Noradrenergic modulation of methamphetamine-induced striatal dopamine depletion.

Noradrenergic (NE) neurons belonging to the locus coeruleus (LC), much more than the A1 and A2 areas, are lost in Parkinson's disease (PD). In this study, we reproduced the selective pattern of NE loss involving axons arising from the LC using the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg). In these experimental conditions, we investigated whether NE loss potentiates methamphetamine-induced striatal dopamine (DA) depletion in mice and rats. Administration of a moderate dose of methamphetamine to C57B1/6N mice or Sprague-Dawley rats produced only a partial striatal DA depletion 7 days after drug administration. Pre-treatment with DSP-4, in both animal species, significantly enhanced methamphetamine-induced striatal DA depletion. Administration of a lower dose of methamphetamine did not decrease striatal DA levels when injected alone, but produced a significant decrease in striatal DA when given to DSP-4-pretreated rodents. Moreover, we found that agents reducing the noradrenergic activity (i.e., the alpha-2 agonist clonidine) enhanced, whereas alpha-2 antagonists decreased, methamphetamine toxicity. Enhancement of methamphetamine toxicity did not occur if the noradrenergic lesion was produced 12 hr after methamphetamine administration. By contrast, exacerbation of methamphetamine toxicity in NE-depleted animals was accompanied by increased extracellular DA levels measured with brain dialysis and by a more severe acute DA depletion measured in striatal homogenates.

Norepinephrine loss selectively enhances chronic nigrostriatal dopamine depletion in mice and rats.

In this study we investigated whether a selective pattern of norepinephrine loss potentiates methamphetamine-induced striatal dopamine depletion in rats. We also evaluated whether chronic norepinephrine depletion reduces the threshold dose of methamphetamine necessary to induce long-lasting striatal dopamine loss in mice and in rats. Pre-treatment with the selective noradrenergic neurotoxin DSP-4 (50 mg/kg, i.p.) in mice and in rats significantly enhanced methamphetamine-induced striatal dopamine depletion. Administration of a low dose of methamphetamine (1 x 5 mg/kg and 3 x 5 mg/kg, respectively, i.p., at 2-h interval) to C57B1/6N mice and Sprague-Dawley rats did not decrease striatal dopamine levels when injected alone but produced a significant decrease in striatal dopamine when given to rodents carrying a long-lasting norepinephrine depletion previously induced by DSP-4. Our results suggest that norepinephrine loss might both enhance neurotoxic damage and decrease the threshold for neurotoxicity to nigrostriatal dopaminergic neurons in different animal species.

Region- and neurotransmitter-dependent species and strain differences in DSP-4-induced monoamine depletion in rodents.

The neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is commonly used as a chemical tool to induce selective denervation of noradrenergic terminals arising from the locus coeruleus and to study the molecular mechanisms underlying degeneration of central noradrenergic axons in rodents. Monoamine depletion in different rodent species after DSP-4 is generally assumed to occur with a similar pattern. To verify this assumption, in the present study we evaluated the different patterns of monoamine depletion produced by DSP-4 in different brain regions of two different strains of mice and rats 3, 7 and 14 days after DSP-4 administration. In this report, we show that there are evident species and strain differences concerning the pattern of norepinephrine depletion in various brain regions. Moreover, serotonin levels are fully preserved following DSP-4 in mice, whereas there is a significant serotonin decrease in specific brain regions after the same dose of DSP-4 in rats. Apart from disclosing species and strain variability among rodents in neurotoxin-induced monoamine depletion, these findings suggest that DSP-4 should be considered as a different neurotoxin, depending on the species and strain in which it is administered.

Norepinephrine loss exacerbates methamphetamine-induced striatal dopamine depletion in mice.

Evidence is accumulating that norepinephrine depletion enhances the neurotoxic effect of the parkinsonism inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we investigated whether norepinephrine loss potentiates methamphetamine-induced striatal dopamine depletion. Injection of C57BL/6N mice with methamphetamine (2 x 5 mg/kg i.p., at 2-h intervals) produced only a partial (50%) striatal dopamine depletion 7 days after drug administration. Pretreatment with the selective noradrenergic neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) enhanced methamphetamine-induced striatal dopamine depletion by 86%, without decreasing striatal dopamine levels when injected alone. Our results extend previous findings obtained with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine in DSP-4-pretreated mice.

Eliminant effects of calcitonin gene related peptide on the tubular epithelial cells in an isolated and perfused rat kidney.

The effect of the infusion of calcitonin gene related peptide (CGRP) on the renal structure and enzyme release from tubular epithelial cells was studied. This study was performed in the model of an isolated perfused kidney to avoid the systemic effects and complex hormonal and neuromediated interaction following the CGRP infusion in the intact experimental animal. After infusion of CGRP, the perfused kidney, studied by semiquantitative histology and electron microscopy, did not show any alteration at the glomerular level; however, important histological lesions were apparent at the proximal tubular level: the brush border was destroyed and the epithelial cells were markedly flattened. This structural damage to epithelial cells was confirmed by electron microscopy. The alanine amino peptidase (AAP) and N-acetyl-glucosaminidase (NAG) were significantly increased in the effluent of the perfusion system, in confirmation of the histological damage. The direct toxic effect of CGRP on the tubular epithelial cells may be related to the reabsorption and tubular transport of this substance.

Evaluation of calcitonin-gene related peptide on haemodynamics of isolated perfused rat kidney.

Outside the central nervous system, calcitonin-gene-related peptide (CGRP) plays an important role in the control of regional blood flow. The present authors studied the renal haemodynamic effects of CGRP in the model of isolated perfused rat kidney (IPRK). This experimental model avoids the complex feed-back mechanisms activated by any modification of renal perfusion pressure. It was found that the infusion of CGRP in the IPRK induced a marked decrease of perfusion pressure; this vasoactive effect is well measured by the glomerular morphometric analysis that shows a striking increase in the glomerular diameter and volume.

Effect of metadoxine on striatal dopamine levels in C57 black mice.

In the present study, we examined the effect of metadoxine on striatal levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites in male C57 Black mice. Striatal content was assayed after systemic administration of metadoxine ranging from 1 micrograms kg-1 to 500 mg kg-1. Striatal dopamine increased 1 h after treatment with metadoxine (150 mg kg-1), but the most notable effect was obtained 24 h after the drug administration. At this time a plateau was reached; the two major metabolites of dopamine showed the same trend. Seven days after metadoxine administration, striatal dopamine approached the control values. Over the same time intervals, striatal 5-HT increased to a lesser extent and 5-hydroxy-indoleacetic acid did not differ significantly from controls. Striatal dopamine increased significantly at a dose of 250 micrograms kg-1 up to a dose of 1 mg kg-1 metadoxine; no further increment was observed between 1 and 500 mg kg-1 metadoxine. Administration of each component at doses equimolar to 1 mg metadoxine showed that pyridoxine produced only a mild increase in striatal dopamine compared with controls. We suggest that the metadoxine-induced striatal dopamine increase is obtained by increasing synthesis of dopamine.

Plasma and tissue concentrations of coenzyme Q10 in the rat after intravenous, oral and topical administrations.

Coenzyme Q10 (CoQ10) distribution into rat liver, heart, kidney and plasma was investigated after intravenous and oral administrations in different vehicles. Moreover, CoQ10 skin levels following topical treatment were evaluated. The liver represented the target organ for this compound in all the cases examined. In the heart, high and persistent CoQ10 concentrations were achieved particularly after solution injection while, following oral treatment, high doses of the drug were needed to reach the same CoQ10 levels. High concentrations of CoQ10 may be achieved also in the skin by topical treatment.

Adriamycin, aclacinomycin and thepirubicin intracardiac distribution examined by fluorescence microscopy.

Male Wistar rats received adriamycin, aclacinomycin or thepirubicin at a dose of 4 mg/kg b.w. by slow infusion. Cardiac tissue sections were examined by fluorescence microscopy to evaluate the distribution of the three anthracyclines. The nuclei regularly exhibited a stronger coloring with respect to the cytoplasm for all three drugs. Adriamycin cytoplasm fluoresced intensely, unlike aclacinomycin and thepirubicin. Our results indicate a lower uptake of these last two molecules into cardiac tissue, thus suggesting a different pharmacokinetic profile which might account for their lower cardiotoxicity.

Comparative histochemical study of adriamycin and adriamycinol in rat liver and heart.

Investigations were carried out into morphological differences between the uptake of adriamycin and its 13-OH metabolite adriamycinol into rat liver and heart. In the liver parenchyma, adriamycinol is mainly stored in the central area of the hepatic lobule, while adriamycin shows a more uniform distribution. In cardiac tissue, adriamycin accumulates within chromatin masses, whereas adriamycinol scarcely enters myocardial cells. The cardiotoxicity of both anthracyclines might be related to interactions with cytomembrane binding sites.

Aclacinomycin tissue distribution in the rat.

This study was undertaken to investigate aclacinomycin distribution in the rat, using a method based on the histofluorescence of tissues treated in vivo with anthracyclines. The target organs were the kidney, lung and pancreas; a fainter fluorescence was also detected in the heart compared with adriamycin due to a quantitatively different fixing of the two anthracyclines. Our findings revealed a preferential uptake into the cell nucleus in all tissues examined except the adrenal gland medulla where a slight fluorescence appeared only in the cytoplasm.

Skin penetration of CoQ10 in the rat.

Skin penetration of coenzyme Q10 (CoQ10) was investigated after topical treatment in the rat. The drug was suspended in olive oil and administered at two different concentrations. Coenzyme levels were found to be directly related to the concentrations employed and the contact time. CoQ10 topical treatment might therefore be proposed as a good pharmacological tool in dermatology and cosmetology.

Plasma and tissue concentrations of coenzyme Q10 in the rat after its oral administration.

Coenzyme Q10 (CoQ10) kinetics was investigated in rat tissues after oral treatment. CoQ10 passes quickly from plasma into the tissue examined, reaching levels higher than physiological ones; the liver shows the maximal CoQ10 concentrations. Our results indicate that oral treatment makes it possible to obtain good tissue levels of CoQ10 that might be of clinical value against endogenous CoQ10 insufficiencies due either to pathological alterations and/or to drug administration.

Plasma and tissue concentrations of coenzyme Q10 in the rat after intravenous administration by a microsphere delivery system or in a new type of solution.

Coenzyme Q10 (CoQ10) distribution into rat liver, heart, kidney, and plasma was investigated after intravenous administration in microsphere delivery system and in solution. The liver represented the target organ for this compound in both cases. Higher plasma levels of CoQ10 were achieved after solution treatment. No significant differences were detected in the other tissues examined.

Comparative nephrotoxicity and tissue accumulation of dactimicin, amikacin and gentamicin.

Dactimicin (ST 900) is a new pseudo-disaccharide aminoglycoside antibiotic which has been shown to be active against systemic infections in mice. Few data have so far been reported on dactimicin tissue accumulation or its potential nephrotoxicity. In this study, nephrotoxicity and renal tissue concentrations of gentamicin, amikacin and dactimicin were compared in Wistar rats. Liver, heart and lung accumulation of these drugs were also evaluated. Groups of 5 rats were respectively injected with 100 mg/kg body weight of the different drugs daily for 7 days. Five control rats were also injected with saline. Twenty-four hours after the last injection, all rats were sacrificed and bled to death. Blood samples were taken for BUN and serum creatinine assay. Kidney, liver, heart and lung tissues, as well as blood, were removed and processed for microbiological assay of gentamicin, amikacin and dactimicin. The results of this study showed that dactimicin, as well as amikacin, did not induce any significant increase in BUN and serum creatinine, while gentamicin administration resulted in severe uraemia in all rats. Consequently a much higher accumulation of gentamicin than amikacin and dactimicin was achieved in serum and tissues.

The pharmacokinetic profile of clofoctol in rat plasma and tissues after oral and rectal administration.

The pharmacokinetics of clofoctol was investigated in rat plasma and tissues after both oral and rectal treatment at a single dose of 300 mg/kg. After oral administration the plasmatic peak was 2.12 +/- 0.92 microgram/ml, occurring at the 90th min, with T/2 of 121.45 +/- 23.41 min. After rectal administration a plasmatic peak of 1.97 +/- 0.61 microgram/ml was reached at the 20th min with T/2 of 41.07 +/- 12.30 min. The kinetic profile of the drug in tissues exhibited a pattern similar to that in the plasma, since the maximal peak of clofoctol in tissues following rectal administration occurred before that obtained after oral administration. Tissue concentrations significantly higher than plasmatic ones were obtained through both administration routes. The present results indicate that clofoctol is well absorbed after both oral and rectal administration; however rectal treatment produces more rapid absorption and elimination compared with oral treatment.

Tissue concentrations of coenzyme Q in liver of rats intoxicated by carbon tetrachloride.

The protective action of hepatic cells of the coenzyme CoQ10 was checked against the well-known hepatolesive agent carbon tetrachloride (CCl4). It was found that CoQ10 pretreatment strongly reduced the CCl4-induced lesions in rat liver. The most important of these lesions was a marked steatosis, together with focal necrosis, Kupffer-cell reaction and signs of phlogosis and fibroblastic proliferation. The protective effects of CoQ10 seemed to be dose-dependent. The variation of CoQ9 concentration in the liver was not significant at any of the doses used.

A rapid and sensitive high-pressure liquid chromatographic method for monitoring josamycin levels in plasma.

In this study a new high-pressure liquid chromatographic method for monitoring plasma levels of josamycin is described. Josamycin propionate was used as the internal standard. After being extracted from plasma by chloroform at an alkaline pH, the compounds were easily separated on a reversed-phase column C8. The mobile phase was methanol: citrate-phosphate buffer 0.01 M pH 2.8 (85:15 v/v); and the wavelength 232 nm. The retention time was 2.2 min for josamycin and 2.7 min for josamycin propionate; the chromatogram lasted about 3.5 min. Using this method, concentrations of josamycin up to 0.3 microgram/ml were determined.

A modification of the soxhlet apparatus for drug extraction from biological fluids.

The authors suggest a method to isolate drugs and toxic substances from biological fluids which appears to be of easier and better applicability than other systems, because it allows the extraction by means of a hot solvent, reduces manual operations and the waste of solvent, and shortens the time of execution for the researchers. A mathematical formula is proposed in order to evaluate the recovery-time curves of any drug shortly and with better accuracy.

The pharmacokinetics of two erythromycin esters in plasma and in saliva following oral administration in humans.

An improved highly sensitive fluorimetric methods has been employed to measure plasma and saliva levels of erythromycin propionate and stearate in eight healthy volunteers following a single oral dose of 7.5 mg/kg. The plasma curves exhibited a mean half-life of 5.22 +/- s. e. m., 0.86 h-1 for the propionate and 2.97 +/- 0.22 h-1 for the stearate. Peak levels were reached at the 2nd h (4.07 +/- 0.29 microgram/ml for the propionate; 2.15 +/- 0.14 microgram/ml for the stearate). The area under the total plasma concentration curve was about 3-fold higher in the case of propionate. The concentration in saliva was about 20% of the corresponding concentration in plasma for the propionate and about 25% for the stearate. A significant positive correlation was observed between plasma and saliva levels for both macrolides.