U-shaped dose-response

There is good evidence to suggest that certain chemicals, other than nutrients, show a J- or U-shaped dose-response relationship at levels of exposure which are lower than those where there is some impairment of the inherent... 

Ginseng extract improves the spatial learning performance of aged rats in an eight-arm radial maze and operant discrimination task (Nitta et al. 1995). It also improves memory performance in active-avoidance (shuttle-box) and passive-avoidance (step-down) tasks, and reinforces staircase-maze learning in both young and aged rats. (Petkov and Mosharrof 1987 Petkov et al. 1990 Petkov et al. 1992). The effects were also very dose dependent, with inverted U-shape dose-response curves. 

Milnacipran is also a dual-action antidepressant which, like venlafaxine, has been shown to be more effective than the SSRIs in the treatment of severe, hospitalized and suicidally depressed patients. At lower therapeutic doses, milnacipran blocks the noradrenaline transporters and therefore resembles the NRI antidepressants. Higher doses result in the serotonergic component becoming apparent (i.e. an SSRI-like action). The main problem with milnacipram appears to be its lack of linear kinetics with some evidence that it has a U-shaped dose-response curve (Figure 7.3). 

Calabrese, E. J., and L. A. Baldwin. U-shaped dose-responses in biology, toxicology, and public health. An. Rev. Public Health 22 15-33, 2001. 

Reserpine [0.1 mg/kg intramuscularly (i.m.)] or yohimbine (0.01 mg/kg i.m.) induces significant impairments in the monkey s ability to perform the delayed response task. HA at a dosage of 0.01 mg/kg i.m. for the yohimbine-treated monkeys markedly improved the memory impairments. The effects exhibited an inverted U-shaped dose-response pattern. The data suggest that HA may improve working memory via an adrenergic mechanism. ... 

Scores of clinical studies with HA have been reported thus far. Favorable efficacy of HA was demonstrated in the treatment of more than 1000 patients suffering from age-related memory dysfunction or dementia in China. An early study conducted on 100 patients with probable AD oral HA (0.15-0.25 mg, t.i.d.) showed significant improvement in all rating scores evaluated by the Buschke Selective Reminding task. An inverted U-shaped dose response curve for memory improvement was... 

BELLE founders noted that risks at low levels are estimated by various means, frequently utilizing assumptions about which there may be considerable uncertainty. BELLE is committed to the enhanced understanding of low-dose responses of all types, whether of an expected nature (e.g., linear, sublinear) or of a so-called paradoxical nature. Paradoxical dose-response relationships might include U-shaped dose-response curves and biphasic dose-response curves. The focus of BELLE now encompasses dose-response relationships to toxic agents, pharmaceuticals, and natural products over wide dosage ranges in in vitro and in vivo systems, including human populations. 

Calabrese EJ and Baldwin LA (2001) Hormesis U-shaped dose responses and their centrality in toxicology. Trends in Pharmacological Sciences 22 285-291. 

Figure 2 Representative examples of inverted U-shaped dose-response relationships displayed by a variety of experimental models and chemical agents. The asterisks indicate statistically significant data ( = P < 0.05, = P < 0.01, = P < 0.005). Absence of statistical significance denotes studies that did not perform statistical analyses on their data. Sources of data for (a)-(p) are References 14-29, respectively.

Calabrese EJ, Baldwin LA. 2001. The frequency of U-shaped dose responses in the toxicological literature. Toxicol. Sci. 62 330-38... 

Davis JM, Svendsgaard DJ. 1992. U-shaped dose-response curves their occurrence and implications for risk assessment. J. Toxicol. Environ. Health 30 71—83... 

Calabrese, E. J. (2008c). Pain and U-shaped dose responses Occurrence, mechanisms and clinical implications. Crit Rev Toxicol 38, 579-590. 

Calabrese, E. J. (2008g). Drug therapies for stroke and traumatic brain injury often displays U-shaped dose responses Occurrence, mechanisms, and chnical implications. Crit Rev Toxicol 38, 557—577. Calabrese, E. J. (2008h). An assessment of anxiolytic drug screening tests Hormetic dose responses predominate. Crit Rev Toxicol 38, 489-542. 

Newhouse et al. (1988 1993 1996)have examined the effects of intravenous nicotine in AD with particular attention on tasks that are affected by mecamylamine. Analysis of the cognitive effects of nicotine in the AD group showed that there was a significant dose-related decrease in verbal learning errors, with a U -shaped dose-response curve. A similar improvement pattern was seen in... 

E. Calabrese, L.A. Baldwin. Hormesis U-Shaped Dose Responses and Their Centrality in Toxicology. TRENDS in Pharmacological Sciences, 22 285-291, 2001. 

The effects of mono- and dinitrophenols as well as aminophenols (APs) on photosynthesis, respiration, and chlorophyll production of the microalga C. pyrenoidosa were analyzed [52], These compounds caused hormesis (dose-response phenomenon characterized by low dose stimulation and high dose inhibition, resulting in either a J-shaped or an inverted U-shaped dose response curve) on chlorophyll production at concentrations of NP, DNP, and AP ranging from 92 to 458 prnolcs L-1. The reader is directed to Chapter 3 of this book for a discussion of hormetic responses of terrestrial receptors to energetic materials. 

Although now there are numerous articles citing hormesis in various scientific databases, there are numerous other terms that have been used to describe dose-response relationships with the same quantitative features of the hormetic dose response. These similar descriptive terms include Yerkes-Dodson Law, nonmonotonic dose-response, nonlinear dose response, J-shaped dose-response, U-shaped dose-response, biphasic dose-response, BELL- haped dose-response, functional antagonism, hormologosis, overcompensation, rebound effect, bitonic, dual effect, bidirectional effect, bimodal effects, Amdt- chulz Law, Hueppe s Rule, and subsidy... 

The adaptive value of hormesis is seen in numerous observations demonstrating that the prior low dose stress response in the so-called hormetic response range also acts as a form of preconditioning that elicits protection against toxicity threats from subsequent toxic exposures. In this sense, the low dose hormetic response would confer a selective advantage to organisms that experienced an initial modest toxic exposure and in situations where the modest toxic exposure was followed by the more massive one a situation that would be expected to occur in both nature and evolutionary history. It is important to emphasize that a characterization of the prior low-dose response (i.e., adaptation) tends to reveal an inverted U-shaped dose response, similar to the hormetic dose response. 

---