Systemic lithium reabsorption from lithium-chloride-coated heat and moisture exchangers.

OBJECTIVE: To evaluate possible reabsorption and systemic effects of lithium released by lithium-chloride-coated heat and moisture exchangers (HMEs) during prolonged mechanical ventilation. DESIGN: Prospective study, including all patients mechanically ventilated for 5-30 days. SETTING: A 7 bed general-traumatological ICU in a University Hospital. PATIENTS: 27 consecutive ICU patients, admitted following trauma, neurosurgery and respiratory insufficiency, mechanically ventilated for at least 5 days, with a lithium coated hygroscopic HME in the circuit. MEASUREMENTS AND RESULTS: Serum lithium levels were measured daily, with a standard laboratory spectrophotometric method, from admission to discharge from the ICU, and showed a reabsorption of lithium in all the patients; in the adults, levels were 5 to 15 times lower than therapeutic range, while in a child therapeutic and even toxic levels were reached. CONCLUSIONS: LiCl coat enhances HMEs' performance greatly, but reabsorption and systemic action must be considered. In adults, serum lithium levels were lower than the therapeutic range, but lithium is effective at low concentrations and it has a narrow therapeutic range; moreover, toxicity can be observed within this range too. In children, the risk of toxicity is much greater. When lithium coated HMEs are used, the risk/benefit ratio between good performance and systemic reabsorption must be evaluated carefully.

Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats.

Dizocilpine coadministered with imipramine (IMI) through an SC-implanted osmotic minipump completely prevents the occurrence of behavioral supersensitivity to quinpirole, as well as the decrease of dopamine D1 and beta-adrenergic receptor function. The present report shows that, in the same experimental conditions, dizocilpine completely antagonized the capacity of IMI to prevent the development of the learned helplessness behavior in rats. Thus suggesting that the blockade of NMDA receptors also antagonizes the antidepressant effect of IMI. Interestingly, rats acutely treated with dizocilpine 30 min before the inescapable shock session behaved similarly to naive animals during the escape test session.

Plasma kinetics of atropine and ipratropium in rats after different routes of administration evaluated by a radioreceptor assay.

Plasma kinetics of atropine and ipratropium was assessed in rat after i.v. (10 mg/kg), oral and i.p. (50 mg/kg) administration by a radioreceptor assay (RRA). The volume of the central compartment and the clearance of both drugs were very similar (about 3 L/kg and 3.5 L/h/kg respectively) while the steady state volume of distribution and the terminal half-life of atropine were higher than those of ipratropium. After i.p. administration the kinetics of ipratropium was very different from what was expected after the i.v. experiment.

Antagonism of aminoglutethimide and adrenocorticotropic hormone (ACTH) studied on slices of adrenal glands of the guinea-pig.

Aminoglutethimide at concentrations from 0.1 to 5 nM is able to inhibit the cortisol release elicited by adrenocorticotropic hormone (ACTH) (from 2.5 to 50 ng/ml) in guinea-pig adrenal cortex slices. The antagonism is a non-competitive one (in a Lineweaver-Burk plot), whereas other drugs (morphine, endorphin, indomethacin, etc.) inhibit ACTH competitively. This is in agreement with the known mechanism of action of aminoglutethimide, which inhibits the synthesis of cortisol by blocking reactions of enzymes such as aromatase and desmolase. From the data one can calculate the dissociation constant (Km) of ACTH with its receptor(s) to be 0.27 pg/ml and the inhibiting constant (Kl) of aminoglutethimide to be 49.78 x 10(-10) M. The maximal response of ACTH was 52.9 ng/ml.

Effect of ACTH, beta-endorphin, morphine and naloxone on the release of cortisol by isolated adrenal glands.

The release of cortisol (determined by RIA) from isolated slices of adrenal glands of guinea pigs is stimulated by ACTH, by beta-endorphin, and by morphine in a concentration-dependent way; naloxone gives a small stimulation which is not related to its concentration. Naloxone inhibits the effect of ACTH (1.11 X 10(-11) M) in a competitive manner with an IC50 of about 3.10(-9) M. Also morphine and beta-endorphin inhibit the effect of ACTH, but not in competitive manner. Naloxone (10(-9)-10(-7) M) gives a concentration-related inhibition of the increase of cortisol release produced by morphine (10(-8) M) and by beta-endorphin (1.44 X 10(-10) M). These data suggest a similarity in the conformation of ACTH, beta-endorphin, morphine and naloxone towards the binding sites of ACTH of the guinea pig adrenal glands.

Effect of morphine and naloxone on the levels of ACTH and beta-endorphin in plasma, brain and pituitary of rats.

The effect of i.p. administration of morphine (25 mg/kg) and of naloxone (50 mg/kg) on the levels of ACTH and beta-endorphin in plasma, in brain and in pituitary has been studied in rats. An opposite effect morphine and naloxone is seen in plasma ACTH with an increase elicited by morphine and a decrease produced by naloxone. Small changes are seen in plasma levels of beta-endorphin as well as in ACTH and in beta-endorphin levels in brain and in pituitary. To every change in ACTH levels in plasma an opposite change in ACTH brain levels is observed.

Inhibition of aminoacid decarboxylases by non-steroidal antiinflammatory drugs.

Several non-steroidal antiinflammatory drugs (NSAID) were shown to inhibit to various extents the decarboxylases of ornithine, lysine, histidine, arginine, and tyrosine. The most sensitive enzyme was ornithine decarboxylase, for which piroxicam, benoxaprofen and aminophenazone showed an IC50 of 0.007 mM; ibuprofen competitively inhibits the lysine decarboxylase. The most effective NSAID's in inhibiting histidine decarboxylase were mefenamic acid, ibuprofen and flufenamic acid. Arginine and tyrosine decarboxylase were inhibited by NSAID's only at high concentrations. None of the decarboxylase inhibitions were reversed by pyridoxal phosphate. Subplantar injection of the 5 amines formed by these aminoacid decarboxylases elicited a paw oedema in rat which was not antagonized by the various NSAID's. Some of the NSAID's stimulated all the decarboxylases and did not antagonize the carrageenin-induced paw oedema. With one exception, all the NSAID's tested in vivo inhibited the elimination of 14CO2 from labeled ornithine and lysine. The inhibition of certain aminoacid decarboxylases, particularly ornithine and lysine decarboxylase, appears to be a noteworthy mechanism of action for certain NSAID's.

Indomethacin and sulindac inhibition of ACTH stimulated cortisol release from adrenal glands in vitro.

In slices of adrenal glands of guinea pig added ACTH (from femtograms to picograms levels) stimulates cortisol synthesis and release. This effect is antagonized in a non-linear competitive way by indomethacin (KE = 1.3 .10(-7)) and by sulindac (KI = 6.9 .10(-10)); indoprofen is a very weak antagonist. A number of other non-steroid antiinflammatory drug are ineffective as antagonists of ACTH.

Kinetics of ouabain outflow from isolated frog heart evaluated by the dose-effect relationship and compared to the outflow kinetics of the tritiated drug.

In isolated frog hearts the kinetics of ouabain disappearance from the receptor biophase(s) related to the effect has been calculated from the relationship between ouabain concentration and its inotropic effect. When 10(-4) - 10(-5) M ouabain is added to the heart, the kinetics is biexponential with a fast component with a time constant of 1.7 min-1 and a slower component with a time constant of 0.28 min-1. The kinetics of the washout curve of 3H ouabain (added together with unlabelled drug, shows, in addition to the slow exponential component of about the same time constant (0.2 min-1) previously seen, another component with a 10 times longer time constant, related to ineffective drug concentrations and corresponding to a washout from aspecific sites. The kinetics of ouabain outflow from compartments which are related to the effect elicited by 10(-4) - 10(-5) M concentrations is formed mainly by two steps with time constants of 1.7 min-1 and 0.28 min-1.