somatic neuropathy may occur.

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