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1.
Ann Burns Fire Disasters ; 32(3): 190-196, 2019 Sep 30.
Article in French | MEDLINE | ID: mdl-32313532

ABSTRACT

High-voltage electrical burn injuries are rare emergencies in pediatric units and always associated with a poor prognosis. Recklessness, lack of knowledge about electric currents and the lack of safety around public electricity infrastructures are the three main factors contributing to the occurrence of high-voltage electrical accidents in children. Mortality is due to acute cardiac and renal complications, and trauma associated with falls. Secondary evolution is dominated by the risk of infection and the severity of functional sequelae. Early diagnosis and prompt treatment is needed to prevent these complications. Therapeutic management is based on early resuscitation and surgical management of tissue damage. We report three cases of high-voltage electrocution in children, with electro-thermal burns associated with severe head injury in one case, and myocardial damage and a compartment syndrome with severe functional sequelae in the other two. These three case reports are an opportunity to discuss literature data.

2.
Physiol Res ; 65(Suppl 5): S601-S609, 2016 12 22.
Article in English | MEDLINE | ID: mdl-28006942

ABSTRACT

Propofol is a short-acting hypnotic agent used in human medicine for sedation and general anesthesia. Its administration can be associated with serious cardiovascular side-effects that include decrease in arterial blood pressure and cardiac output. The aim of the present study was to evaluate propofol effects on mitochondrial respiration, myocardial contractility and electrophysiology in the same samples isolated from the heart ventricles of adult rats. Mitochondrial oxygen consumption was measured in permeabilized samples dissected from free walls of both ventricles using high-resolution respirometry. State LEAK was determined with malate and glutamate. Active respiration was induced by ADP (state PI) and further by succinate, a Complex II substrate (PI+II). Rotenone was injected to measure state PII. Antimycin A, a Complex III inhibitor was used to determine residual oxygen consumption (ROX). N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride and ascorbate were injected simultaneously for respirometric assay of cytochrome c oxidase activity (CIV). Isometric contractions and membrane potentials were determined on multicellular preparations isolated from right and left ventricles. Propofol concentrations used ranged from 0.005 to 0.5 mmol/l. All respiratory parameters were significantly higher in the left control ventricles compared to the right ones. Propofol significantly decreased Complex I activity at concentration 0.025 mmol/l and papillary muscle contraction force at 0.1 mmol/l. Propofol did not affect action potential duration at any concentration studied. Our study suggests that mechanisms contributing to the impaired myocardial contraction during propofol anesthesia might include also mitochondrial dysfunction manifested by compromised activity of the respiratory Complex I.


Subject(s)
Heart Ventricles/drug effects , Hypnotics and Sedatives/toxicity , Mitochondria, Heart/drug effects , Myocardial Contraction/drug effects , Oxygen Consumption/drug effects , Propofol/toxicity , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cardiac Output/drug effects , Cardiac Output/physiology , Dose-Response Relationship, Drug , Heart Ventricles/physiopathology , Male , Mitochondria, Heart/physiology , Myocardial Contraction/physiology , Oxygen Consumption/physiology , Rats , Rats, Wistar
3.
Chirality ; 24(7): 558-65, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22589120

ABSTRACT

Experimental hyperlipidemia has shown to decrease cytochrome P450 3A4 and 2C11 expression and to increase liver concentrations and the plasma protein binding of halofantrine (HF) enantiomers. The present study examined the effect of hyperlipidemic (HL) serum on the metabolism of HF enantiomers by primary rat hepatocytes. Hepatocytes from normolipidemic (NL) and HL (poloxamer 407 treated) rats were incubated with rac-HF in cell media with or without additional rat serum (5%). In those incubations with rat serum, the hepatocytes were preincubated or coincubated with serum from NL or HL rats. Rat serum-free hepatocyte incubations served as controls. Stereospecific assays were used to measure HF and desbutylhalofantrine (its major metabolite) enantiomer concentrations in whole well contents (cells + media). Concentrations of desbutylhalofantrine were not measurable. The disappearance (apparent metabolism) of (-)-HF exceeded that of antipode, but HF metabolism did not differ between hepatocytes from NL and HL rats. Coincubation of HL rat serum with NL hepatocytes caused a significant decrease in the disappearance of (-)-HF, whereas in HL hepatocytes, a substantially decreased apparent metabolism was noted for both enantiomers. Compared with NL serum, (-)-HF disappearance was significantly lowered upon preincubation of NL hepatocytes with HL serum. A combination of factors including diminished drug metabolizing or lipoprotein receptor expression, and increased plasma protein binding in the wells, may have contributed to a decrease in apparent metabolism of the HF enantiomers in the presence of lipoproteins from HL rat serum.


Subject(s)
Hepatocytes/drug effects , Hepatocytes/metabolism , Lipoproteins/blood , Lipoproteins/pharmacology , Phenanthrenes/chemistry , Phenanthrenes/metabolism , Animals , Antimalarials/chemistry , Antimalarials/metabolism , Hyperlipidemias/blood , Hyperlipidemias/metabolism , Rats , Rats, Sprague-Dawley , Stereoisomerism
4.
Xenobiotica ; 34(1): 1-29, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14742134

ABSTRACT

1. The activity of drug-metabolizing enzymes (DMEs) in extrahepatic organs is highest in the kidneys. Generally, the kidneys contain most, if not all, of the DMEs found in the liver. Surprisingly, some of these DMEs show higher activity in the kidneys than in the liver. 2. Most of the renal DMEs are localized in the cortex of the kidneys, especially in the proximal tubules. DMEs are also found in the distal tubules and collecting ducts. 3. Renal diseases such as acute and chronic renal failure and renal cell carcinoma alter the regulation of both hepatic and extrahepatic phase I and II DMEs. Changes in the expression of these DMEs seem to be tissue and species specific. 4. Generally, there is significant down-regulation of most of the phase I and a few of phase II DMEs at the protein, mRNA and activity levels. Unfortunately, the mechanisms leading to the alteration in DMEs in renal diseases remain unclear, although many theories have been made. 5. The presence of some circulating factors such as cytokines, nitric oxide, parathyroid hormones and increased intracellular calcium play a role in the regulation of DMEs in renal diseases.


Subject(s)
Enzymes/biosynthesis , Kidney Diseases/enzymology , Animals , Calcium/metabolism , Cyclic AMP/metabolism , Down-Regulation , Enzymes/metabolism , Humans , Kidney/enzymology , Liver/enzymology , Organ Specificity , Parathyroid Hormone/metabolism , Pharmaceutical Preparations/metabolism
5.
Phytother Res ; 17(6): 688-90, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12820243

ABSTRACT

The strongly basic alkaloidal fraction of the traditional medicinal plant Rhazya stricta (RS) was given orally to mice, in a single dose of 10 mg/kg (group 1) or, twice daily for 3 days at the same dose (group 2). A third group (control) received normal saline. Liver homogenates from all animals were used to assess the microsomal activity of cytochrome P450 and its isoforms as well as its catalytic activity (using theophylline as a substrate). RS alkaloidal fraction had no significant effect on the total amount of microsomal cytochrome P450, but it caused a significant increase in the cytochrome P450 isoforms CYPs 1A1 and 1A2. It also significantly increased the concentrations of some metabolites of theophylline. These results suggest that RS has the potential to interact with other drugs that are biotransformed by cytochrome P450, when given concomitantly with it.


Subject(s)
Apocynaceae , Cytochrome P-450 Enzyme System/metabolism , Microsomes, Liver/drug effects , Phytotherapy , Plant Extracts/pharmacology , Theophylline/pharmacokinetics , Administration, Oral , Animals , Drug Interactions , Male , Mice , Microsomes, Liver/metabolism
6.
Life Sci ; 69(13): 1559-71, 2001 Aug 17.
Article in English | MEDLINE | ID: mdl-11554617

ABSTRACT

A turpentine-induced inflammatory reaction (TIIR) down-regulates multiple isoforms of hepatic cytochrome P450 (P450) and increases microsomal lipid peroxidation. Since the synthesis of nitric oxide (NO*) is stimulated by inflammatory reactions, and NO* can depress the P450, it was of interest to investigate in vivo whether L-NAME and theophylline, by its anti-inflammatory properties, could prevent the depression of P450 caused by a TIIR. Control and rabbits with a TIIR received L-NAME for 72 h, and the activity of P450 was assessed in vivo and in vitro. In vivo, TIIR reduced theophylline systemic clearance by 50% (p<0.05), P450 total content by 67%, and the amount of CYP1A1/2 proteins by around 60% (p<0.05). L-NAME partially prevented the decrease in theophylline systemic clearance and in P450 total content, as well as the increase in lipid peroxidation; however, L-NAME did not hinder CYP1A1/2 proteins down-regulation. L-NAME did not modify the in vitro ability of the serum of rabbits with TIIR to decrease P450 activity, suggesting that the effect of L-NAME is not associated to a decrease in serum mediators. As assessed by the concentration in seromucoids, theophylline did not modify the severity of the inflammatory reaction, nor did it prevent the decrease in P450 activity. In conclusion, a TIIR down-regulates and reduces P450 activity, decrease that is at least in part mediated by NO*; theophylline does not prevent TIIR-induced P450 decrease in activity.


Subject(s)
Cytochrome P-450 Enzyme System/biosynthesis , Down-Regulation/drug effects , Enzyme Inhibitors/pharmacology , Inflammation/enzymology , Liver/enzymology , NG-Nitroarginine Methyl Ester/pharmacology , Animals , Hepatocytes/drug effects , Hepatocytes/enzymology , Inflammation/chemically induced , Irritants , Liver/drug effects , Male , Phosphodiesterase Inhibitors/pharmacology , Rabbits , Theophylline/pharmacology , Turpentine
7.
J Contam Hydrol ; 51(1-2): 97-125, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11530929

ABSTRACT

A model is developed for hydrocarbon biodegradation, which includes saturated and unsaturated flow, multi-species transport, heat transport, and bacterial growth processes. Numerical accuracy of the model was tested against analytical solutions. The model was also verified against laboratory results for a saturated-flow problem and reasonable match was obtained. Expressions are proposed for inhibition due to water content and temperature fluctuations. Bioactivities under cyclic water content variation were studied under no-flow conditions. A quantitative approach was used to reconcile some of the apparent contradictory conclusions regarding the efficiency of biodegradation of soils under wetting and drying conditions. The efficiency depends on the nature of the oxygenation process. For cases involving the presence of dissolved oxygen and the absence of O2 vapor, subjecting the soil to constant water content close to its optimal value for degradation is most efficient. However, wetting and drying can enhance degradation if O2 is only provided through aeration or direct contact between air and the medium. Also presented are the results of a typical field application of the model and a discussion of the effects of tides, saturation inhibition, and heat inhibition. Other inhibition factors, such as pH or salinity, can be easily incorporated in the formulation. The quantitative approach developed here can be used in assessing bioremediation not only in tidal aquifers but also in areas where water-table or temperature effects are of significance. The approach can be useful in the design of remediation strategies under water-flow or no-flow conditions involving water content and temperature fluctuations.


Subject(s)
Hydrocarbons/metabolism , Models, Theoretical , Oxygen/metabolism , Soil Pollutants/metabolism , Water Pollutants, Chemical/metabolism , Biodegradation, Environmental , Soil Microbiology , Solubility , Temperature , Volatilization , Water Movements
8.
Drug Metab Dispos ; 29(7): 1007-12, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11408367

ABSTRACT

Serum from humans with an upper respiratory viral infection (HS(URVI)) and from rabbits with a turpentine-induced acute inflammatory reaction (RS(TIAR)) reduces the activity of hepatic cytochrome P450 (P450) following 4 h of incubation. The aim of the present study was to assess the effect of HS(URVI) and RS(TIAR) on P450 activity and expression following 24 h of incubation with hepatocytes from control (H(CONT)) and rabbits with a TIAR (H(INFLA)). RS(TIAR) incubated with H(CONT) for 24 h reduced P450 content and activity, and CYP3A6 by 45%, without changing CYP1A1 and 1A2; when incubated with H(INFLA), RS(TIAR) decreased P450 content and activity without affecting CYP1A1 or 1A2. HS(URVI) incubated for 4 h with H(CONT) decreased P450 activity without affecting the amounts of CYP1A1, 1A2, or 3A6, although when incubated for 24 h, P450 activity and CYP3A6 amount decreased. HS(URVI) incubated with H(INFLA) for 4 h reduced P450 content and activity, and incubated for 24 h reduced activity, P450 content, and amount of CYP1A1 and 1A2 proteins. The present study demonstrates that 1) the effect of RS(TIAR) and HS(URVI) depends upon the susceptibility of the hepatocyte, i.e., H(CONT) or primed H(INFLA); 2) P450 down-regulation is preceded by a decrease in P450 activity; 3) the nature of the inflammatory reaction determines the repercussions on P450 activity and expression; and 4) CYP3A6 is more vulnerable than CYP1A1 and 1A2 to the down-regulation provoked by an inflammatory challenge.


Subject(s)
Blood , Cytochrome P-450 Enzyme System/metabolism , Down-Regulation , Inflammation/blood , Respiratory Tract Infections/blood , Virus Diseases/blood , Animals , Humans , Inflammation/enzymology , Male , Rabbits , Respiratory Tract Infections/enzymology , Virus Diseases/enzymology
9.
Drug Metab Dispos ; 28(9): 1112-20, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10950858

ABSTRACT

Serum of rabbits with a turpentine-induced acute inflammatory reaction (RS(INFLA)) and serum of humans with a viral infection (HS(INF)) were previously shown to diminish hepatic cytochrome P450 (P450) content and activity. To document the role of reactive oxygen intermediates in the serum-mediated decrease in P450 content and activity, hepatocytes of rabbits with an acute inflammatory reaction (H(INFLA)) were incubated with RS(INFLA) and HS(INF) for 4 h, and total P450 content (spectrally measurable P450), P450 activity (assessed by estimating the formation of theophylline metabolites), and amount of CYP1A1, CYP1A2, and CYP3A6 proteins were measured. RS(INFLA) or HS(INF) decreased P450 content and activity without affecting the amount of CYP1A1 and -1A2 H(INFLA). Exposure of H(CONT) or H(INFLA) to hydrogen peroxide (0.01-1.0 mM) and sodium nitroprusside (0.01-1.0 mM) produced a dose-dependent decrease in P450 content and in the formation of theophylline metabolites without modifying the amount of CYP1A1 and CYP1A2, whereas lipid peroxidation increased. Incubation of L-NAME (0.05-1.0 mM), dimethylthiourea (6.25-50 mM), or N-acetylcysteine (0.01-1.0 mM) with H(INFLA) partially prevented the decrease in P450 content and activity and the increased lipid peroxidation induced by RS(INFLA) and HS(INF). On the other hand, 3-amino-1,2,4-triazole (10-100 mM) or diethyldithiocarbamate (1.0-10 mM) potentiated RS(INFLA)- and HS(INF)-mediated decreases in P450 content and activity and the increase in lipid peroxidation, without affecting the amount of CYP1A1 or -1A2; DL-buthionine-(S,R)-sulfoximine (2.5-25 mM) potentiated only the inhibition of 1,3-dimethyluric acid formation. It is concluded that reactive oxygen intermediates are implicated in the decrease of H(INFLA) P450 content and activity induced by 4 h of exposure to RS(INFLA) or HS(INF).


Subject(s)
Acute-Phase Reaction/enzymology , Cytochrome P-450 Enzyme System/metabolism , Reactive Oxygen Species/physiology , Acute-Phase Reaction/blood , Amitrole/pharmacology , Animals , Biotransformation , Buthionine Sulfoximine/pharmacology , Cytochrome P-450 Enzyme System/drug effects , Ditiocarb/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Free Radical Scavengers/pharmacology , Humans , Hydrogen Peroxide/pharmacology , Liver/cytology , Liver/drug effects , Liver/metabolism , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitroprusside/pharmacology , Rabbits , Theophylline/pharmacokinetics , Thiourea/analogs & derivatives , Thiourea/pharmacology
10.
Br J Pharmacol ; 128(2): 365-73, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10510446

ABSTRACT

1 To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3-methylcholanthrene (3MC) pre-treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73+/-0.43 to 1.48+/-0.13 ml min-1 kg-1 (P<0. 05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU) and 1,3-dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. 2 Turpentine-induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. 3 Pre-treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre-treatment with 3MC prevented the hypoxia-induced decrease in amount and activity of the P450. 4 It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre-treatment with 3MC prevents the hypoxia-induced depression of the P450.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/metabolism , Hypoxia/enzymology , Inflammation/enzymology , Liver/enzymology , Methylcholanthrene/pharmacology , Animals , Apoproteins/metabolism , Area Under Curve , Cytochrome P-450 CYP1A1/biosynthesis , Cytochrome P-450 CYP1A2/biosynthesis , Cytochrome P-450 Enzyme System/biosynthesis , Down-Regulation/physiology , Inflammation/chemically induced , Irritants , Liver/drug effects , Male , Phosphodiesterase Inhibitors/pharmacology , Rabbits , Theophylline/metabolism , Theophylline/pharmacology , Turpentine
11.
Liver Transpl Surg ; 5(2): 119-25, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10071351

ABSTRACT

We compared the capacity of University of Wisconsin (UW) and of sodium-lactobionate-sucrose (SLS) hypothermic preservation solutions to maintain the integrity of the hepatic cytochrome P-450-dependent mono-oxygenase system. Isolated rat hepatocytes were stored for 0, 10, 24, and 48 hours in UW or SLS solution and were subsequently cultured shortly at 37 degrees C. Cell viability declined slightly but significantly in a time-dependent manner during cold preservation in either UW or SLS solution, and warm culture exacerbated this effect. Total cytochrome P-450 declined gradually after cold preservation and warm culture to reach values of 70% and 52% of unstored controls in cells preserved for 24 and 48 hours in cold UW solution, respectively. Storage in cold SLS solution yielded a similar decrease to 79% and 59% of unstored controls for the equivalent preservation times. Cytochrome P-450 activity was assessed by the metabolism of theophylline after various cold preservation times in UW or SLS solutions. Production of the major metabolite 1,3-dimethyluric acid was not significantly affected by extended cold preservation periods in either UW or SLS solutions. Similarly, the amount of residual theophylline remained stable in all groups, suggesting that alternative metabolic routes were not modified. These studies show that cold preservation in SLS solution is as effective as that in UW solution in terms of cell viability, cytochrome P-450 content, and activity toward theophylline. In addition, the significant reduction in cytochrome P-450 in conjunction with unaffected theophylline disposition suggests that certain cytochrome P-450 isoforms are specifically damaged by cold preservation and rewarming.


Subject(s)
Cryopreservation , Cytochrome P-450 Enzyme System/metabolism , Liver/drug effects , Liver/metabolism , Organ Preservation Solutions/pharmacology , Adenosine/pharmacology , Allopurinol/pharmacology , Animals , Cell Survival/physiology , Chlorpromazine/pharmacology , Disaccharides/pharmacology , Glutathione/pharmacology , Insulin/pharmacology , Liver/cytology , Liver/physiology , Male , Raffinose/pharmacology , Rats , Rats, Sprague-Dawley , Sucrose/pharmacology , Theophylline/metabolism
12.
Life Sci ; 63(15): 1361-70, 1998.
Article in English | MEDLINE | ID: mdl-9768874

ABSTRACT

There is increasing evidence suggesting that several mediators are involved in the cascade of events leading to the depression of the cytochrome P450 (P450) by an inflammatory reaction. The present study aimed to confirm the presence of mediators in the serum (RS(INFLA)) and hepatocytes (H(INFLA)) of rabbits with an acute inflammatory reaction, and in the serum of humans with an acute upper respiratory tract viral infection (HS(URTVI)). The inflammatory reaction was induced by the s.c. injection of 5 ml of turpentine. Incubation of RS(INFLA) or HS(URTVI) with H(INFLA) depressed the P450, diminished the formation of theophylline metabolites (3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid), and increased lipid peroxidation. The addition of preheated RS(INFLA) or HS(URTVI) to H(INFLA) did not diminish the amount of P450 or theophylline metabolites, and prevented the increase in lipid peroxidation. Incubating the filtrate of RS(INFLA) or HS(URTVI) dialyzed through membranes with cut-off of 10, 30, 50 and 100 kd, with H(INFLA) showed that rabbit and human mediators have molecular weights ranging from 10 to 30 kd. Incubation of H(INFLA) with hepatocytes from control rabbits (H(CONT)) did not decrease further the P450. However, when RS(INFLA) was added to co-cultured H(CONT) + H(INFLA), the depression of P450 was 37% greater (p<0.05), and the amount of theophylline metabolites generated was around 30% (p<0.05) smaller than that observed when H(CONT) or H(INFLA) were incubated with RS(INFLA). Based on the present results we may speculate that human and rabbit serum mediators are proteins of molecular weights ranging from 10 to 30 kd, and in addition, primed hepatocytes once exposed to the serum mediators release mediators able to depress the P450 in H(CONT).


Subject(s)
Acute-Phase Reaction/blood , Blood Proteins/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Liver/drug effects , Pneumonia, Viral/blood , Acute-Phase Reaction/chemically induced , Animals , Blood Proteins/chemistry , Cells, Cultured , Coculture Techniques , Humans , Lipid Peroxidation , Liver/enzymology , Male , Molecular Weight , Protein Denaturation , Rabbits , Theophylline/metabolism , Turpentine/toxicity
13.
Gen Pharmacol ; 30(4): 499-505, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9522166

ABSTRACT

1. Both L-dopa and low doses of apomorphine potentiated withdrawal symptoms such as jumping, "wet dog" shakes and burrows. L-dopa reduced hypothermia and potentiated body weight loss, whereas apomorphine produced opposite effects. 2. Higher doses of apomorphine attenuated jumping and burrows but had no effect on "wet dog" shakes. On the other hand, and with the exception of sulpiride, all other dopamine (DA) antagonists produced effects opposite those of the agonists with regard to jumping, "wet dog" shakes and burrows. 3. In addition, DA antagonists reduced hypothermia and body weight loss. The effects of DA agonists and antagonists were investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether DA-mediated effects are somehow linked to noradrenergic pathways. 4. Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than did untreated mice. 6-OHDA reversed the effects of apomorphine on "wet dog" shakes and burrows while abolishing those of L-dopa on all withdrawal symptoms, the only exception being jumping, which remained unchanged. 5. 6-OHDA also reversed the effects of sulpiride on all withdrawal symptoms while reversing the effects of pimozide on jumping, and it abolished its effect on hypothermia. 6. These findings provide evidence suggesting that the effects of DA agonists and antagonists are dependent at least partly on intact noradrenergic pathways.


Subject(s)
Analgesia , Analgesics, Opioid/pharmacology , Dopamine Agents/pharmacology , Dopamine Antagonists/pharmacology , Dopamine/pharmacology , Hypothermia/chemically induced , Morphine/adverse effects , Substance Withdrawal Syndrome/etiology , Adrenergic Agents/pharmacology , Analysis of Variance , Animals , Apomorphine/pharmacology , Levodopa/pharmacology , Male , Mice , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Oxidopamine/pharmacology
14.
Br J Pharmacol ; 121(6): 1164-70, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9249253

ABSTRACT

1. Infection and inflammation trigger a cascade of mediators that eventually will down-regulate the hepatic cytochrome P450 (P450). The present study aimed to characterize the mediators contained in the serum of rabbits with an acute inflammatory reaction (AIR) induced by the s.c. injection of turpentine (5 ml), and in the serum of humans with an acute upper respiratory tract viral infection. 2. Hepatocytes from control (H(CONT)) rabbits and rabbits with an AIR (H(INFLA)) were isolated and cultured. Compared with H(CONT) in H(INFLA) the production of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) was reduced as was the amount of total P450, while lipid peroxidation was increased. Incubation of H(INFLA) with serum of rabbits with an AIR (RS(INFLA)) for 4 h further reduced the formation of the metabolites of theophylline as well as the amount of P450, and enhanced the lipid peroxidation. RS(INFLA) obtained 6, 12 and 24 h after the injection of turpentine showed the same ability to down-regulate hepatic P450 as the serum obtained at 48 h. 3. The efficacy (Emax) of RS(INFLA) to inhibit the formation of theophylline metabolites differed, i.e. 1,3DMU > 1MU > 3MX, and the potency of serum mediators (IC50) was similar for 3MX and 1MU, but lower for 1,3DMU. 4. Incubation of serum of human volunteers (HS(INFLA)) with a viral infection with H(CONT) or H(INFLA) reduced the production of theophylline metabolites, as well as the amount of P450, and increased the lipid peroxidation. HS(INFLA) depressed 1,3DMU more efficiently than 3MX and 1MU. HS(INFLA) reduced 3MX with greater efficacy than did RS(INFLA). Potency was very variable but not different from rabbits. 5. It is concluded that the serum of rabbits with an AIR or of humans with a viral infection contain several mediators that inhibit noncompetitively various isoenzymes of the hepatic P450. The decrease in P450 induced by HS(INFLA) or RS(INFLA) is closely associated with the increase in lipid peroxidation (r2= 0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 down-regulation.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Down-Regulation , Inflammation Mediators/metabolism , Liver/enzymology , Animals , Biotransformation , Cells, Cultured , Humans , Inflammation Mediators/blood , Lipid Peroxidation , Male , Rabbits , Theophylline/pharmacokinetics , Virus Diseases/metabolism
15.
Psychopharmacology (Berl) ; 132(1): 67-73, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9272761

ABSTRACT

Numerous previous attempts have been made to study the involvement of alpha2-adrenoceptors in the expression of morphine withdrawal by studying the effects of selective alpha2-agonists and antagonists administered immediately before precipitation of withdrawal by an opioid antagonist such as naloxone. In the present investigation, we examined the effects of chronic treatment with clonidine (alpha2-agonist), idazoxan and yohimbine (alpha2-antagonists), concomitantly administered with morphine, on the expression of the withdrawal signs. In contrast to their acute effects, clonidine potentiated, while yohimbine and idazoxan attenuated the withdrawal signs precipitated by naloxone in morphine-dependent mice. In addition, mice chronically treated only with yohimbine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were not influenced by naloxone administration. Mice chronically treated with clonidine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were further potentiated by naloxone administration. The results suggest that down-regulation of alpha2-adrenoceptors by morphine is a major adaptation contributing to development of dependence on opioids and also point the way to more effective treatment of narcotic dependence. This suggestion was based on the hypothesis that the suppression of noradrenergic system during chronic morphine treatment by alpha2-antagonists might diminish noradrenergic hyperactivity and consequently the development of dependence and withdrawal signs.


Subject(s)
Adrenergic Agents/therapeutic use , Clonidine/therapeutic use , Idazoxan/therapeutic use , Morphine/toxicity , Narcotics/toxicity , Receptors, Adrenergic, alpha-2/drug effects , Substance Withdrawal Syndrome/prevention & control , Yohimbine/therapeutic use , Animals , Drug Interactions , Male , Mice
16.
Drug Metab Dispos ; 25(2): 191-5, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9029050

ABSTRACT

It has been shown that selected isoforms of cytochrome P450 (P450) can generate nitric oxide from L-arginine analogs; however, the effect of L-arginine analogs on the catalytic activity of P450 remains unknown. To assess the effect of N-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) and L-arginine (150 mg/kg) on the activity of P450, these compounds were administered intravenously every 8 hr for 2 days to groups of six New Zealand rabbits. Thereafter, the biotransformation of theophylline was documented in vivo (2.5 mg/kg i.v.) and ex vivo in hepatocytes of control and treated animals. In vivo, compared with control rabbits, both L-NAME and L-arginine increased theophylline plasma concentrations secondary to a reduction in theophylline systemic clearance by 46% and 42% (p < 0.05), respectively. Ex vivo, the effect of L-arginine analogs on P450 activity was documented by measuring the production of 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) after incubation of theophylline (176 microM) with hepatocytes for 4 hr. L-NAME reduced the formation of 3MX, 1MU, and 1,3DMU by 42%, 45%, and 32% (p < 0.05), respectively. However, L-arginine reduced only the formation of 3MX by 34% (p < 0.05). In the in vitro studies, incubation of L-NAME or L-arginine with hepatocytes did not modify the biotransformation of theophylline. It is concluded that L-NAME and L-arginine inhibit the activity of several apoenzymes of P450, the probable mechanism being a catalysis-dependent inhibition.


Subject(s)
Arginine/pharmacology , Enzyme Inhibitors/pharmacology , Liver/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Theophylline/pharmacokinetics , Animals , Area Under Curve , Biotransformation , Cells, Cultured , Half-Life , Liver/metabolism , Male , Metabolic Clearance Rate , Nitric Oxide Synthase/antagonists & inhibitors , Rabbits
17.
Pharmacol Biochem Behav ; 55(1): 49-54, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8870037

ABSTRACT

The effects of histamine antagonists on naloxone-precipitated withdrawal symptoms were studied in morphine-dependent mice. Chlorpheniramine (0.5-10 mg/kg), a H1-blocker, given 1P 30 min before naloxone challenge produced a dose-dependent potentiation of withdrawal body weight loss, burrowing, and hypothermia, but did not influence either jumping or wet-dog shakes. On the other hand, cimetidine (10-100 mg/kg), a H2-blocker, produced dose-dependent potentiation of withdrawal hypothermia and jumping. Cimetidine was without effect on wet-dog shakes, burrowing, and body weight loss. The effect of chlorpheniramine was investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether histamine-mediated effects are some-how linked to noradrenergic pathways. Intracerebral injection of 6-OHDA in 5-day-old mice pups resulted in hyperlocomotion by the end of 30 days before initiation of morphine dependence. Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than nontreated mice. 6-OHDA (50 micrograms) lesions completely blocked the potentiating effect of chlorpheniramine on burrowing, hypothermia, and even reversed the effect on body weight loss. These findings suggest that both histamine H1- and H2-receptors may be involved in the expression of precipitated withdrawal in morphine-dependent mice and histamine receptors function as modulators of noradrenergic neurotransmission.


Subject(s)
Histamine/physiology , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Norepinephrine/physiology , Substance Withdrawal Syndrome/physiopathology , Animals , Behavior, Animal/drug effects , Chlorpheniramine/pharmacology , Cimetidine/pharmacology , Dose-Response Relationship, Drug , Histamine H1 Antagonists/pharmacology , Histamine H2 Antagonists/pharmacology , Hypothermia/chemically induced , Hypothermia/physiopathology , Male , Mice , Morphine Dependence/physiopathology , Morphine Dependence/psychology , Oxidopamine/pharmacology , Substance Withdrawal Syndrome/psychology , Sympatholytics/pharmacology , Weight Loss/drug effects
18.
Behav Pharmacol ; 7(4): 334-340, 1996 Aug.
Article in English | MEDLINE | ID: mdl-11224426

ABSTRACT

Modification of naloxone-precipitated withdrawal symptoms by drugs acting on alpha-adrenoceptors was investigated in morphine-dependent mice. Clonidine (0.05-1mg/kg) attenuated most withdrawal symptoms, but potentiated withdrawal hypothermia. Jumping was attenuated by doses of clonidine up to 0.3mg/kg, but markedly potentiated by 1mg/kg. Prazosin (0.05mg/kg) neither had effects of its own, nor influenced those of clonidine. Both yohimbine (0.05-5mg/kg) and idazoxan (1-10mg/kg) potentiated naloxone-precipitated withdrawal symptoms. When tested against a low dose of clonidine (0.2mg/kg), idazoxan dose-dependently reduced the suppressive effects of clonidine on jumping, "wet dog" shakes, burrowing and body-weight loss but potentiated the hypothermic response of clonidine. Yohimbine similarly reduced the suppressive effect of clonidine on body-weight loss and potentiated its hypothermic response, but unlike idazoxan, it did not influence the inhibition by clonidine of "wet dog" shakes, and markedly reversed the suppression of jumping and burrowing into potentiation. Yohimbine and idazoxan also differed with respect to their antagonistic profile against a high dose of clonidine (1mg/kg). Yohimbine further aggravated the potentiation of jumping by clonidine, reduced the effect on body-weight loss and reversed the suppression of burrowing by clonidine. On the other hand, idazoxan markedly reduced the potentiation of jumping by clonidine, and reversed its effect on "wet dog" shakes and burrowing. These findings indicate that clonidine has a biphasic effect on jumping, and disclose differences in the antagonistic profiles between yohimbine and idazoxan. The results suggest that in addition to alpha(2)-adrenoceptors, non-adrenergic imidazoline receptors sensitive to clonidine and idazoxan but not to yohimbine may modulate the expression of morphine withdrawal symptoms.

19.
Neurosci Res ; 25(2): 155-60, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8829152

ABSTRACT

Both oxotremorine and physostigmine both in doses ranging from 25 to 100 micrograms/kg produced dose-dependent attenuation of withdrawal jumping and potentiation of 'wet dog' shakes, burrowing, hypothermia and body weight loss precipitated by naloxone (1 mg/kg, i.p.) in morphine-dependent mice. On the other hand, atropine sulphate (2-20 mg/kg) dose-dependently attenuated all naloxone precipitated withdrawal symptoms except withdrawal hypothermia which was further potentiated. However, the peripherally acting derivative atropine methyl nitrate (2-10 mg/kg) also attenuated all naloxone-induced withdrawal symptoms except jumping, which was not significantly modified. Hyoscine (0.2-20 mg/kg) exhibited a biphasic effect on withdrawal jumping. Withdrawal jumping was potentiated by low and attenuated by high doses of hyoscine. Withdrawal body weight loss was dose-dependently attenuated but 'wet dog' shakes, burrowing and hypothermia were markedly potentiated by hyoscine. Our results suggest that a combination of central muscarinic activation and peripheral muscarinic blockade can partially ameliorate precipitated morphine withdrawal. Differences observed between atropine and hyoscine with regard to their modifying effects on withdrawal symptoms may be explained on the basis that the drugs may be acting on the different subpopulations of the muscarinic receptor or through non-cholinergic systems.


Subject(s)
Atropine/pharmacology , Cholinesterase Inhibitors/pharmacology , Morphine/adverse effects , Muscarinic Antagonists/pharmacology , Narcotics/adverse effects , Physostigmine/pharmacology , Substance Withdrawal Syndrome/physiopathology , Animals , Behavior, Animal/drug effects , Body Temperature/drug effects , Drug Interactions , Male , Mice , Naloxone/pharmacology , Narcotic Antagonists/pharmacology
20.
Gen Pharmacol ; 26(7): 1579-81, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8690249

ABSTRACT

1. In morphine-dependent mice, muscimol, a GABAA agonist when given i.p. 30 min before naloxone, attenuated the naloxone-precipitated withdrawal symptoms of jumping, "wet dog" shakes and burrowing, but not body weight loss. 2. Muscimol produced a hypothermic effect which was further aggravated by naloxone.


Subject(s)
GABA Agonists/pharmacology , Morphine Dependence , Muscimol/pharmacology , Naloxone/adverse effects , Narcotic Antagonists/adverse effects , Substance Withdrawal Syndrome/prevention & control , Animals , Male , Mice , Naloxone/antagonists & inhibitors
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