The Dose—Response Relation

Tallarida, Ronald J.; Jacob, Leonard S.

doi:10.1007/978-1-4684-6265-4_1

Cited by 15 publications

(12 citation statements)

References 8 publications

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“…Insurmountable antagonists directly remove a portion of the receptor population from interaction with agonists, either permanently through alkylation or temporarily through long-term or pseudoirreversible receptor binding (Tallarida and Jacob, 1979;Kenakin, 1997). The mechanisms underlying the consequences of repeated agonist treatment are less clear but may involve such processes as receptor down-regulation, desensitization, internalization, and/or phosphorylation (Law et al, 2000;Taylor and Fleming, 2001).…”

mentioning

confidence: 99%

Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Walker

Young²

2002

J Pharmacol Exp Ther

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High doses of insurmountable antagonists or frequent administration of high doses of agonists are required to alter the potency of opioid agonists to produce discriminative stimuli. In the present study, insurmountable antagonism and repeated agonist treatment were combined to remove or disable a large enough proportion of -opioid receptors to alter the potency or maximal effect for four agonists in male Sprague-Dawley rats trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio 15 schedule of food reinforcement. All agonists produced 88 to 100% morphine responding and were differentially sensitive to clocinnamox antagonism (fentanyl Ͻ morphine Յ buprenorphine ϭ nalbuphine). Repeated treatment with 20 mg/kg per day morphine for 6 days decreased by 2-to 3-fold the potency of fentanyl, morphine, and buprenorphine to produce morphine responding. After morphine treatment, 3.2 mg/kg clocinnamox produced a 7-fold further decrease in morphine potency. Clocinnamox (10 mg/kg) produced a 7-and 12-fold further decrease in morphine and fentanyl potency, respectively, a reduction in the slope of the morphine doseresponse curve, and a suppression of the maximal morphine responding for buprenorphine. Repeated treatment with 10 mg/kg per day morphine for 6 days failed to alter the potency of nalbuphine to produce morphine responding. In these morphine-treated rats, doses of 3.2 or 10 mg/kg clocinnamox suppressed the maximal morphine responding. Taken together, these data indicate that combined insurmountable antagonist and repeated agonist treatment produce additive effects at -opioid receptors to diminish discriminative stimulus effects in a manner predicted by the relative efficacy of opioid agonists.

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mentioning

confidence: 99%

Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Walker

Young²

2002

J Pharmacol Exp Ther

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“…Linear regression analysis of the transformed data (table 1 ) yielded signifi cant regressions (p < 0.05) for both data sets with slopes not significantly different from 1 for both dilators (table 1 ). These data indicate that the competitive model of antagonism is valid [22,23], The pAj values, estimates of the negative logarithm of the dissociation con stant, Ki [22,23], for Rp 8CPT cAMPs against Sp 8CPT cAMPs or 8-Br cGMP were not significantly different (table 1). A similar conclusion is drawn if the data were fitted to lines constrained to have slopes equal to one (as suggested by Tallarida and Murray [23]) (data not shown).…”

Section: Effects Ojrp Analogs O F Camp On Vasodilationmentioning

confidence: 86%

“…The potency of Rp 8CPT cAMPs to inhibit Sp cAMPs and 8-Br cGMP was assessed by performing Schild analysis [22,23] of these data (table 1). Linear regression analysis of the transformed data (table 1 ) yielded signifi cant regressions (p < 0.05) for both data sets with slopes not significantly different from 1 for both dilators (table 1 ).…”

Section: Effects Ojrp Analogs O F Camp On Vasodilationmentioning

confidence: 99%

“…Prelimi nary experiments indicated that this 'maximum' was not different from diameters observed when the ves sels were exposed to Ca2+-free PSS in the absence of phenylephrine. Schild analysis was performed as de scribed by [22,23] with EC,» values (effective concen tration that produced 50% of maximal vasodilation) estimated by nonlinear curve fitting of individual data sets [24] using SigmaPlot for Windows (Jandel Scien tific, San Rafael, Calif., USA). Data were statisticallyanalyzed by Student's t tests (for comparison of two means), analysis of variance, or regression analysis as appropriate.…”

Section: Data and Statisticsmentioning

confidence: 99%

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Rp Diastereomeric Analogs of cAMP Inhibit both cAMP- and cGMP-lnduced Dilation of Hamster Mesenteric Small Arteries

Jackson

1996

Pharmacology

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Cross talk between the adenosine (3’,5’-cyclic monophosphate) (cAMP) and the guanosine (3’,5’-cyclic monophosphate) (cGMP) signalling pathways in vascular smooth muscle may occur such that cAMP may act through cGMP-dependent protein kinase rather than cAMP-dependent protein kinase to induce relaxation of this tissue. Therefore, it was hypothesized that due to this crosstalk, competitive antagonists of cAMP may not show much selectivity in inhibition of cAMP- or cGMP-induced vasodilation. To test this hypothesis, the effects of Rp-diastereomeric phosphorothioate derivatives of cAMP, putative competitive antagonists of cAMP at cAMP-dependent protein kinase, were assessed on vasodilation induced by Sp-phosphorothioate derivatives of cAMP, dibutyryl cAMP, 8-Br cGMP and sodium nitroprusside. Hamster mesenteric arteries (200–400 µm i.d.) were cannulated and pressurized to 75 mm Hg and constricted to ∼50% of maximum with 1 µmol/l phenylephrine. Vasodilators were then added in cumulative fashion and diameter responses recorded in the absence and presence of (Rp)-adenosine (3’,5’-cyclic monophos-phorothioate) (Rp cAMPs) or (Rp)-8-(parachlorophenylthio) adenosine (3’,5’-cyclic monophosphorothioate) (Rp 8CPT cAMPs). Rp cAMPs (0.1-0.5 mmol/l) inhibited dilations induced by the cAMP agonists, (Sp)-adenosine (3’,5’-cyclic monophosphorothioate) (Sp cAMPs) and dibutyryl cAMP, but also inhibited dilations induced by 8-Br cGMP and sodium nitroprusside (p < 0.05 and n > 4 for all). In a more detailed study we found that Rp 8CPT cAMPs (0.025-0.25 mmol/l) competitively inhibited dilations induced by both Sp 8CPT cAMPs and 8-BR cGMP with equal potency: the pA₂ for Rp8 CPT cAMPs against Sp 8CPT cAMPs (3.6 ± 1.2) was similar to the pA₂ for Rp 8CPT cAMPs against 8-Br cGMP (4.1 ± 1.2) (p > 0.05, d.f. = 37). These data support the hypothesis that both cAMP and cGMP act through a common protein kinase to cause vasodilation and urge caution in the use of Rp-diastereomeric analogs of cyclic nucleotides to dissect out specific signal transduction pathways in blood vessels.

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“…[3] Many small molecules have shown strong dose-dependent PK and clearance in both animal models and patients. [4] For example, increasing dose of mezlocillin from 20 mg/kg to 200 mg/kg resulted in a 50% decrease in plasma clearance due to saturation of both biliary and renal excretion pathway.…”

mentioning

confidence: 99%

Dose Dependencies and Biocompatibility of Renal Clearable Gold Nanoparticles: From Mice to Non‐human Primates

Peng

et al. 2017

Angew Chem Int Ed

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While dose dependencies in pharmacokinetics and clearance are often observed in clinically used small molecules, very few studies have been dedicated to the understandings of potential dose-dependent in vivo transport of nanomedicines. Here we report that the pharmacokinetics and clearance of renal clearable gold nanoparticles (GS-AuNPs) are strongly dose-dependent once injection doses are above 15 mg kg : high dose expedited the renal excretion and shortened the blood retention. As a result, the no-observed-adverse-effect-level (NOAEL) of GS-AuNPs was >1000 mg kg in CD-1 mice. The efficient renal clearance and high compatibility can be translated to the non-human primates: no adverse effects were observed within 90 days after intravenous injection of 250 mg kg GS-AuNPs. These fundamental understandings of dose effect on the in vivo transport of ultrasmall AuNPs open up a pathway to maximize their biomedical potentials and minimize their toxicity in the future clinical translation.

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The Dose—Response Relation

Cited by 15 publications

References 8 publications

Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Rp Diastereomeric Analogs of cAMP Inhibit both cAMP- and cGMP-lnduced Dilation of Hamster Mesenteric Small Arteries

Dose Dependencies and Biocompatibility of Renal Clearable Gold Nanoparticles: From Mice to Non‐human Primates

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