Chronic dosing

FIGURE 5.56 The threshold region for chronic dose-response curves. [Reprinted with permission from Tardiff, R.G., and Rodricks, J.V. (1987). (Eds.), Toxic Substances and Human Risks Principles of Data Interpretation. New York Plenum Press.]... 

Benzodiazepines do not induce their own metabolism, and thete is no evidence for the development of pharmacokinetic toletance (Gteenblatt and Shader 1986). The behavioral tolerance seen with chronic dosing is explicable entirely on the basis of pharmacodynamic tolerance (as described earlier in the overview of neuropharmacology). 

As a result of these features clozapine is likely to have little effect on A9 (SN) neurons and does not cause their depolarisation in chronic dosing. 

The measurement of carotenoid absorption is fraught with difficulties and riddled with assumptions, and it is therefore a complex matter. Methods may rely on plasma concentration changes provoked by acute or chronic doses, oral-faecal mass balance method variants and compartmental modelling. 

The risk of major bleeding from chronic aspirin therapy is approximately 2% and is dose-related. Aspirin doses higher than 75 to 81 mg are no less effective than doses of 160 to 325 mg, but do have lower rates of bleeding. Therefore, chronic doses of aspirin should not exceed 81 mg. 

Pain management is an important component of therapy and is similar to that of acute pancreatitis. Non-opioid analgesics are preferred, but the severe and persistent nature of the pain often requires opioid therapy. Patients can require chronic doses of opioid analgesics, with a resulting risk of addiction. Pain can also be managed by removing the stimulus of exacerbation if identified.31,38... 

Fluoxetine 94 4-6 days with chronic dosing 4-1 6 days (active metabolite) Yes... 

Borthakur G, K Sprandel, ES Hwang et al. 2005. Effect of chronic dosing of lycopene as a tomato-based beverage on oxidative stress biomarkers. FASEB J 19(4) A472. 

Dafters, R.I., Hyperthermia following MDMA administration in rats effects of ambient temperature, water consumption, and chronic dosing, Physiol. Behav. 58(5), 877-882, 1995. 

Death or malformations have been documented at single oral doses of 2.5 to 33 mg As/kg body weight, at chronic doses of 1 to 10 mg As/kg body weight, and at dietary levels >5 and <50 mg As/kg diet. 

The SSRIs, with the possible exception of citalopram and sertraline, may have a nonlinear pattern of drug accumulation with chronic dosing. 

Biologic half-life in slowest phase of elimination. bA-S days with chronic dosing norfluoxetine, 4-16 days. 

A large proportion of the mercury in the kidney is bound to metallothionein, which has a capacity to bind mercury strongly [37-39]. The role for metallothionein in the kidney is probably protective [37]. Chronic dosing of rats with mercuric chloride over a period of 3 weeks induced an approximately 6-fold increase in the renal metallothionein levels, which provides an explanation for the almost linear increase of mercury in kidneys over several weeks of daily exposure. A protective role of metallothionein would explain findings that the... 

While rDNA techniques offer exciting possibilities, there are many unanswered questions about the potential toxicity that each new product represents. For example, acute clinical toxicities of interferons (IFNs) include flu-like syndrome, fever, chills, malaise, anorexia, fatigue, and headache. Chronic dose-limiting toxicities include neutropenia, thrombocytopenia, impairment of myeloid maturation, reversible dose-related hepatotoxicity, some neurological toxicity (stupor, psychosis, peripheral neuropathy) and gastrointestinal toxicity. Some of these toxicities would be difficult to ascertain in rodents, and, in fact, may be species-specific. 

Stochastic radiation effects are typically associated with those that occur over many months or years (i.e., are typically chronic instead of acute). Chronic doses are typically on the order of background doses (0.3 rem [0.003 Sv] or less) and are not necessarily associated with larger doses that could result from a terrorist attack with radiological weapons. However, stochastic health effects are defined here as effects that occur many years after chronic or acute exposure to radiological contaminants. Stochastic effects are categorized as cancers and hereditary effects. Because no case of hereditary effects (e.g., mutation of future generations) has been documented, this discussion focuses on cancer risk. 

Squibb RE, Tilson HA. 1982b. Neurobehavioral changes in adult Fischer-344 rats exposed to dietary levels of chlordecone (Kepone ) A 90-day chronic dosing study. Neurotoxicology 3(2) 59-65. 

Although a single dose of ginseng has little acute effects, chronic dosing (twice daily, 5 days) reduces anxiety in behavioral models (open-field... 

Neither an acute dose of dihydromethysticin (100 mg/kg) or chronic doses of ( )-kavain altered levels of dopamine, serotonin, or their metabolites in the striatum and cortex of rats (Boonen et al. 1998). However, kavalactones have complex and mixed effects on monoamine levels in the nucleus accumbens, depending both on which kavapyrone was... 

Some studies found kava to be effective using only 2 acute doses (preoperatively), while others found benefit after chronic doses (Bhate et al. 1989 Lehmann et al. 1989 Volz and Kieser 1997). Another interesting study found kavain to be equivalent in efficacy to the benzodiazepine oxazepam on standard measures of anxiety (Anxiety Status Inventoiy and Zung s Self-Rating Anxiety Scale) (Lindenberg and Pitule-Schodel 1990). There were no serious side effects reported in the clinical studies reviewed by Pittler and Ernst (2000). 

Similar to LSD and other monoamine hallucinogens, mescaline suppresses locomotor and exploratory behavior in novel environments (Wing et al. 1990). Also similar to LSD, tolerance develops to the behavioral effects of chronic doses of mescaline (Murray et al. 1977). Mescaline increases aggression in rat models (Sbordone et al. 1978) however, this is an elicited aggression (by electric shock) and does not necessarily generalize to human behavior. Increased aggression is not characteristic of humans using mescaline. 

Many studies reviewed by Tanda and Goldberg (2000) have found evidence for interactions of nicotine with caffeine and drug discrimination studies have further expanded these investigations (Sect. 6.6). The bidirectional, dose-dependent nature of caffeine effects on nicotine discrimination invites comparisons with parallel studies of nicotine self-adminisfration. However, whereas very large chronic doses of caffeine that were much above those obtained by consumers of caffeinated beverages potentiated nicotine self-administration (Shoaib et al. 1999), there is a... 

Hea e, A. D. E. Body, and G. E. Neely. Injuty and yield responses of soybean to chronic doses of ozone and sulfur dioxide in the field. Phytopathology 64 132-136, 1974. 

The most important research needs are related to the determination of the responses of natural ecosystems and agroecosystems to chronic exposure to oxidant pollutants. In particular, chronic-dose-response models are needed to understand the responses of the dominant primary-producer species constituting forest ecosystems in both the eastern and the western United States. The resulting alteration of interactions with other sub ems-—e.g., consumers and decomposers—must also be investigated. 

---