Chronic dosing multiple

Topical intranasal decongestants (e.g., oxymetolazine, xylome-tolazine, phenylephrine, and naphazoline) are OTC options that provide prompt relief of nasal congestion. Nasal decongestants are dosed multiple times daily.15 Tachyphylaxis, rebound congestion, and rhinitis medicamentosa may occur with chronic use therefore, use should be limited to 3 to 5 days.8,12 These may be used 5 to 10 minutes before administration of intranasal corticosteroids in patients with blocked nasal passages.15... 

Chronic and multiple dosing Clinical experience with long-term use of tizanidine at... 

Pharmacokinetic information gained following single-dose administration can be used to help predict the likely events following chronic dosing, either as a constant-rate infusion or multiple dosing, which often involves giving a fixed dose at set time intervals. 

Oral bioavailability of mibefradil is dose dependent and ranges from 37% to over 90% with doses of 10 mg or 160 mg, respectively. The plasma half-life is 17 to 25 hours after multiple doses, and it is more than 99% protein bound (15). The metabolism of mibefradil is mediated by two pathways esterase-catalyzed hydrolysis of the ester side chain to yield an alcohol metabolite and CYP3A4-catalyzed oxidation. After chronic dosing, the oxidative pathway becomes less important and the plasma level of the alcohol metabolite of mibefradil increases. In animal models, the pharmacological effect of the alcohol metabolite is about 10% compared to that of the parent compound. After metabolic inactivation, mibefradil is excreted into the bile (75%) and urine (25%), with less than 3% excreted unchanged in the urine. 

In an experimental model of multiple sclerosis, repeated high doses of antigen (myelin basic protein) deleted both the clinical and pathological manifestations of the disease. The effects of Varicella vaccine on 50 patients with chronic progressive multiple sclerosis have therefore been studied (3). The patients were immunized with Varicella vaccine and followed for 1 year. All were seropositive for Varicella before immunization and all had rises in Varicella antibodies after being given the vaccine. There was improvement in 14 patients, 4 became worse, and 29 were unchanged. Four patients developed mild chickenpox after immunization. No other untoward adverse effects occurred. 

Basic and advanced life-support measures should be utilized as necessary. Activated charcoal effectively adsorbs theophylline and should be employed in both acute and chronic overdoses. Multiple-dose activated charcoal (MDAC) has been shown to significantly increase drug clearance and reduce serum theophylline... 

The maximal plasma level after a single oral dose of 100 mg tolrestat is about 5-8/i.gml-1 which is reached after about 2h. Multiple oral dosing (twice daily) results in a steady state after 6 days, and no unexpected accumulation occurs, yielding linear pharmacokinetics even during chronic dosing (data from Wyeth-Ayerst Int. Inc.). 

Whole body Variety and number of animals Chronic studies possible Minimum restraint Large historical database Controllable environment Minimum stress Minimum labor Messy Multiple routes of exposure skin, eyes, oral Variability of dose Cannot pulse exposure easily Poor contact between animals and investigators Capital intensive Inefficient compound usage Difficult to monitor animals during exposure Cleaning effluent air Inert materials Losses of test material Even distribution in space Sampling Animal care Observation Noise, vibration, humidity Air temperature Safe exhaust Loading Reliability... 

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

In a study of carcinogenesis, DBCP was orally administered to rats and mice 5 times/week at maximally tolerated doses and at half those doses. ° As early as 10 weeks after initiation of treatment, there was a high incidence of squamous cell carcinomas of the stomach in both species. In female rats there were also mammary adenocarcinomas. Chronic inhalation resulted in carcinomas of the respiratory tract in mice and multiple site tumors in rats. ... 

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