The influence of mass of [11C]-laniquidar and [11C]-N-desmethyl-loperamide on P-glycoprotein blockage at the blood-brain barrier.

INTRODUCTION: An earlier report suggested that mass amount of PET tracers could be an important factor in brain uptake mediated by P-glycoprotein. Thereby, this study investigated the influence of mass dose of laniquidar, desmethyl-loperamide and loperamide on the P-glycoprotein-mediated brain uptake of, respectively, [(11)C]-laniquidar and [(11)C]-N-desmethyl-loperamide ([(11)C]-dLop). METHODS: Wild-type (WT) mice were injected intravenously with solutions of 5.6 MBq [(11)C]-laniquidar (either no carrier added or 60 mg/kg laniquidar added) or with 5.0-7.4 MBq [(11)C]-dLop (either no carrier added or 3 mg/kg desmethyl loperamide). Mice were killed, and brain and blood were collected, weighted and counted for radioactivity. Mdr1a(-/-) knockout mice were incorporated as the control group. RESULTS: Injection of (11)C-laniquidar (no carrier added) in WT mice resulted in a statistical significant lower brain uptake (0.7±0.2 %ID/g) compared to the carrier-added formulation (60 mg/kg laniquidar) (3.1±0.3 %ID/g) (P=.004), while no statistical difference could be observed between formulations of [(11)C]-dLop. The [(11)C]-laniquidar and [(11)C]-dLop blood concentrations were not significantly different between the tested formulations in WT mice. In control animals, no effect of mass amount on brain uptake of both tracers could be demonstrated. CONCLUSIONS: These results demonstrate the bivalent character of laniquidar, acting as a substrate at low doses and as a blocking agent for P-glycoprotein transport in the brain at higher doses. In comparison, no difference was observed in [(11)C]-dLop uptake between carrier- and no-carrier-added formulations, which confirms that desmethyl-loperamide is a substrate of P-glycoprotein at the blood-brain barrier.

Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats.

The effects of the peripherally restricted opioid agonist loperamide were compared to those of morphine in the formalin test in rats. Both loperamide and morphine were efficacious in producing antihyperalgesia after both subcutaneous and intracisternal administration. The antihyperalgesic effects of peripherally administered loperamide and morphine were antagonized by both naloxone and its quaternary derivative naloxone methiodide. The effects of intracisternally administered loperamide and morphine were antagonized by naloxone SC. However, quaternary naloxone SC did not block the effects of intracisternally administered loperamide, and, quaternary naloxone blocked intracisternally morphine only at a dose approximately 10-fold higher than that required to block peripherally administered morphine. In addition, approximately 10-fold higher doses of naloxone administered SC were required to antagonize loperamide compared to doses required to antagonize morphine when the agonists were administered subcutaneously, suggesting that the effects of loperamide might be mediated by opioid receptors different from those which mediated the effects of morphine. However, neither the kappa-receptor selective antagonist nor-binaltorphimine nor the delta-receptor selective antagonist naltrindole blocked the effects of either opioid agonist. The present results are consistent with the interpretation that the antihyperalgesic effects of opioid agonists can have both a peripheral and a central component of action, and that the peripheral component of action is sufficient to produce antihyperalgesia in the formalin test after peripheral administration. The present results provide further evidence that peripherally restricted opioid agonists might provide clinically useful treatment of some pain states, in particular pain states that might involve sensitization of peripheral nociceptors.

Different actions of 2 antidiarrheal agents, lidamidine and loperamide, on motility of the isolated cat colon muscle.

Besides their action on intestinal absorption and secretion antidiarrheal agents may affect gastrointestinal motility. Little is known about motor actions in the large intestine. Therefore, the effects of loperamide and lidamidine on contractile and myoelectrical activity were studied in strips of the circular muscle of the cat colon in vitro. Both drugs caused a concentration dependent increase in spontaneous contractions, but the potency of loperamide was greater than that of lidamidine and the efficacy of lidamidine greater than that of loperamide. The corresponding EC50 were 2.9 X 10(-9) M and 1.4 X 10(-5) M, respectively, and the EC100 2.7 X 10(-7) M and 10(-4) M, respectively. In the myoelectrical tracings loperamide stimulated predominantly spike activity, lidamidine oscillatory potentials. The effect of loperamide was antagonized by naloxone, thus indicating an action on opiate receptors. The effect of lidamidine was not inhibited by a variety of drugs. Tetrodotoxin and alpha-adrenergic inhibitors even exaggerated the lidamidine effect, probably by a suppression of tonic nervous inhibition. The receptor for the lidamidine action has yet to be determined. In conclusion, the motor effects may play an important role in the antidiarrheal action of loperamide, but probably not in that of lidamidine, at least not within the range of clinically used doses.

Nufenoxole, a new antidiarrhoeal agent, inhibits fluid secretion in the human jejunum.

Nufenoxole is an orally active antidiarrhoeal agent which binds to opioid receptors in the brain and myenteric plexus of the intestine. A perfusion technique has been used to investigate the effect of nufenoxole (1 mg/kg intrajejunally) on water and solute transport stimulated by the secretagogue, dioctyl sodium sulphosuccinate, in the human jejunum in vivo. Nufenoxole reversed the direction of jejunal transport of salt and water from net secretion to net absorption. These changes in water and electrolyte transport were inhibited by intravenous naloxone, the opioid antagonist. Nufenoxole possesses potent antisecretory properties, which are mediated via opioid receptors and may contribute to its antidiarrhoeal action in man.

Antagonism of the antidiarrhoeal effect of clonidine and the lethal effect of noradrenaline in rats: a reliable procedure to evaluate the in-vivo alpha 1- and alpha 2-blocking activity of drugs?

Eight compounds with alpha-adrenergic blocking activity were tested for their ability to antagonize the antidiarrhoeal effect of clonidine (clonidine test) and the lethal effect of noradrenaline (noradrenaline test). Six of the compounds studied are alpha-adrenergic blocking agents with known alpha 2/alpha 1 selectivity. Two compounds, ketanserin (R 41 468) and butanserin (R 53 393), are 5-hydroxytryptamine S2-antagonists. The ED50-values (mg kg-1) obtained in the clonidine test were: phentolamine (0.34), RX781094 (0.34), yohimbine (0.51), piperoxan (9.36), butanserin (greater than 5.0), prazosin (greater than 10.0), phenoxybenzamine (greater than 40.0), and ketanserin (greater than 80.0). In the noradrenaline test the ED50's (mg kg-1) were: butanserin (0.014), prazosin (0.032), phentolamine (0.59), phenoxybenzamine (1.02), ketanserin (4.69), RX781094 (12.4), piperoxan (21.5), and yohimbine (25.0). The selectivity alpha 2/alpha 1-ratios (ED50 clonidine/ED50 noradrenaline were: yohimbine (0.020), RX781094 (0.027), piperoxan (0.44), phentolamine (0.58), ketanserin (greater than 39), prazosin (greater than 312), and butanserin (greater than 357). These results show that yohimbine and RX781094 are equipotent and relatively selective alpha 2-antagonists; piperoxan and phentolamine block both alpha 1- and alpha 2-receptors at closely related doses; ketanserin, prazosin and butanserin are selective blockers of alpha 1-receptors, ketanserin being very weak, prazosin and butanserin being very potent compounds in this respect. The potent and selective alpha 1-blocking activity of butanserin, combined to its 5-HT S2-antagonism makes butanserin a very interesting experimental drug in view of earlier reported data concerning the amplifying effects between 5-hydroxytryptaminergic and noradrenergic vascular mechanisms.