Oral variability

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... 

Male mice, oral, variable doses for l-,5 days Increased plaque-forming cells in spleen againsl Institoris et ul... 

The inhalation RfD is derived from the NOAEL by applying uncertainty factors similar to those listed above for oral RfDs. A UF of 10 is used when e.Ktrapolating from animals to humans in addition to the calculation of the human equivalent dose, to account for interspecific variability in sensitivity to the to. icant. The resulting RfD value for inhalation c. posure is generally reported as a concentration in air in mg/m for continuous, 24 hour/day c. posurc, although it may be reported as a corresponding inhaled intake (in mg/kg-day). A human body weight of 70 kg and an inhalation rate of 20 nv /day are used to convert between an inhaled intake e.xprcsscd in units of mg/kg-day and a concentration in air e. pressed in mg/m. ... 

Miltefosine, an alkylphosphocholine derivative, is a new antileishmanial drug and the first effective oral treatment of visceral leishmaniasis. However, there are concerns regarding teratogenicity, rapid emergence of resistance, and variable cure rates, possibly due to species differences in drug sensitivity. The mechanism of action of miltefosine is not known. 

Methadone is a p receptor agonist with special properties that make it particularly useful as a maintenance agent. Rehably absorbed orally, it does not reach peak concentration until about 4 hours after administration and maintains a large extravascular reservoir (Kreek 1979). These properties minimize acute euphoric effects. The reservoir results in a plasma half-life of 1—2 days, so there are usually no rapid blood level drops that could lead to withdrawal syndromes between daily doses. Effective blood levels are in the range of 200-500 ng/mL. Trough levels of 400 ng/mL are considered optimal (Payte and Khouri 1993). There is wide variability among individuals in blood levels with identical doses (Kreek 1979), and some have inadequate levels even with doses as high as 200 mg/day (Tennant 1987 Tenore 2003). 

Practical activities should embody as best as possible the scientifie proeesses that have been preseribed by the American Association for the Advancement of Science observation, elassification, numerieal relations, measurements, time-spaee relations, eommunieation (oral, pictorial, written), deriving of conclusions, prediction ( what would happen if. .hypothesis making, production of operational definitions, identifieation and control of variables, experiment and explanation of experimental data. Different theoretical perspectives should be used with the aim to optimize the positive eognitive and affeetive outcomes. The use, sometimes together, sometimes separately, of different perspeetives can act complimentarily and can lead to positive results (Niaz, 1993 Tsaparhs, 1997). 

An intermediate-duration oral MRL of 0.0007 mg/kg/day was derived for methyl parathion based on the observation of electrophysiological effects in the central and peripheral nervous systems of male rats exposed to methyl parathion through gavage administration of 0.22 mg/kg/day to the dams on days 5-15 of gestation and days 2-28 of lactation, followed by direct administration of the same dose to the male pups for 8 weeks. More marked effects occurred at the two higher doses, 0.44 and 0.88 mg/kg/day. The effects were dose-related, and were statistically significant at all three dose levels. The MRL was derived by dividing the LOAEL from this study (0.22 mg/kg/day) by an uncertainty factor of 300 (3 for a minimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 

Used to derive an intermediate oral MRL of0.0007 mg/kg/day dose divided by an uncertainty factor of300 (10 for extrapolation from animals to humans, 10 for human variability, and 3 for a minimal LOAEL). 

Two orally bioavailable compounds that target HIV-1 attachment have been described. BMS-806 and BMS-043 bind to gpl20 (reviewed by Kadow et al. 2006) and demonstrate variable activity when tested in vitro against panels of virus isolates (Lin et al. 2003). BMS-043 has shown efficacy in short-term monotherapy studies... 

The chronic-duration oral MRL was derived based on the observation of increased serum levels of alkaline phosphatase (an indicator of hepatotoxicity) in dogs consuming 0.6 mg/kg/day for 1 year (Hoechst 1989c). The choice of this end point is supported by the observation of hydropic hepatic cells in rats that consumed 5 mg/kg/day for 2 years (EMC 1959b). The chronic-duration MRL of 0.002 mg/kg/day was derived by dividing the NOAEL for elevated serum alkaline phosphatase (0.18 mg/kg/day) by an uncertainty factor of 100 (10 for extrapolating from animals to humans, and 10 for human variability). 

From this it can be decided whether it makes sense to identify toxicity risk using LD values determined for a means of penetration different from inhalation, skin or orally. If it does make sense, it will be possible to estimate risk although regulations did not provide any criteria. Note that on top of the space of variables mentioned above it is possible to have in this space bodies , which can be of help in interpreting axes. 

The only difficulty in this method (in addition to the calculations, which are easily carried out using computers) is the fact that it is impossible to analyse tables with values that are missing, so there is a need to choose substances for which there are a whole range of LC and LD values. Since this is impossible, three tables were used, which all have in common the L050 variables for rat and mouse, orally and by intraperitoneal means of penetration, so that the coherence of the three tables and a strong enough relationship between them could be ablished. The purpose was to determine, if, in the absence of one of the classification criteria set by regulation, it was possible to choose another available criterion to determine the risk level of toxicity. 

The onset of torsades de pointes associated with oral drug therapy is somewhat variable and in some cases may be delayed often, a patient can be taking a drug known to cause torsades de pointes for months or longer without problem, until another risk factor for the arrhythmia becomes present, which then may trigger the arrhythmia. 

Cyclosporine USP was first approved by the FDA in 1983 but was associated with a variable oral absorption. The development... 

Noroviruses greater than 5 yr Variable 12-24 hours fecal-oral, food, aerosol Nausea, vomiting, diarrhea, abdominal cramps, headache, fever, chills, myalgia... 

Two to three weeks of fluconazole or itraconazole solution are highly effective and demonstrate similar clinical response rates.32 Doses of 100 to 200 mg are effective in immunocompetent patients but doses up to 400 mg are recommended for immunocompromised patients. Due to variable absorption, ketoconazole and itraconazole capsules should be considered second-line therapy. In severe cases, oral azoles may prove ineffective, warranting the use of amphotericin B for 10 days. Although echinocandins and voriconazole are effective in treatment of esophageal candidiasis, experience remains limited. 

Intravenous antibiotic administration is the most common delivery method for surgical prophylaxis. Intravenous administration ensures complete bioavailability while minimizing the impact of patient-specific variables. Oral administration is also used in some bowel operations. Non-absorbable compounds like erythromycin base and neomycin are given up to 24 hours prior to surgery to cleanse the bowel. Note that oral agents are used adjunctively and do not replace IV agents. 

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