230 research outputs found
Epidemiology of Cytochrome P450-mediated Drug-Drug Interactions
Drug-drug interactions (DDIs) comprise an important cause of adverse drug reactions leading to excess hospitalizations. Drug metabolism is catalyzed by 75% by cytochrome P450 (CYP) enzymes and thus they are often involved in pharmacokinetic DDIs. In general, DDIs are studied in randomized controlled clinical trials in selected study populations. The overall aim of the present studies was to perform observational pharmacoepidemiological surveys on CYP-mediated DDIs in diseases important at the population level.
The prevalence of co-administrations of four prodrugs (losartan, codeine, tramadol, and clopidogrel), three sulphonylureas (glibenclamide, glimepiride, and glipizide), or two statins (lovastatin and simvastatin) with well established agents altering CYP activity, as well as of statins with fibrates, was studied in Finland utilizing data from a university hospital medication database (inpatients) and the National Prescription Register of the Social Insurance Institution of Finland, Kela (outpatients). Clinical consequences of potential DDIs were estimated by reviewing laboratory data, and information from hospital care and cause-of-death registers.
Concomitant use of study substrates with interacting medication was detected in up to one fifth of patients in both hospital and community settings. Potential CYP3A4 interactions in statin users did not manifest in clear adverse laboratory values but pharmacodynamic DDIs between statins and fibrates predisposed patients to muscular toxicity. Sulphonylurea DDIs with CYP2C9 inhibitors increased the risk of hypoglycaemia. CYP3A4 inhibitor use with clopidogrel was not associated with significant changes in mortality but non-fatal thrombosis and haemorrhage complications were seen less often in this group. Concomitant administration of atorvastatin with clopidogrel moderately attenuated the antithrombotic effect by clopidogrel. The overall mortality was increased in CYP3A4 inducer and clopidogrel co-users. Atorvastatin used concomitantly with prodrug clopidogrel seems to be beneficial in terms of total and LDL cholesterol concentrations, and overall mortality compared with clopidogrel use without interacting medication.
In conclusion, CYP-mediated DDIs are a common and often unrecognized consequence of irrational drug prescribing.Siirretty Doriast
Levosimendan : Studies on its mechanisms of action and beyond
Acute heart failure syndrome represents a prominent and growing health problem all around the world. Ideally, medical treatment for patients admitted to hospital because of this syndrome, in addition to alleviating the acute symptoms, should also prevent myocardial damage, modulate neurohumoral and inflammatory activation, and preserve or even improve renal function. Levosimendan is a cardiac enhancer having both inotropic and vasodilatory effects. It is approved for the short-term treatment of acutely decompensated chronic heart failure, but it has been shown to have beneficial clinical effects also in ischemic heart disease and septic shock as well as in perioperative cardiac support. In the present study, the mechanisms of action of levosimendan were studied in isolated guinea-pig heart preparations: Langendorff-perfused heart, papillary muscle and permeabilized cardiomyocytes as well as in purified phosphodiesterase isoenzyme preparations. Levosimendan was shown to be a potent inotropic agent in isolated Langendorff-perfused heart and right ventricle papillary muscle. In permeabilized cardiomyocytes, it was demonstrated to be a potent calcium sensitizer in contrast to its enantiomer, dextrosimendan. It was additionally shown to be a very selective phosphodiesterase (PDE) type-3 inhibitor, the selectivity factor for PDE3 over PDE4 being 10000 for levosimendan. Irrespective of this very selective PDE3 inhibitory property in purified enzyme preparations, the inotropic effect of levosimendan was demonstrated to be mediated mainly through calcium sensitization in the isolated heart as well as the papillary muscle preparations at clinically relevant concentrations. In the isolated Lagendorff-perfused heart, glibenclamide antagonized the levosimendan-induced increase in coronary flow (CF). Therefore, the main vasodilatory mechanism in coronary veins is believed to be the opening of the ATP-sensitive potassium (KATP) channels. In the paced hearts, CF did not increase in parallel with oxygen consumption (MVO2), thus indicating that levosimendan had a direct vasodilatory effect on coronary veins. The pharmacology of levosimendan was clearly different from that of milrinone, which induced an increase in CF in parallel with MVO2. In conclusion, levosimendan was demonstrated to increase cardiac contractility by binding to cardiac troponin C and sensitizing the myofilament contractile proteins to calcium, and further to induce coronary vasodilatation by opening KATP channels in vascular smooth muscle. In addition, the efficiency of the cardiac contraction was shown to be more advantageous when the heart was perfused with levosimendan in comparison to milrinone perfusion.Sydämen akuutti vajaatoiminta muodostaa maailmanlaajuisesti huomattavan ja yhä laajenevan terveydenhoito-ongelman. Kyseessä on sairaalahoitoa vaativa oireyhtymä, jossa optimaalisen lääkehoidon tulee olla paitsi oireenmukaista, myös ehkäistä sydänlihas- ja munuaisvauriota sekä hillitä neurohumoraalista aktivaatiota ja tulehdusreaktioita. Levosimendaani on sydämen supistusvireyttä lisäävä aine, jolla on myös verisuonia laajentava ominaisuus. Se on hyväksytty akuutisti dekompensoituneen kroonisen vajaatoiminnan lyhytaikaiseen hoitoon. Sillä on kuitenkin edullisia vaikutuksia myös iskeemisessä vajaatoiminnassa ja septisessä sokissa sekä perioperatiivisena kardiologisena tukena. Tässä työssä levosimendaanin vaikutusmekanismeja tutkittiin eristetyissä marsun sydänlihaspreparaateissa: Langendorff-perfusoidussa sydämessä, papillaarilihaksessa ja permeabilisoiduissa sydänlihassoluissa sekä puhdistetuissa fosfodiesteraasi-isoentsyymi (PDE) preparaateissa. Levosimendaani lisäsi supistusvireyttä voimakkaasti sekä eristetyssä sydämessä, että papillaarilihaksessa. Sydänlihassoluissa se osoittautui tehokkaaksi kalsiumherkistäjäksi, toisin kuin sen optinen enantiomeeri, dextrosimendaani. Lisäksi se osoittautui erittäin valikoivaksi PDE tyyppi-3 estäjäksi. Selektiivisyys PDE3:n ja PDE4:n välillä oli 10 000 kertainen. Huolimatta PDE3:a estävästä ominaisuudesta, levosimendaanin supistusvireyttä lisäävän vaikutuksen eristetyssä sydämessä ja papillaarilihaksessa osoitettiin välittyvän kalsiumherkkyyttä lisäävän ominaisuuden kautta. Eristetyssä sydämessä glibenklamidi esti levosimendaanin aiheuttaman sepelvaltimovirtauksen nousun. Näin ollen sepelsuonia laajentava vaikutus näyttäisi välittyvän ATP-herkkien kaliumkanavien (KATP) kautta. Tahdistetussa sydämessä levosimendaanin aiheuttama sepelvaltimovirtauksen nousu ei ollut yhdensuuntainen hapenkulutuksen nousun kanssa. Tämä osoittaa, että levosimendaanilla oli suora sepelsuonia laajentava vaikutus. Levosimendaanin farmakologinen vaikutus oli selvästi erilainen kuin milrinonin, joka lisäsi sepelvaltimovirtausta yhdensuuntaisesti hapenkulutuksen nousun kanssa. Tässä työssä osoitettiin, että levosimendaanin sydämen supistusvireyttä lisäävä ominaisuus liittyy sen sitoutumiseen sydänlihassolun troponiini C molekyyliin ja tätä kautta supistuvien proteiinien lisääntyvään kalsiumherkkyyteen ja että, sepelvaltimovirtausta lisäävä ominaisuus liittyy sen KATP kanavia avaavaan ominaisuuteen. Lisäksi osoitettiin, että levosimendaanilla perfusoidun sydämen supistusvireyden nousu oli hapenkulutukseltaan edullisempaa kuin milrinonilla perfusoidun sydämen supistusvireyden nousu
A Pharmacological Approach towards Myocardial Protection: New Perspectives in Acute and Chronic Cardiac Disease
Several cardiac diseases include myocardial ischaemia (acute or chronic), heart failure (systolic or diastolic) and left ventricular hypertrophy (either as a “primary” cause or developed secondary to other diseases) share the commonality of myocardial energetic deficiency or suboptimal myocardial metabolism. Therefore, approaches to modify myocardial metabolism in order to improve energetics present as an attractive therapeutic option. This is particularly useful when other options are limited: for example, lack of optimal symptom control with “maximal” treatment, or contraindications to other pharmacological treatment (by virtue of impairment of left ventricular systolic function and/or hypotension). The objective of this thesis is to examine the biochemical effects of various pharmacological agents towards modulation of myocardial metabolism, both in the acute (e.g. acute coronary syndrome) and chronic cardiac disease settings (e.g. diabetic heart). In particular, the effects of perhexiline, an interesting drug known to possess not only metabolic effects (by virtue of inhibiting carnitine palmitoyl transferase-1 [CPT-1], thereby shifting myocardial fatty acid oxidation towards glycolysis) but also anti-inflammatory effects, will be further explored. First, the pharmacokinetics and myocardial uptake profile of the individual perhexiline enantiomers were examined. This study showed that the myocardial uptake of both perhexiline enantiomers in patients were slow; and that in multivariate backward stepwise analysis, (-)-perhexiline was inversely correlated with on-treatment heart rate. This finding suggested that the weak calcium antagonist effect of perhexiline may potentially lie predominantly within the (-)- enantiomer. Additionally, other aspects of myocardial metabolism, including the nexus between inflammatory activation and metabolic effect, were investigated. In a study involving 12 patients presenting with acute coronary syndrome and hyperglycaemia, rapid reversal of hyperglycaemia with insulin infusion in 12 hours improved the anti-aggregatory effect of platelets, independent of the platelet content of the pro-inflammatory marker thioredoxin-interacting protein (TXNIP). Furthermore, this thesis also investigated the potential insulin sensitization effect of perhexiline in diabetic patients. This is a corollary of increased glucose utilization, which appears to be relevant even against the background of concomitant therapy with other insulin-sensitizing agents such as AMPK activators or ACE-inhibitors. Furthermore, platelet content of TXNIP tended to fall slightly (but not significantly) after perhexiline treatment, implying its lack of significant critical role in the improvement of both nitric oxide responsiveness and insulin sensitization. However, its overall contribution still cannot be completely ruled out. Lastly, in an in vitro experiment, the potency of inhibition of CPT-1 by both perhexiline enantiomers was investigated. It was found that the 50% inhibitory concentrations of both enantiomers were not significantly different. This provided evidence that the (differential) toxicity seen with the individual enantiomers (in previous studies) might be independent of CPT-1 inhibition. The CPT-1 inhibitory potency of several other cardiac drugs, including fluorinated perhexiline (developed by collaborators in Aberdeen, UK) and dronedarone (a benzofluranyl compound, structurally similar to amiodarone) was also determined in this thesis, and it was shown in particular that dronedarone was a potent CPT-1 inhibitor. The overall thrust of this work reinforces the concept that CPT-1 inhibition is seen with a large number of cardiovascular drugs, and is retained by enantiomers and structural analogues of perhexiline. The myocardial uptake of perhexiline and its enantiomers indicates a relatively slow process of equilibration with its primary sites of action.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201
Myocardial purine metabolism : aspects of myocardial ATP metabolism and pharmacological intervention
The heart is obliged to contract continuously. This
implicates for a human with an average heart rate of 70 beats
per minute in about 70 years more than 2.5 billions of
contractions. For this contraction ATP is needed as the main
substrate. As a consequence continuous ATP production by the
heart is obligatory. This ATP is mainly produced by the
oxygen-dependent oxidative phosphorylation. Disturbances of the
oxygen delivery, such as that induced by partial occlusion of
one or more coronary arteries can lead to a distortion of the
balance between ATP production and consumption. As a res11lt,
ATP is dephosphorylated, and subsequently the products
adenosine, inosine, hypoxanthine, xanthine and uric acid pass
the cellular membrane and appear in the coronary effluent.
Because of the importance of adequate ~TP levels for the heart,
the following 4 main ::.\'Venues have been investigated in this
study, which forms the substance of my thesis
Angina Pectoris
Angina is the most common disorder affecting patients with ischemic heart disease. This book provides a thorough review of fundamental principles of diagnosis, pathophysiology and treatment of angina pectoris, representing an invaluable resource not only for cardiologists, but also for general practitioners and medical students
The Pharmacokinetics and Pharmacodynamics of Calcium Antagonist Drugs in Cardiovascular Disease - Influence of Age, Disease State and Renal Function
This thesis has investigated several aspects of the clinical pharmacology of calcium antagonist drugs
THE EFFECTS OF THERAPEUTIC HYPOTHERMIA ON CYTOCHROME P450-MEDIATED METABOLISM: STUDIES IN TRANSLATIONAL RESEARCH
Therapeutic hypothermia decreases neurological damage in patients experiencing out-of-hospital cardiac arrest (CA). In addition to hypothermia, critically ill patients are treated with an extensive pharmacotherapeutic regimen. The majority of these medications are hepatically eliminated via the cytochrome P450 (CYP450) system. Changes in drug clearance could limit the putative benefit of hypothermic therapy. With the increased use of therapeutic hypothermia and the fact that critically ill patients receive multiple medications, it is crucial to understand the effects of hypothermia on the disposition and metabolism of drugs used in this population. Thus, it was the overall aim of this research to investigate the effects of therapeutic hypothermia on CYP450-mediated metabolism in an animal model of CA, in human liver microsomes, and in normal healthy subjects. Specifically, hypothermia produced a ~2 fold decrease in the systemic clearance (CLS) of intravenous chlorzoxazone, a specific CYP2E1 probe substrate, in a CA rat model when compared to CA rats treated under normothermic temperatures. The mechanism behind this decrease in CLS was a hypothermia-mediated decrease in the affinity of CYP2E1 for chlorzoxazone. We extended the experimental period to investigate the effects of hypothermia after re-warming, on CYP2E1 and CYP3A2 activity and expression. Our results indicate that rats with CA treated under normothermic temperatures demonstrated a significant decrease in the activities of CYP2E1 and CYP3A2, 24 hrs after injury compared to control. Furthermore, CA significantly decreased the expression of CYP3A2, but not the expression of CYP2E1. CA also produced a ~ 10-fold increase in plasma concentrations of interleukin-6 (IL-6) compared to Control. The CA-mediated reduction in CYP3A2 and CYP2E1 activity, mRNA, and the increase in IL-6 plasma concentrations was attenuated by hypothermia. We also investigated the effects of mild and moderate hypothermia on CYP2E1 and CYP3A4 enzyme kinetics in human liver microsomes. Both mild and moderate hypothermia significantly decreased the Vmax of CYP2E1 and CYP3A4. However, hypothermia increased the Km of CYP2E1 but not CYP3A4. These data demonstrate that mild and moderate hypothermia may produce isoform specific alterations of human CYP450-mediated metabolism. Lastly, in a pilot analysis, we showed that mild hypothermia may potentially alter the ClS and the volume of distribution (Vss) of midazolam in mildly hypothermic normal healthy volunteers.Collectively, this work provides evidence that therapeutic hypothermia alters CYP450-mediated metabolism both during cooling and after re-warming. Based on the magnitude of these changes it is clear that intensivists should be cognizant of these alterations and monitor drug levels and outcomes in their patients when possible. In addition to increased clinical attention, future research efforts are essential to delineate precise dosing guidelines and mechanisms of the effects of hypothermia on drug disposition, metabolism, and response
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