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Biomedical subjects

M Palmi

Publications and source records attributed to M Palmi.

At least 19 recordsLinked to original sources
PubMed1998

N-Dealkylation of chlorimipramine and chlorpromazine by rat liver microsomal cytochrome P450 isoenzymes.

The role of different cytochrome P450 isozymes (CYP) in the N-demethylation of chlorimipramine and chlorpromazine has been investigated in liver microsomes from rats by studying the effects of multiple subchronic doses of chlorimipramine, chlorpromazine, phenobarbital and beta-naphthoflavone on the N-demethylation of ethylmorphine, mono-N-demethyl-chlorimipramine and chlorpromazine and on the hydroxylation of aniline. With control microsomes, CYP-dependent metabolism of chlorimipramine and chlorpromazine (100 nmol; 30 min incubation) resulted in the formation of predominantly chlorimipramine (46.5 +/- 4.9 nmol) whereas chlorpromazine (14.1 +/- 0.9 nmol) accounted for only part of the overall metabolism of chlorpromazine. Multiple doses of chlorimipramine increased the capacity of microsomes to N-demethylate ethylmorphine (9.8 +/- 0.73 and 6.08 +/- 0.06 nmol min(-1) (mg protein)(-1) for chlorimipramine-treated and control rats, respectively) as well as itself (4.65 +/- 0.25 and 3.10 +/- 0.33 nmol min(-1) (mg protein)(-1), respectively). Multiple doses of chlorpromazine induced aniline-hydroxylase activity (1.11 +/- 0.16 and 0.94 +/- 0.06 nmol min(-1) (mg protein)(-1) for chlorimipramine and control microsomes, respectively) but the capacity to N-demethylate itself was unchanged. Phenobarbital treatment induced ethylmorphine N-demethylation activity, but did not affect N-demethylation activity, towards chlorimipramine and chlorpromazine. In control microsomes the N-demethylation capacity of chlorimipramine or chlorpromazine (0.160 +/- 0.025 and 0.015 +/- 0.003 nmol min(-1) (mg protein)(-1), respectively) was one order of magnitude lower than that of chlorimipramine or chlorpromazine. The capacity to N-demethylate either chlorimipramine or chlorpromazine was increased by treatment with either phenobarbital or beta-naphthoflavone. In control microsomes, sulphaphenazole markedly inhibited both chlorimipramine-N-mono- and di-N-demethylation, whereas quinidine markedly inhibited the rate of formation of chlorpromazine. The CYP2C and CYP2D subfamilies seem to be involved in the mono N-demethylation of chlorimipramine and chlorpromazine, respectively. Moreover the CYP1A and CYP2B subfamilies might participate in the N-demethylation of either chlorimipramine or chlorpromazine. This could have important implications in the clinical use of chlorimipramine and chlorpromazine in view of the genetic polymorphism of CYP2C and CYP2D isozymes in man.

Animals↗
PubMed1995

Inhibition of interleukin-1 beta-induced pyresis in the rabbit by peptide 204-212 of lipocortin 5.

The intracerebroventricular administration of interleukin-1 beta (12.5 ng/kg) in rabbits caused a prompt rise of prostaglandin E2 concentration (+ 632.6 +/- 243.9%) in the cerebrospinal fluid followed by hyperthermia (+ 1.61 +/- 0.14 delta degrees C). The intracerebroventricular administration of an anti-inflammatory nonapeptide (amino acids 204-212, SHLRKVFDK) derived from lipocortin 5, thereafter referred to as lipocortin 5-(204-212)-peptide, inhibited in a significant manner both the increase in cerebrospinal fluid [prostaglandin E2] and the febrile response induced by the cytokine. This inhibitory effect is probably due to interference by the peptide with phospholipase A2 activity. A control peptide (FKRVHDLKS) formed by the same amino acids in a randomly shuffled sequence had no effect. These results show that, in addition to the anti-inflammatory effect previously reported, the peptide 204-212 of lipocortin 5 possesses, like glucocorticoids, anti-pyretic activity. The research on lipocortin-derived peptides may lead to the development of novel anti-inflammatory and anti-pyretic compounds.

Amino Acid Sequence↗
PubMed1995

Rat tissue concentrations of chlorimipramine, chlorpromazine and their N-demethylated metabolites after a single oral dose of the parent compounds.

A single oral dose of 90 mg kg-1 chlorimipramine or chlorpromazine, corresponding to 54.5 or 55.9 mumol, respectively, was given to male Sprague-Dawley rats and concentrations of parent drugs and their N-desmethyl metabolites measured by gas chromatography in plasma and major organs (brain, liver, lung, kidney, heart, spleen and peritoneal fat). In the case of chlorimipramine, N-desmethyl metabolite levels were consistently higher than those of the parent drug for the entire observation period of 24 h in all tissues except fat, while lower N-desmethyl metabolite/parent compound ratios were observed for chlorpromazine. N-Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination-rate limited, while those of chlorpromazine were formation-rate limited. In all analysed organs, the maximu detectable drug+metabolite concentrations accounted for only 2.3 and 4.6% of the initial dose of chlorimipramine and chlorpromazine. Chlorpromazine treatment gave rise to an area under the total amount-time curve (AUC0-24) for parent drug+metabolites, 3.9-fold that for chlorimipraine. Closer scrutiny discloses a conversion ratio of parent compound to N-desmethyl metabolite of 1.1 for chlorpromazine and of 2.2 for chlorimipramine, indicating the greater efficiency of chlorimipramine metabolism in all compartments. The expected high conversion index found in the liver (2.3) reaches its maximum of 5.4 in the lung. Fractional data analysis of chlorimipramine and chlorpromazine distribution patterns revealed greater organ transfer for the N-desmethyl metabolites than for the more stably-located parent compounds. The N-desmethyl metabolites of chlorimipramine apparently moved from liver to lung, kidney and spleen, whereas N-desmethylchlopromazine moved preferentially to the brain and lung tissue. This single dose study of chlorimipramine and chlorpromazine kinetics, highlights the two distinct dispositional processes at work in the rat in all likelihood, attributable to different absorption patterns, to a slower metabolism and, thus, to the longer persistence of chlorpromazine.

Adipose Tissue↗
PubMed1994

Increase of extracellular brain calcium involved in interleukin-1 beta-induced pyresis in the rabbit: antagonism by dexamethasone.

1. This study investigates the role of extracellular brain calcium in the hyperthermia induced by interleukin-1 beta (IL-1 beta). 2. Intracerebroventricular (i.c.v.) injection of IL-1 beta (12.5 ng kg-1) in rabbits caused a prompt and sustained rise in cerebrospinal fluid (CSF) Ca2+ concentration ([Ca2+]) followed by enhanced prostaglandin E2 (PGE2) release and hyperthermia. 3. A linear and significant correlation was observed between the increase in [Ca2+] induced by IL-1 beta and the rise in body temperature. 4. Ventriculo-cisternal perfusion with artificial CSF containing the calcium chelator EGTA (1.3 mM) blocked the IL-1-induced PGE2 release and countered the febrile response. 5. I.c.v. administration of dexamethasone (Dex) (2.4 and 24 micrograms kg-1) 100 min prior to IL-1 beta, dose-dependently antagonized the cytokine-induced Ca2+ increase, the PGE2 release and the febrile response. 6. These results suggest that changes in extracellular brain calcium are involved in the regulation of body temperature. In this light, the antipyretic action of Dex may be related to its effect on Ca2+ uptake.

Animals↗
PubMed1993

Toxic injury to rat gut musculature following intraperitoneal administration of 2-t-butyl-4-methoxyphenol.

The 100-fold increase in toxicity of intraperitoneal (i.p.) rather than orally administered 2-t-butyl-4-methoxyphenol (BHA) is adduced to the depressive effect which this compound exerts on the contractility of the gut musculature. A structure/activity relation study shows the t-butyl group on the benzene ring as being the major determinant of i.p. BHA toxicity. Contractile activity, elicited by field electrical stimulation, acetylcholine or Ba2+, of the ileum longitudinal muscle preparation from BHA-treated rats was greatly reduced 30 min after i.p. injection, and almost absent during the subsequent 48 h. Electron-microscope examination of ileum longitudinal muscle also showed partial destruction of cell membranes 4 h after BHA administration with subsequent mitochondrial swelling and destruction of cristae, myofibrillar fragmentation and cell necrosis. Comparable suppression of contractile activity and morphological damage were observed in BHA or t-butylbenzene incubated ileum segments where longitudinal smooth muscle contractility was irreversibly depressed in a time- and dose-dependent manner. These convergent findings point to the toxic effect of i.p. BHA on gut musculature with consequent impairment of intestinal transit.

Administration, Oral↗
PubMed1993

HPLC determination of inorganic cation levels in CSF and plasma of conscious rabbits.

An HPLC method is described using conductimetric detection for the quantitative determination of sodium, potassium, magnesium, and calcium in cerebrospinal fluid (CSF) and plasma of conscious rabbits. This method enabled the four cations to be estimated with rapidity, sensitivity, accuracy, and precision. The mean millimolar concentrations +/- SD found in CSF and (plasma) of 15 untreated animals were as follows: sodium, 146.96 +/- 17.84 (135.06 +/- 20.11); potassium, 3.32 +/- 0.56 (4.57 +/- 1.03); magnesium, 0.90 +/- 0.20 (0.72 +/- 0.13); and calcium, 1.47 +/- 0.19 (3.32 +/- 0.59).

Animals↗
PubMed1993

Calcium antagonist and antiperoxidant properties of some hindered phenols.

1. The calcium antagonist and antioxidant activities of certain synthetic and natural phenols, related to BHA (2-t-butyl-4-methoxyphenol), were evaluated in rat ileal longitudinal muscle and in lipid peroxidation models respectively. 2. Compounds with a phenol or a phenol derivative moiety, with the exception of 2,2'-dihydroxy-3,-3'-di-t-butyl-5,5'-dimethoxydiphenyl (di-BHA), inhibited in a concentration-dependent manner the BaCl2-induced contraction of muscle incubated in a Ca(2+)-free medium. Calculated pIC50 (M) values ranged between 3.32 (probucol) and 4.96 [3,5-di-t-butyl-4-hydroxyanisole (di-t-BHA)], with intermediate activity shown by khellin < gossypol < quercetin < 3-t-butylanisole < BHA < nordihydroguaiaretic acid (NDGA) < 2,6-di-t-butyl-4-methylphenol (BHT) and papaverine. 3. The Ca2+ channel activator Bay K 8644 overcame the inhibition sustained by nifedipine, BHA and BHT, while only partially reversing that of papaverine. 4. BHA, BHT, nifedipine and papaverine also inhibited in a concentration-dependent fashion CaCl2 contractions of muscle depolarized by a K(+)-rich medium. This inhibition appeared to be inversely affected by the Ca(2+)-concentration used. 5. The inhibitory effects of nifedipine, papaverine, BHA and BHT were no longer present when muscle contraction was elicited in skinned fibres by 5 microM Ca2+ or 500 microM Ba2+, suggesting a plasmalemmal involvement of target sites in spasmolysis. 6. Comparative antioxidant capability was assessed in two peroxyl radical scavenging assay systems. These were based either on the oxidation of linoleic acid initiated by a heat labile azo compound or on lipid peroxidation of rat liver microsomes promoted by Fe2+ ions. Across both model systems,di-t-BHA, NDGA, BHT, di-BHA, BHA and quercetin ranked as the most potent inhibitors of lipid oxidation, with calculated pICso (M) values ranging between 7.4 and 5.7.7. Of the 32 compounds studied only 15 phenolic derivatives exhibited both antispasmogenic andantioxidant activity. Within this subgroup a linear and significant correlation was found betweenantispasmogenic activity and antioxidation. These bifunctional compounds were characterized by the presence of at least one hydroxyl group on the aromatic ring and a highly lipophilic area in the molecule.8. Di-t-BHA is proposed as a lead reference compound for future synthesis of new antioxidants combining two potentially useful properties in the prevention of tissue damage after ischaemia reperfusion injury.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Pharmacokinetics of chlorimipramine, chlorpromazine and their N-dealkylated metabolites in plasma of healthy volunteers after a single oral dose of the parent compounds.

A single oral dose of 0.7 mg kg-1 chlorimipramine (n = 18) and chlorpromazine (n = 16) was given to each subject 45 days apart and plasma concentrations of parent drugs and their monodesmethyl and didesmethyl metabolites were measured by GC. Ingestion of chlorimipramine resulted in an area under the plasma concentration-time curve (AUC0-24) for parent drug plus metabolites 5-fold higher than that observed in the same subjects following chlorpromazine intake (600 +/- 87 and 124 +/- 14 ng mL-1, respectively). Plasma chlorimipramine levels reached a mean peak value of 43.8 ng mL-1, which occurred 2 h after administration. Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination rate-limited and those of chlorpromazine appeared to be formation-rate-limited. The response to single doses of these two drugs in healthy subjects highlights the two distinct dispositional processes involved, thus offering pharmacokinetic explanation of the hitherto empirical discrepancy in dosage levels in chronic treatment.

Administration, Oral↗
PubMed1992

Calcium changes in rabbit CSF during endotoxin, IL-1 beta, and PGE2 fever.

New Zealand rabbits were chronically incannulated in the lateral ventricle and cisterna magna to assess the hypothesis that calcium concentration (Ca) of cerebrospinal fluid (CSF) varies during fevers of diverse origin. In normothermic and febrile animals recovering from surgery, CSF Ca was positively and significantly correlated to rectal temperature (TR). IV injection of E. coli endotoxin and ICV injection of human recombinant interleukin 1 beta (hrIL-1 beta) induced a TR rise of 1.7 +/- 0.3 degrees C (mean +/- SEM) and 1.45 +/- 0.25 degrees C, respectively, accompanied by significant increases in CSF Ca. After endotoxin administration, maximal Ca increases ranged between 0.21 and 0.48 mM above basal values in individual animals (p < 0.01), whereas after administration of hrIL-1 beta increases were 0.17 and 0.25 mM (p < 0.05). Acetylsalicylic acid (ASA) countered the fever induced by both endotoxin and hrIL-1 beta administrations and concomitantly antagonized the Ca increase in CSF. HrIL-1 beta-derived nonapeptide was characteristically devoid of pyrogenic effect and did not modify CSF Ca. Although ICV injection of prostaglandin E2 (PGE2) increased TR by 2.1 +/- 0.77 degrees C, it failed to have any effect on CSF Ca. Differently from the other Ca enhancers, PGE2, however, increased CSF protein concentration (protein). These findings suggest that brain calcium metabolism plays a role in fever development and that prostaglandin involvement is only engaged once changes in CSF calcium concentration have taken place.

Animals↗
PubMed1991

GABA-like immunoreactivity in different cellular populations of cerebellar cortex of rats before and after treatment with amino-oxyacetic acid.

The postembedding immunogold procedure was used to detect changes in the levels of gamma-aminobutyric acid (GABA)-like immunoreactivity at the ultrastructural level in the cerebellar cortex of control rats and rats treated with the GABA transaminase inhibitor, amino-oxyacetic acid (AOAA), in order to increase the levels of GABA. GABA-immunoreactive structures were labelled using an antiserum directed against GABA coupled to bovine serum albumin and a secondary antibody conjugated to colloidal gold. The density of gold particles per square micron of tissue was taken as a measure of GABA-like immunoreactivity. In separate groups of control and AOAA-treated animals, the levels of GABA were assessed biochemically in the cerebellum, the cortex, the ventral mesencephalon and the striatum. Six hours after treatment with AOAA the GABA levels in the cerebellum, the cortex, the ventral mesencephalon and the striatum. Six hours after treatment with GABA immunoreactivity of the Golgi and basket cell terminals was significantly greater than that of mossy fibres, granule cell dendrites and perikarya and glial cells. The value obtained for Golgi terminals was the highest of all the structures examined and was twice that of their perikarya. Six hours after treatment with AOAA the GABA immunoreactivity in Golgi and basket cell terminals and in glial cells was greatly enhanced. The drug treatment slightly enhanced the immunoreactivity in mossy fibres and granule cell dendrites but induced no change in granule cell bodies. Thus, in both control and treated rats, the highest GABA immunoreactivity was present in the terminals of GABAergic cells, and the lowest in putative glutamatergic cells. The results demonstrate that there is a high degree of selectivity in the changes in GABA levels following the inhibition of GABA transaminase in the cerebellum. They also confirm the potential of the use of postembedding methods for the quantification of endogenous amino acid at cellular and subcellular levels, in relative and possibly also absolute terms.

4-Aminobutyrate Transaminase↗
PubMed1990

4-Aminopyridine activates an inhibitory alpha 1-adrenergic mechanism unmasked by nifedipin on the electrically stimulated rat vas deferens.

4-Aminopyridine (4-AP) acts by blocking voltage dependent potassium channels in excitable membrane thus increasing the influx of extracellular (Ca2+) in response to an action potential. 4-AP exerts either in vivo or in vitro effects in many organs. The present report deals with a study on the electrically stimulated rat vas deferens of the action of 4-AP on Ca2+ mediated mechanism related to the adrenergic transmission. To avoid the interference of the non-adrenergic components we used the epididymal portion of the vas. 4-AP was shown to enhance the electrically-stimulated contractions in a way which was inversely related to external Ca2+. This effect was abolished by nifedipine (1 x 10(-6) M). Unexpectedly, however, 4-AP acted synergistically with nifedipine by enhancing the inhibition of the electrically-induced tension sustained by nifedipine. This property of 4-AP was shared by noradrenaline, phenylephrine, clonidine, serotonin, morphine and ATP. Their inhibitory effects were antagonized by prazosin (1 x 10(-8) M), yohimbine (2.5 x 10(-5) M), methysergide (1 x 10(-4) M), naloxone (1.2 x 10(-7) M), and theophylline (6 x 10(-6) M) respectively. The inhibitory effect of 4-AP was antagonized only by prazosin (1 x 10(-8) M) and was not observed in vas deferens of rats pretreated with reserpine. It is concluded that 4-AP is able not only to activate excitatory mechanisms but also to stimulate inhibitory alpha 1-adrenergic mechanisms.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗