[The tolerability of nasal drugs with special regard to preservatives and physico-chemical parameters]. / Die Verträglichkeit von Nasalia unter besonderer Berücksichtigung des Einflusses von Konservierungsmitteln und physikalisch-chemischen Parametern.

BACKGROUND: Recent technical developments allow preservative-free nasal drug application in multi-dose systems. New pharmaceutical formulations for better tolerable nasal sprays are now possible and consequently reformulations introduced to the market. Therefore, a representative and systematic overview on comparable products is mandatory. METHODS: Marketed nasal products in the indication groups: decongestants, antiallergics, care and wound-healing, hormones and saline solutions were tested for their cytotoxic properties according to DIN EN 30 993 - 5, pH, and osmolality. RESULTS: In all indication groups reformulation to preservative-free application resulted in significant increase of cell growth and reduction of cytotoxicity. Physico-chemical galenic properties are of considerable importance too. With decongestants tolerability is dependant on the concentration of the active compound. CONCLUSIONS: Our data lead to the conclusion that preserved nasal sprays are obsolete, when preservative-free alternatives are available. Attention should be paid to galenic properties and dosage of the active.

Treatment of rhinitis medicamentosa with fluticasone propionate--an experimental study.

The efficacy of fluticasone propionate aqueous nasal spray (0.05% w/w) in the treatment of rhinitis medicamentosa has been studied in an animal model (guinea pig). Rhinitis medicamentosa was induced through the instillation of 0.05% naphthazoline nitrate (Privine) for 8 weeks. Fluticasone propionate nasal spray was then administered to the animals for 2 weeks. The spray successfully cleared the interstitial edema which is the pathologic hallmark of rhinitis medicamentosa. The study suggests that fluticasone propionate nasal spray can be beneficial in the treatment of patients with rhinitis medicamentosa.

Phototoxicity of naphazoline. Evidence that hydrated electrons, nitrogen-centered radicals, and OH radicals trigger DNA damage: a combined photocleavage and laser flash photolysis study.

The potential phototoxic activity of naphazoline (NP), 2-(1-naphthylmethyl)imidazoline, was investigated by studying its photoreactivity toward DNA. Photocleavage studies combined with laser flash photolysis experiments provide clear evidence that the transient species produced under NP photolysis react with DNA, thereby promoting its breakage under both aerobic and anaerobic conditions. Hydrated electrons and nitrogen-centered radicals are involved in the photodamage under anaerobic conditions. Hydroxyl radicals generated by Haber-Weiss reaction seem to initiate the photocleavage observed under aerobic conditions. A photodynamic mechanism involving the participation of singlet oxygen does not seem to play a crucial role in the photoinduced DNA breakage. The interaction between the NP and the biopolymer is also investigated by using both steady state and time-resolved spectroscopy.

Structure-activity relationships of (arylalkyl)imidazole anticonvulsants: comparison of the (fluorenylalkyl)imidazoles with nafimidone and denzimol.

A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (alpha-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-1-(2-naphthalenyl)ethanone), are undergoing clinical evaluation. Our structure-activity relationship (SAR) studies revealed that in addition to the naphthalenyl and phenethylphenyl aryl moieties of nafimidone and denzimol, respectively, fluorenyl, benzo[b]thienyl, and benzofuranyl aryl groups provided several highly active (arylalkyl)imidazole anticonvulsants. These structurally diverse aryl moieties, and comparable anticonvulsant activities, lend credence to the hypothesis that the pharmacophore of this class of anticonvulsants is the alkylimidazole portion of the molecule, with the lipophilic aryl portion enabling penetration of the blood-brain barrier. We focused our SAR studies on the (fluorenylalkyl)imidazole series. A representative compound from this series is 1-(9H-fluoren-2-yl)-2-(1H-imidazol-1-yl)ethanone. This agent was twice as potent as nafimidone in inhibiting maximal electroshock seizures in mice (po ED50's = 25 and 56 mg/kg, respectively) and considerably less toxic in the rat (po LD50's = 4550 and 504 mg/kg, respectively). The tertiary alcohol alpha-(9H-fluoren-2-yl)-alpha-methyl-1H-imidazole-1-ethanol was as potent as denzimol in mice (po ED50's = 10 and 12 mg/kg, respectively). This series of imidazole anticonvulsants was highly selective; while many compounds displayed potent antielectroshock activity, little or not activity was observed against pentylenetetrazole-induced clonic seizures or in the horizontal screen test for ataxia. All active compounds that we tested in this series, as well as denzimol and nafimidone, potentiated hexobarbital-induced sleeping time in mice, probably by imidazole-mediated inhibition of cytochrome P-450. The SAR's for the anticonvulsant activity and the sleeping time potentiation were similar. The propensity of these (arylalkyl)imidazole anticonvulsants to interact strongly with cytochrome P-450 and thereby impair the metabolism of other antiepileptic drugs may severely limit their clinical utility as anticonvulsants.