Oral gavage dosing can induce stress and potentially confound experimental measurements, particularly when blood pressure and heart rate are endpoints of interest. Thus, we developed a pill formulation that mice would voluntarily consume and tested the hypothesis that pill dosing would be significantly less stressful than oral gavage. C57Bl/6 male mice were singly housed and on four consecutive days were exposed to an individual walking into the room (week 1, control), a pill being placed into the cage (week 2), and a dose of water via oral gavage (week 3). Blood pressure and heart rate were recorded by radiotelemetry continuously for 5 hr after treatment, and feces collected 6–10 hr after treatment for analysis of corticosterone metabolites. Both pill and gavage dosing significantly increased mean arterial pressure (MAP) during the first hour, compared to control. However, the increase in MAP was significantly greater after gavage and remained elevated up to 5 hr, while MAP returned to normal within 2 hr after a pill. Neither pill nor gavage dosing significantly increased heart rate during the first hour, compared to control; however, pill dosing significantly reduced heart rate while gavage significantly increased heart rate 2–5 hr post dosing. MAP and heart rate did not differ 24 hr after dosing. Lastly, only gavage dosing significantly increased fecal corticosterone metabolites, indicating a systemic stress response via activation of the hypothalamic-pituitary-adrenal axis. These data demonstrated that this pill dosing method of mice is significantly less stressful than oral gavage.
While polymeric coating operations are commonplace in the pharmaceutical industry, film coating processes are still not fully understood, which presents serious challenges with current regulatory requirements. Novel analytical technologies and various modeling techniques that are being used to better understand film coating processes are discussed. This review article also examines the challenges of implementing process analytical technologies in coating operations, active pharmaceutical ingredients in polymer film coatings, the use of high-solids coating systems and continuous coating and other novel coating application methods.
It has been postulated that fetal vascular abnormalities in aryl hydrocarbon receptor null (ahr −/− ) mice may alter cardiovascular homeostasis in adulthood. We tested the hypothesis that blood pressure regulation in adult heterozygous mice (ahr +/− ) would be normal, compared to ahr −/− mice, since no vascular abnormalities have been reported in the heterozygote animals. Mean arterial blood pressure (MAP) was measured using radiotelemetry prior to and during treatment with inhibitors of the autonomic nervous system, nitric oxide synthase (NOS), angiotensin converting enzyme (ACE), or endothelin-1 A receptor (ET A ). Also, indices of renin-angiotensin system (RAS) activation were measured. ahr +/− and ahr −/− mice were normotensive and hypotensive, respectively, compared to wild-type (ahr +/+ ) littermates. Responses of all genotypes to autonomic nervous system inhibition were normal. ahr +/− mice responded normally to NOS inhibition, while the responses of ahr −/− mice were significantly blunted. In contrast, ahr +/− mice were significantly more responsive to inhibition of ACE, an ET A antagonist, or both, while ahr −/− mice were significantly less response to ACE inhibition and more response to an ET A antagonist. ahr +/− mice also exhibited significant increases in plasma renin and ACE activity, plasma sodium, and urine osmolality, indicative of RAS activation. Thus, normotension in ahr +/− mice appears to be maintained by increased RAS and ET-1 signaling, while hypotension in ahr −/− mice may result from decreased RAS signaling. In conclusion, despite the lack of overt fetal vascular abnormalities in ahr +/− mice, the loss of a single ahr allele has a significant effect on blood pressure regulation.
Abstract. Recent studies have shown the importance of monitoring microenvironmental conditions (temperature, relative humidity) experienced by the tablet bed during a pan coating process, thereby necessitating the need to understand how various process parameters influence these microenvironmental conditions. The process parameters studied in this work include exhaust air temperature, spray rate, inlet airflow rate, gun-to-bed distance, coating suspension percent solids, and atomization and pattern air pressure. Each of these process parameters was found to have an impact on the tablet bed relative humidity (RH), as measured using PyroButton data logging devices. A higher tablet bed RH was obtained with an increase in spray rate and atomization air pressure and with a decrease in exhaust air temperature, inlet airflow rate, gun-to-bed distance, suspension percent solids, and pattern air pressure. Based on this work, it can be concluded that the tablet bed thermodynamic conditions are a cumulative effect of the various process conditions. A strong correlation between the tablet bed RH and the frequency of tablet coating defect (logo bridging) was established, with increasing RH resulting in a higher percent of logo bridging events.
Rationale
Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects.
Objectives
We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy.
Methods
An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks.
Measurements and Main Results
Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased.
Conclusions
Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF, and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF.
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