Subject(s)
Cannabis/adverse effects , Health Education , Marijuana Abuse/prevention & control , Public Opinion , Adolescent , Adult , Bibliometrics , Cannabinoid Receptor Modulators/physiology , Cannabinoids/adverse effects , Cannabinoids/therapeutic use , France , Humans , Knowledge , Legislation, Drug , Marijuana Abuse/epidemiology , Marijuana Abuse/psychology , Risk Assessment , Young AdultABSTRACT
The European Union (EU) has 25 member-states and 455 million inhabitants. Statistics on traffic accidents in the EU show that more than 45,000 people are killed annually, including 5200 in France. At the same time, nearly two million persons in the EU require medical treatment for traffic-accident-related injuries, including 109,000 in France. In addition, traffic accidents are the major cause of death of those individuals aged 15 to 24 years. One third of the EU inhabitants will be hospitalized during their life due to a traffic accident with a cost over 160 billion euro (2-3% of the Gross Domestic Product). An important contributing factor to crashes is the use of alcohol and/or illicit drugs or medication when driving, as they exert negative effects on cognition and psychomotor functions. For illicit drugs, abuse of cannabis with or without alcohol is a major concern for the EU. In fact, three million Europeans use cannabis daily and 80% of them drive after use. A number of French studies since 1999 have underlined the high prevalence of cannabis found in the blood of injured or killed drivers. From medical or judicial observations, it is clear that cannabis use increases the risk of traffic accidents. Many groups outside Europe have also shown the association between drug abuse and crashes. The number of casualties related to certain medicines, especially benzodiazepines remains at a high level, particularly in the elderly. In many countries the prevalence of medicinal drugs associated with car accidents is higher than with cannabis. Annex III of the European Union Council Directive of July the 29th 1991 in fact states that a driving license should not be issued to or renewed for applicants or drivers who are dependent on psychotropic substances or use them regularly. Recently, France has categorized the medicinal drugs available in the country by using three pictograms: level one yellow, "be careful"; level two orange, "be very careful"; level three red, "don't drive". It is an important campaign that increases awareness among the public and the medical professionals about the potential dangerous effects of medicinal drugs when driving. The EU objective of reducing the number of fatalities to 25,000 by 2010 will require strengthening measures against the use of alcohol, illicit and medicinal drugs by not well-informed drivers. It is not only a really great challenge, but also a significant investment towards improving public health in France as well as in Europe.
Subject(s)
Accidents, Traffic/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions , Illicit Drugs/adverse effects , Alcohol Drinking/adverse effects , European Union/statistics & numerical data , Humans , Prescription Drugs/adverse effects , Substance-Related Disorders/epidemiologyABSTRACT
As members of the pharmacology training group set up by the committee of pharmacological science of the French Academy of Pharmacy, we examine the situation of pharmacology in drug discovery. Today, it is obvious that by integrating genome sequencing, cellular and molecular biology, and bioinformatics, pharmacology has become a cross-disciplinary science. Pharmacologists must become knowledgeable in a wide range of domains, using the major points in each to direct them towards the discovery and development of new therapeutic agents. It is also clear that pharmacology remains a major factor in the different steps of drug discovery, from the molecular and cellular stages, to clinical and pharmaceutical developments.
Subject(s)
Drug Therapy/trends , Pharmacology/trends , France , Molecular Biology/trends , Pharmacology, Clinical/trendsABSTRACT
Epidemiological studies have reported that cigarette smoking may protect from neurodegenerative diseases such as Parkinson's disease. These protective effects are thought to be mediated by nicotine. Recent data showed that nicotine significantly decreases respiratory control ratio (RCR) and superoxide anion generation of brain mitochondria. Thus, we investigated nicotine effects on rat brain in two experimental models: first, an in vitro anoxia/reoxygenation experiment and secondly, an in vivo rotenone-induced Parkinson-like syndrome. Anoxia/reoxygenation impaired mitochondrial respiration by 43.68% whereas in the presence of nicotine, it was less impaired, by 31.1% at 10(-7) M. In rats chronically administered rotenone (3 mg/kg/day), we observed profound mitochondrial damage: the RCR decreased by 50.36% and the superoxide anion generation and the membrane anisotropy increased by 56.03 and 13.43%, respectively. All of these indications of mitochondrial damage were limited by chronic administration of nicotine. Nicotine developed mitochondrial effects in vivo and in vitro at very low concentration. All these results were in accordance with epidemiological studies, which report a protective effect of nicotine in neurodegenerative diseases. Thus, we propose that one effect of nicotine is to preserve mitochondrial functions of the rat central nervous system.
Subject(s)
Brain/drug effects , Mitochondria/drug effects , Nicotine/administration & dosage , Animals , Brain/metabolism , Cell Hypoxia/drug effects , Cell Hypoxia/physiology , Dose-Response Relationship, Drug , Male , Mitochondria/metabolism , Oxygen Consumption/drug effects , Oxygen Consumption/physiology , Rats , Rats, WistarABSTRACT
We have previously shown, as have other authors, that trans-resveratrol (E-resveratrol, 3,4,5-trihydroxy-E-stilbene) reduces reactive oxygen species (ROS) generation of mitochondria freshly isolated from healthy rat brains and that it also counteracts the effect of uncouplers (CCCP) on mitochondrial respiration and oxidative phosphorylation. Two main mechanisms have been shown: firstly, a scavenger effect toward O2- and secondly inhibition of complex III ROS generation. We now report on the effects of resveratrol in a pathological model that mimics the ischemia followed by the reperfusion process which may occur in the human brain. Isolated brain mitochondria were submitted first to hypoxia then to reoxygenation. The aim of this study was to determine the extent of mitochondrial damage induced by this experimental model, to demonstrate which mitochondrial functions were altered and to quantify the extent to which they were prevented by resveratrol. Resveratrol was either added to mitochondria freshly isolated from healthy rat brains or was injected by subcutaneous chronically implanted pumps (0.5, 2 and 10 mg/kg/day for 7 days). The rats were then sacrificed and mitochondria were extracted from brains. To evaluate the respective effects of hypoxia and reoxygenation on mitochondrial functions and the relevant effects of resveratrol, this drug was added (first protocol) either before the complete process (i.e., hypoxia and reoxygenation), or after anoxia before reoxygenation. We found that resveratrol prevented alterations of mitochondrial functions. This substance partly counteracted the decrease in respiratory control and the increase in ROS generation. It fully inhibited the alteration of membrane fluidity and the mitochondrial step of the apoptotic process (evidenced by cytochrome c release and membrane potential collapse). The effects of resveratrol were concentration-dependent (in vitro) or dose-dependent (ex vivo, second protocol). They were not significantly different when the drug was added before or after hypoxia, which suggests that in this model, reoxygenation was the most deleterious process and the stage at which resveratrol was most effective.
Subject(s)
Antioxidants/pharmacology , Mitochondria/metabolism , Oxygen/metabolism , Prosencephalon/metabolism , Stilbenes/pharmacology , Animals , Antioxidants/administration & dosage , Apoptosis/drug effects , Cell Hypoxia , Cytochromes c/metabolism , Dose-Response Relationship, Drug , In Vitro Techniques , Lipid Peroxidation/drug effects , Membrane Fluidity/drug effects , Prosencephalon/ultrastructure , Rats , Reactive Oxygen Species/metabolism , Resveratrol , Stilbenes/administration & dosageABSTRACT
The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), alpha-estradiol and beta-estradiol on the main functions of purified rat brain mitochondria were investigated in basal conditions and after being submitted to various stresses including anoxia-reoxygenation, uncoupling and apoptosis. In basal conditions, DHEA (1 microM) and alpha-estradiol (1 microM) inhibited the respiratory control ratio (RCR) from 3.1 to 2.3 (25%). After anoxia-reoxygenation, DHEA (1 microM) and alpha-estradiol (1 microM) reversed significantly (P<0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the state 4. This effect was observed when DHEA was added either before anoxia or before reoxygenation and when alpha-estradiol was added before anoxia. The mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%, respectively, protected by DHEA and alpha-estradiol at 1 microM. They also limited by about 50%, the cytochrome c release induced by the anoxia-reoxygenation. The oxygen consumption of mitochondria in presence of NADH (130 microM) and cytochrome c (5 microM) was significantly inhibited by DHEA and alpha-estradiol with high EC(50) of 30 and 22 pM, respectively. At 1 microM, they also inhibited the 10 microM carbonyl cyanide m-chlorophenylhydrazone-induced uncoupling to about 35% whereas beta-estradiol only decreased it to 9%. Our results indicated that DHEA and alpha-estradiol partly preserved the mitochondrial functions altered by an anoxia-reoxygenation with a concentration-dependent effect. The mechanism involved was independent of the classical genomic effect of steroids, the antioxidant properties but implicated a direct action on the mitochondrial membranes.
Subject(s)
Adjuvants, Immunologic/pharmacology , Brain/metabolism , Carrier Proteins , Dehydroepiandrosterone/pharmacology , Estradiol/pharmacology , Mitochondria/metabolism , Adenosine Triphosphatases/metabolism , Animals , Apoptosis/drug effects , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Cell Hypoxia/drug effects , Cytochrome c Group/metabolism , Electron Transport/drug effects , Electron Transport/physiology , Electron Transport Complex I , Electron Transport Complex II , Electron Transport Complex III/metabolism , Electron Transport Complex IV/metabolism , Free Radicals/metabolism , Lipid Peroxidation/drug effects , Membrane Fluidity/drug effects , Membrane Proteins/metabolism , Mitochondria/drug effects , Mitochondrial Proton-Translocating ATPases , Multienzyme Complexes/metabolism , NADH, NADPH Oxidoreductases/metabolism , Oxidative Stress/drug effects , Oxidoreductases/metabolism , Oxygen/pharmacology , Oxygen Consumption/drug effects , Rats , Reactive Oxygen Species/metabolism , Succinate Dehydrogenase/metabolism , Uncoupling Agents/pharmacologyABSTRACT
Benzodiazepines are well tolerated by young adults whereas in elderly people they are less safe and globally induce more central nervous system side-effects and falls. Falls result from a decrease of vigilance and an alteration of postural reflex. This latter includes the reception of sensory information and central integration modulated mainly by dopaminergic D2 receptors and motor stimulation. Benzodiazepines act simultaneously on the three stages, decreasing their efficacy. The risk increases when certain other drugs are coprescribed, especially synergistic drugs such as another psycholeptic drug, an aminoside or a centrally active antihypertensive drug. Thus their co-prescription with a benzodiazepine increases the risk of falls. The pharmacokinetic parameters of benzodiazepines may be modified or remain constant during ageing. The choice of molecules whose parameters do not vary seems advisable. Whatever the selected benzodiazepine, it is obvious that it must be administered at the lowest possible dose, this dose being increased only if necessary, the overall prescription being time limited.
Subject(s)
Accidental Falls/statistics & numerical data , Aged/physiology , Anti-Anxiety Agents/adverse effects , Aging/metabolism , Analgesics/administration & dosage , Analgesics/adverse effects , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/pharmacokinetics , Antidepressive Agents/administration & dosage , Antidepressive Agents/adverse effects , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Arousal/drug effects , Benzodiazepines , Drug Interactions , Female , France/epidemiology , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/adverse effects , Humans , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/adverse effects , Hypnotics and Sedatives/pharmacokinetics , Male , Muscle Tonus/drug effects , Posture , Psychomotor Performance/drug effects , Receptors, Dopamine D2/drug effects , Reflex, Abnormal/drug effects , Risk , Sensation/drug effects , SolubilityABSTRACT
The purpose of this study was to investigate the possible effect of the trimetazidine derivative S-15176 on carnitine palmitoyltransferase1 (CPT-1) activity in rat heart and liver mitochondria. S-15176 was compared with the other antianginal agents amiodarone, perhexiline and trimetazidine, which do not show any hemodynamic effects and which are believed to exert their effects by switching the cellular metabolism towards glucose utilization at the expense of lipid metabolism, increasing the yield of oxygen utilization. S-15176 inhibited CPT-1 in vitro and was more effective in heart (IC(50)= 16.8 micro M) than in liver ( 50.8 +/- 3.0 micro M). In the heart, its was less effective than the physiological inhibitor malonyl-CoA (IC(50)= 2.1 micro M), but it was more potent than amiodarone (IC(50)= 140 micro M). Kinetic experiments demonstrated a non-competitive inhibition of CPT-1 by S-15176 indicating that the two compounds did not share the same site of action. CPT-1 inhibition was also obvious ex vivo, in heart and liver tissues, after a 2 week treatment with S-15176. This inhibitory effect may shift heart and liver metabolism from fatty acid to glucose oxidation and contribute to the anti-ischemic effects of the drug.
Subject(s)
Carnitine O-Palmitoyltransferase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Mitochondria, Heart/drug effects , Mitochondria, Liver/drug effects , Piperazines/pharmacology , Animals , Antioxidants/pharmacology , Carnitine O-Palmitoyltransferase/metabolism , Fatty Acids/metabolism , Glucose/metabolism , Male , Malonyl Coenzyme A/pharmacology , Mitochondria, Heart/enzymology , Mitochondria, Liver/enzymology , Oxidation-Reduction/drug effects , Rats , Rats, WistarABSTRACT
S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes. The effect of S16950 was not significant.
Subject(s)
Antioxidants/pharmacology , Cyclosporine/pharmacology , Immunosuppressive Agents/pharmacology , Lymphocytes/drug effects , Piperazines/pharmacology , Trimetazidine/pharmacology , Adult , Antibodies, Monoclonal , Antioxidants/chemistry , Calcium/metabolism , Cells, Cultured , Cyclosporine/blood , DNA Fragmentation , Drug Interactions , Female , Humans , Immunosuppressive Agents/blood , Male , Mitochondria/drug effects , Piperazines/chemistry , Thymidine/metabolism , Trimetazidine/analogs & derivatives , Trimetazidine/chemistryABSTRACT
AIMS: Despite a lack of data, the antiviral agent ganciclovir is not indicated in AIDS patients with diarrhoea because of its presumed poor oral bioavailability. To assess the effect of diarrhoea on ganciclovir intestinal absorption, we conducted a pharmacokinetic study in 42 HIV-infected patients categorized into three groups: A, HIV stage A and B (n = 15); B, AIDS stage C (n = 13); C, AIDS with chronic diarrhoea and wasting syndrome (n = 14). METHODS: Each patient was evaluated for nutritional (body mass index, albumin, transferrin serum levels), inflammatory (haptoglobin, orosomucoid), immunological (CD4 count, plasma viral load) and intestinal (D-xylose test, faecal fat and nitrogen output, intestinal permeability) status. Ganciclovir (1 g) was administered orally to fasted patients. Six blood samples were collected over 24 h. Serum was analysed for ganciclovir by h.p.l.c. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modelling program, MP2. RESULTS: Mean intestinal permeability (lactulose/mannitol urinary ratio) was increased in group C (0.2) compared with group A (0.05) and B (0.1) patients. Drug concentration-time profiles were best described by a two-compartment model. Apparent oral clearance (CL/F) and central volume of distribution (V1/F) were influenced by clinical status (group). For groups A and B combined, final parameter estimates of CL/F and V1/F were 256 +/- 98 l h(-1) and 1320 +/- 470 l, respectively. Final parameter estimates for group C were 118 +/- 108 l h(-1) and 652 +/- 573 l for CL/F and V1/F, respectively. The 95% confidence intervals on differences between A and B combined and C were statistically significant ([ + 70, + 206] for CL/F, and [+ 314, + 1022] for V1/F). Compared with groups A and B, ganciclovir CL/F was significantly decreased in group C patients. CONCLUSIONS: AIDS patients with diarrhoea and severe disease may benefit from ganciclovir therapy, but a dose adjustment may be required according to their digestive and immunological status.
Subject(s)
Antiviral Agents/pharmacokinetics , Diarrhea/complications , Ganciclovir/pharmacokinetics , HIV Infections/metabolism , HIV Wasting Syndrome/complications , Acquired Immunodeficiency Syndrome/metabolism , Administration, Oral , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Biological Availability , Chromatography, High Pressure Liquid , Diarrhea/drug therapy , Diarrhea/metabolism , Female , Ganciclovir/administration & dosage , Ganciclovir/therapeutic use , HIV Infections/complications , HIV Wasting Syndrome/drug therapy , HIV Wasting Syndrome/metabolism , Humans , Intestinal Absorption/drug effects , Male , Middle Aged , Models, Biological , Nutritional Status/drug effects , Permeability , Time Factors , Weight LossABSTRACT
In this study, we investigated the effects of nicotine on rat brain mitochondria. The polarographic studies determined the effects on the respiratory chain, whereas enzymatic assays and [3H]-nicotine binding allowed us to precisely identify its target and site of action. The measurements of oxygen consumption showed a significantly concentration-dependent inhibition by nicotine (EC50 was 4.95x10(-11) M), and a maximal decrease of 23.90% at 10(-7) M. Nicotine bound to complex I of the respiratory chain and inhibited the NADH-Ubiquinone reductase activity. We also showed that nicotine and NADH were competitive on complex I. Effects of cotinine, the main nicotine metabolite, and nornicotine, were also investigated: nornicotine inhibited the mitochondrial respiration whereas cotinine did not. Because the complex I generates superoxide anion, we investigated the effects of nicotine, following NBT oxidation, and showed that nicotine was able to inhibit this reactive oxygen species (ROS) generation by 15.74% with an EC50 of 2.02x10(-11) M. In conclusion, the present study shows that nicotine interacts with the complex I of brain mitochondrial respiratory chain and decreases ROS generation. This may explain a part of the beneficial and protective effects of nicotine in few neurodegenerative diseases, as suggested by many epidemiological studies.
Subject(s)
Carrier Proteins , Mitochondria/drug effects , Nicotine/analogs & derivatives , Nicotine/pharmacology , Oxidative Phosphorylation/drug effects , Superoxides/metabolism , Adenosine Triphosphatases/metabolism , Alkaloids/pharmacology , Animals , Anthraquinones/pharmacology , Antimycin A/pharmacology , Azocines , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cotinine/pharmacology , Electron Transport Complex I , Electron Transport Complex II , Hexamethonium/pharmacology , Male , Membrane Proteins/metabolism , Mitochondria/metabolism , Mitochondrial Proton-Translocating ATPases , Multienzyme Complexes/metabolism , NAD/metabolism , NADH, NADPH Oxidoreductases/metabolism , Neuroprotective Agents/pharmacology , Oxidation-Reduction , Oxidoreductases/metabolism , Oxygen Consumption/drug effects , Prosencephalon/ultrastructure , Pyridines/pharmacology , Quinolizines , Rats , Rats, Wistar , Reactive Oxygen Species , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/metabolism , Rotenone/pharmacology , Succinate Dehydrogenase/metabolism , Synaptosomes/drug effects , Synaptosomes/metabolismABSTRACT
Curcumin is a natural compound showing antiproliferative properties. Recent studies suggest that these properties might be due to its ability to induce apoptosis in tumor cells. As mitochondria play a pivotal role in the induction of the apoptotic process, we analyzed the effect of curcumin on mitochondrial function. Curcumin induced an increase in rat liver mitochondrial membrane permeability, resulting in swelling, loss of membrane potential and inhibition of ATP synthesis. These effects were mediated by the opening of the permeability transition pore. Curcumin pore induction involved the oxidation of membrane thiol functions and required the presence of low Ca(2+) concentrations. These data suggest that mitochondria might be a target by which curcumin induces apoptosis of tumor cells.
Subject(s)
Curcumin/pharmacology , Ion Channels , Membrane Proteins/drug effects , Membrane Proteins/metabolism , Sulfhydryl Compounds/metabolism , Animals , Antineoplastic Agents/pharmacology , Calcium/metabolism , Chelating Agents/pharmacology , Dose-Response Relationship, Drug , Intracellular Membranes/drug effects , Intracellular Membranes/physiology , Light , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mitochondria, Liver/metabolism , Mitochondrial Membrane Transport Proteins , Mitochondrial Permeability Transition Pore , Mitochondrial Swelling/drug effects , Oxidation-Reduction/drug effects , Oxygen Consumption/drug effects , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Scattering, RadiationABSTRACT
Second generation antihistamines are recognised as being highly effective treatments for allergy-based disease and are among the most frequently prescribed and safest drugs in the world. However, consideration of the therapeutic index or the benefit/risk ratio of the H1 receptor antagonists is of paramount importance when prescribing this class of compounds as they are used to treat non-life threatening conditions. There are many second generation antihistamines available and at first examination these appear to be comparable in terms of safety and efficacy. However, the newer antihistamines in fact represent a heterogeneous group of compounds, having markedly differing chemical structures, adverse effects, half-life, tissue distribution and metabolism, spectrum of antihistaminic properties, and varying degrees of anti-inflammatory effects. With regard to the latter, there is growing awareness that some of these compounds might represent useful adjunct medications in asthma therapy. In terms of safety issues, the current second generation grouping includes compounds with proven cardiotoxic effects and others with the potential for adverse drug interactions. Moreover, some of the second generation H1 antagonists have given cause for concern regarding their potential to cause a degree of somnolence in some individuals. It can be argued, therefore, that the present second generation grouping is too large and indistinct since this was based primarily on the concept of separating the first generation sedating compounds from nonsedating H1 antagonists. Although it is too early to talk about a third generation grouping of antihistamines, future membership of such a classification could be based on a low volume of distribution coupled with a lack of sedating effects, drug interactions and cardiotoxicity.
Subject(s)
Asthma/drug therapy , Histamine H1 Antagonists/adverse effects , Anti-Asthmatic Agents/adverse effects , Anti-Asthmatic Agents/pharmacokinetics , Anti-Asthmatic Agents/therapeutic use , Central Nervous System/drug effects , Contraindications , Heart/drug effects , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/therapeutic use , Humans , Inflammation/drug therapy , Inflammation Mediators/metabolism , Receptors, Histamine H1/metabolismABSTRACT
The consequences of ischaemia-reperfusion injury from kidney recipients on delayed graft function and graft survival still remain a matter of debate. Using an autotransplanted pig kidney model, the influence of trimetazidine added to two standard preservation solutions (Euro-Collins and University of Wisconsin) was studied. The renal parameters were analysed over a period of 12 weeks after transplantation. The degree of interstitial fibrosis, and the number of CD4, CD8 and macrophage positive cells were analysed at 2, 4-5 and 11-12 weeks after the transplantation. Glomerular filtration and sodium reabsorption were significantly more improved after cold-flush and preservation with trimetazidine-supplemented solutions than with trimetazidine-free solutions. The cytoprotective action of trimetazidine also reduced interstitial fibrosis and the number of infiltrating CD4 and CD8-positive cells. These results indicate that the condition of cold preservation may influence long-term kidney graft functions and that trimetazidine reduces to a certain extent the degree of interstitial fibrosis.