Dose-dependent effect

Hillefors-Berglund M, Liu Y, von Euler G Persistent, specific and dose-dependent effects of toluene exposure on dopamine D2 agonist binding in the rat caudate-putamen. Toxicology 77 223-232, 1993... 

Figure 1 illustrates the dose-dependent effects of ketamine on these three endpoints. A dose of 20 mg/kg significantly delayed tonic limb extension but did not protect against the lethality associated with this severe convulsive response. Higher doses significantly delayed the initial clonic convulsive response and prevented tonic limb extension. At these doses, the tonic extension response was replaced-with the abrupt onset of continuous clonic limb convulsions, which persisted until death from apparent respiratory depression. The onset of the continuous clonic convulsions and lethality was also delayed in a dose-dependent manner, at the higher doses of ketamine. 

Generalization tests indicated that a number of compounds were able to substitute for PCP (table 1). Ketamine and tiletamine, which are structurally similar to PCP, produced dose-dependent effects mimicking PCP. These compounds are interesting examples of the structural requirements of molecules for PCP-mimetic activity, demonstrating that neither the piperidine nor the phenyl moieties are absolutely necessary for activity. 

Aro, A., Teirila, J., Gref, C-G., Dose-dependent effect on serum cholesterol and apoprotein B concentrations by consumption of boiled, non-filtered coffee, Atherosclerosis, 83, 257, 1990... 

Alonso-Alvarez, C., Bertrand, S., Devevey, G., Gaillard, M., Prost, J., Faivre, B., and Sorci, G. 2004. An experimental test of the dose-dependent effect of carotenoids and immune activation on sexual signals and antioxidant activity. Am. Nat. 164 651-659. 

Monti, J. M. Jantos, H. (1992). Dose-dependent effects of the 5-HT1A receptor agonist 8-OH-DPAT on sleep and wakefulness in the rat. J. Sleep Res. 1,... 

Dose-dependent effects of transdermal nicotine on early morning awakening and rapid eye movement sleep time in nonsmoking normal volunteers. J. Clin. Psychopharmacol. 14, 264-7. 

Neave N, Reid C, Scholey AB, Thompson JM, Ayre G and Wesnes K (2000). Dose-dependent effects of flumazenil on cognition, mood and cardio-respiratory physiology in healthy volunteers. British Dental Journal, 189, 668-674. 

In vitro culture isolated brain cells exposed for 20 h to graded concentrations of nickel chloride up to 116 mg Ni/L DOMESTIC DOG, Canis familiaris Diet Time- and dose-dependent effects on kinetics of brain microtubule polymerization effects reversed on removal of Ni2+ from culture media 4... 

Significant dose-dependent effect on electric organ activity within 60 min 37... 

Hughes, M.F. and E.M. Kenyon. 1998. Dose-dependent effects on the disposition of monomethylarsonic acid and dimethylarsinic acid in the mouse after intravenous administration. Jour. Toxicol. Environ. Health 53 A 95-112. 

In doses of 1.2 mg Ni/kg and up to 20 mg Ni/kg, nickel chloride caused increased resorption rates and a number of malformations in murine foetuses, specific to the foetal skeletal system, as shown by atomic absorption [425]. It was believed that nickel chloride might influence embryos during the passage through the oviduct, with subsequent effect on the development after implantation [426]. Preimplantation mouse embryos have also been used to investigate toxic effects of nickel chloride on early embryo development in vitro, and a dose-dependent effect has been found [427]. 

Valerian extracts show sedative and anxiolytic effects. Whereas passionflower and chamomile have relatively specific anxiolytic effects, valerian shows more general sedative effects, but all effects occur in a dose-dependent manner (Della Logia et al. 1981 Leuschner et al. 1993). The sedative effects of valerian extract are moderate when compared to diazepam and the neuroleptic chlorpromazine (Leuschner et al. 1993). However, valepotriates reverse the anxiogenic effects of diazepam withdrawal in rats in the elevated plus maze. This effect is dose dependent, effective at 12 mg/kg but not 6 mg/kg. Interestingly, the fragrant valerian compound bornyl acetate has sedative effects in mice, but only when inhaled (Buchbauer et al. 1992). 

A methodologically controlled study of valerian in sleep was published that utilized both double-blind and placebo controls, as well as randomization (Gessner and Klasser 1984). Also employed were two doses of valerian (60 and 120 mg), computerized EEG power spectral analysis and psychometric mood questionnaires. Valerian increased sleep stages 1, 2, and 3 and reduced stage 4 and REM. Dose-dependent effects were noted, where the 120 mg dose produced greater sedative effects. Peak effects occurred 2-3 hours after administration. Mood ratings did not differ, positively or negatively, between the experimental and control conditions. 

Jenkins et al. demonstrated that the secondary bile acid, deoxycholic acid could induce micronuclei formation in the oesophageal adenocarcinoma cell line, OE33. The induction of micronuclei demonstrated a dose-dependent effect and occurred under both neutral and acidic pH conditions. An example of a micronucleus induced by treatment of the OE33 oesophageal adenocarcinoma cell line with deoxy cholic acid is shown in Figure 4.3. 

L9. Levy, G., Dose dependent effects in pharmacokinetics. In Importance of Fundamental Principles in Drug Evaluation (D. H. Tedeschi and R. E. Tedeschi, eds.), pp. 141-172. Raven, New York, 1968. 

The pharmacokinetics of meropenem in pediatric patients 2 years of age and oider are essentiaiiy simiiar to those in aduits. In infants and chiidren 2 months to 12 years of age, no age- or dose-dependent effects on pharmacokinetic parameters were observed. Mean haif-iife was 1.13 hours, mean voiume of distribution at steady state was 0.43 L/kg, mean residence time was 1.57 hours, ciearance was 5.63 mL/min/kg and renai ciearance was 2.53 mL/min/kg. The eiimination haif-iife is siightiy proionged (1.5 hours) in pediatric patients 3 months to 2 years of age. 

Tanida, M., Niijima, A., Fukuda, Y., Sawai, H., Tsuruoka, N., Shen, J., Yamada, S., Kiso, Y., and Nagai, K. (2005). Dose-dependent effects of L-carnosine on the renal sympathetic nerve and blood pressure in irethane-anesthetized rats. Am J Physiol. Regul. Integr. Comp. Physiol. 288, R447-455. 

Striatum and lateral septum. Interestingly, in contrast to our findings in the hippocampus, CRH has biphasic effects in these brain structures. Low doses of CRH (0.1 and 0.3 pg) were found to decrease extracellular levels of 5-HT. Higher doses of CRH (1.0 and 3.0 pg) have, however, no effect or increase 5-HT levels in the striatum and lateral septum (Price et al. 1998 Price and Lucki 2001). The biphasic effects on levels of 5-HT in these brain regions may be related to the dose-dependent effects of CRH on the firing rate of DRN 5-HT neurones as described above. Interestingly, local injection of CRH in the DRN results in a decrease in extracellular 5-HT in the striatum and septum (Price and Lucki 2001). 

A further issue is raised with regard to dose-dependent effects, suggesting dual or U-shaped psychotropic responses, because recent studies have indicated that neurosteroids may induce anxiogenic or anxiolytic responses in relation to the dosage used and subsequent metabolizing steps involved [Melchior and Ritzmann 1994a, 1994b]. 

TABLE 5.3. Dose-dependent effects on volume of distribution ... 

Induction of DNA single-strand breakage in rat liver after in-vivo exposure to N-nitrosodiethanolamine was demonstrated in three studies and dose-dependent effects were shown. In one of these studies, the DNA strand-breaking potential of 7V-nitroso-diethanolamine was found to be abolished by inhibition of sulfotransferase by 2,6-dichloro-4-nitrophenol. Unscheduled DNA synthesis was not detected in rats or mice in an in-vivo/in-vitro hepatocyte DNA repair assay after treatment with 7V-nitrosodi-ethanolamine. A single study in mice exposed in vivo to 7V-nitrosodiethanolamine did not find any significant induction of structural or numerical chromosomal aberrations or micronuclei in bone-marrow cells. 

In contrast to the SSRIs, venlafaxine has an ascending dose-response curve consistent with its sequential, concentration (and hence dose) dependent effects on serotonin and NE uptake pumps (Table 7-9). At 225 mg per day, the magnitude of the antidepressant effect is 50% higher than that seen with the SSRIs. Also consistent with its dual mechanism of action at higher concentrations, venlafaxine at a dose of 225 mg per day produced an antidepressant response in hospitalized patients with melancholia superior to both placebo and fluoxetine (114, US, 116, H7, H8, H9, 120, 121, 122, 123, 124,125, 126,127, 128,129, 130,131, 132,... 

The sum of the concentration of venlafaxine and ODV is probably more important than their relative ratio. Thus, CYP 2D6 deficiency, which occurs in approximately 7% of Caucasians, has fewer clinical implications for venlafaxine than for drugs that are biotransformed by this isoenzyme to either centrally inactive metabolites (e.g., paroxetine) or metabolites that have a different pharmacological profile than the parent drug (e.g., TCAs). The increase in venlafaxine plasma levels is offset by a parallel decline in ODV levels such that the sum is the same. Nevertheless, a substantial inhibition of CYP 3A3/4 could result in a meaningful increase in both venlafaxine and ODV plasma levels, particularly in patients who are CYP 2D6 deficient. Such an increase would be expected to result in an increase in the incidence or severity of the known dose-dependent effects of venlafaxine mediated by its inhibition of the neuronal uptake pumps for serotonin and NE. 

Nefazodone has appreciable nonlinear pharmacokinetics because of its metabolism by and inhibition of CYP3A3/4 ( 313). At doses of 200 mg per day, nefazodone undergoes an extensive first-pass metabolism such that its bioavailability is only approximately 20%. At doses of 400 mg per day, its bioavailability is appreciably higher, as are its plasma drug levels. This phenomenon is most likely due to inhibition of its own first-pass metabolism by CYP 3A/4. For this reason, dose-dependent effects of nefazodone can increase nonlinearly with higher doses. 

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