Pulmonary peptide delivery: effect of taste-masking excipients on leuprolide suspension metered-dose inhalers.

The purpose of this study was to evaluate the effect of taste-masking excipients on in vitro and in vivo performance of a leuprolide metered-dose inhaler (MDI) suspension formulation. Taste-masking excipients (aspartame and menthol) were added to a leuprolide suspension MDI formulation. The leuprolide MDI formulation with the taste-masking excipients was characterized in terms of milling time, particle size distribution, dose delivery and uniformity, and drug absorption in dogs. The data were compared with a formula that did not contain taste-masking excipients. It was found that the longer milling time for the leuprolide suspension with the taste-masking excipients was required to obtain a similar particle size distribution compared with the formula without taste-masking excipients using a fluid energy mill. Although measurable differences in mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were not observed between the two formulations, the percent of particles < or = 5 microns and the actuator retention for the formula with the taste-masking excipients were significantly different from the formula without taste-masking excipients using the Marple-Miller cascade impactor. Taste-masking excipients did not show a significant effect on valve delivery and through-can dose uniformity. However, the mean ex-actuator dose was 150.4 mg for the formula with the taste-masking excipients and 162.2 mg for the reference formula, respectively, indicating a significant difference. In tracheostomized dogs, both formulations showed comparable pharmacokinetic parameters including Cmax, Tmax, AUC0-12 and bioavailability (F%), indicating that the taste-masking excipients do not have an effect on lung absorption of leuprolide acetate. Therefore, inclusion of taste-masking excipients in the leuprolide MDI suspension formulation showed a significant impact on drug micronization, exactuator dose, and particle deposition pattern. Mechanistically, the unfavorable performance of leuprolide MDI in the presence of taste-masking excipients could be due to modification of the properties of the suspension itself and alteration of propellant evaporation following actuation.

Mercury exposure in chloralkali plants.

The employees of two chloralkali plants were studied to correlate the signs and symptoms of mercury toxicity with levels of exposure. For purposes of comparison, the workers were divided into three groups. These groups were selected on the basis of hours worked in the mercury cell room or in other areas of mercury exposure. The population of the first plant was studied from 1957-1978, and preliminary findings were published in 1964. The second plant's population was studied for 3.5 years beginning in 1976. Time-weighted average exposure levels to mercury vapor in the high exposure group generally ranged between 0.05 to 0.10 mg/m3. No significant differences in the frequency of objective or subjective findings were noted among the three groups except for a lower post exposure systolic and post exposure diastolic blood pressure in the high exposure group in the second plant's population. There was no correlation of mercury vapor exposure with subjective or objective weight loss.

Correction of urinary mercury concentration by specific gravity, osmolality, and creatinine.

Corrections for specific gravity, osmolality, and creatinine were applied to identical urinary mercury data in order to investigate the reproducibility of the corrected mercury concentration in a person's urinary spot samples throughout a 24-hour period; and the extent to which it is possible to predict a person's 24-hour mercury excretion from the corrected mercury concentration in the corresponding spot samples. The data indicate that on the average these corrections improve reproducibility by a factor of approximately 2. In individual cases, the uncorrected and corrected values of mercury concentration can differ by as much as a factor of 6. Similar effects were observed in the correlation of the mercury concentration of a spot sample and the corresponding 24-hour excretion of mercury. For this set of data, the corrections for specific gravity and osmolality turned out to be almost identical. The correction for creatinine was more effective than the other corrections by a small but statistically significant amount.

Inorganic mercury intoxication reminiscent of amyotrophic lateral sclerosis.

Two employees in a mercuric oxide manufacturing plant developed neurologic changes not previously reported from the exposure to inorganic mercury or elemental mercury vapor. The symptoms, physical findings and laboratory studies resembled those found in amyotrophic lateral sclerosis (ALS) and organic mercury intoxication. Nineteen employees are reported who precipitously developed signs and symptoms which may be regarded to be the early onset of a symptom complex of mercury intoxication that would likely have progressed to the ALS-like syndrome if the progression had not been interrupted by removal of the individuals from exposure to mercury. All symptoms, signs, and laboratory findings returned completely to normal after approximately three months in a mercury free work environment.