Dosages of up to 30 mg rhDNase I per day were well tolerated in healthy volunteers and CF patients [69,87]. Severe bronchospasms or anaphylactic reactions, as seen after inhalation of bovine DNase I, have never been observed with rhDNase I. The most common adverse effects reported after daily inhalation of 2.5 mg rhDNase I were voice alterations (hoarseness), pharyngitis, rash, laryngitis, and conjunctivitis [74,76,78]. All these events are generally mild and transient. In patients with severe pulmonary disease (FVC < 40%), rhinitis, fever, dyspepsia, dyspnea, and an FVC decrease of > 10% have also been reported [76,88]. Facial edema has been reported to an exceptional degree in patients receiving 2.5 or 10 mg rhDNase I twice daily . It has also been shown that rhDNase I may increase airway inflammation by releasing elastase and proinflammatory cytokines that are bound to DNA in the airway secretions [89-91]. However, other studies did not confirm this observation [92-94]. Antibodies against rhDNase I have been found in the serum of 3% of CF patients receiving 2.5 mg rhDNase I once daily for 6 months . Whether these antibodies decrease the efficacy of rhDNase I is not known. Experiments on cell cultures and animals showed that rhDNase I did not have teratogenic, mutagenic, or carcinogenic activity, and that it did not affect the fertility and reproductive performance of either male or female rats at doses much higher (>29-fold) than recommended .
rhDNase I can be used in conjunction with standard CF therapies, but it should not be used in patients with known hypersensitivity to rhDNase I and Chinese hamster ovary (CHO) products. Caution is also indicated in pregnant women and nursing mothers, since it is not known whether rhDNase I is excreted in human milk [62,88]. Patients are advised not to take rhDNase I shortly before going to bed, as clearance of their mucus will be ineffective in their sleep [62,65,88].
Pharmacokinetic studies on animals have been reviewed by Green . In animal studies, inhalation of a single high dose of rhDNase I revealed a low bioavailability of <15% in rats and <2% in monkeys. Estimation of the bioavailability of rhDNase I in animals following repeated inhalation was confounded by the development of serum antibodies against rhD-Nase I. The half-life of rhDNase I in the lungs of rats is about 11 h [62,95]. In human studies, neither short-term nor long-term inhalation of rhDNase I at doses of 30 and 5 mg per d resulted in a significant increase of the DNase I concentration in serum [74,87]. The half-life of rhDNase I in the lungs of CF patients is much shorter than in animals and is estimated to be between 2 and 5 h [96,97]. An rhDNase I binding protein has been identified in the serum of rats, which may modulate the activity of rhDNase I .
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