Increased α2- and β1-adrenoceptor densities in postmortem brain of subjects with depression: differential effect of antidepressant treatment.

BACKGROUND: Brain α2- and β-adrenoceptor alterations have been suggested in suicide and major depressive disorder. METHODS: The densities of α2-, β1- and β2-adrenoceptors in postmortem prefrontal cortex of 26 subjects with depression were compared with those of age-, gender- and postmortem delay-matched controls. The effect of antidepressant treatment on α2- and β-adrenoceptor densities was also evaluated. α2- and β-adrenoceptor densities were measured by saturation experiments with respective radioligands [(3)H]UK14304 and [(3)H]CGP12177. β1- and β2-adrenoceptor subtype densities were dissected by means of β1-adrenoceptor selective antagonist CGP20712A. RESULTS: Both, α2- and β1-adrenoceptors densities were higher in antidepressant-free depressed subjects (n=14) than those in matched controls (Δ~24%, p=0.013 and Δ~20%, p=0.044, respectively). In antidepressant-treated subjects (n=12), α2-adrenoceptor density remained increased over that in controls (Δ~20%), suggesting a resistance of α2-adrenoceptors to the down-regulatory effect of antidepressants. By contrast, β1-adrenoceptor density in antidepressant-treated depressed subjects was not different from controls, suggesting a possible down-regulation by antidepressants. The down-regulation of β1-adrenoceptor density in antidepressant-treated depressed subjects differs from the unaltered β1-adrenoceptor density observed in citalopram-treated rats and in a group of non-depressed subjects also treated with antidepressants (n=6). β2-adrenoceptor density was not altered in depressed subjects independently of treatment. LIMITATIONS: Antidepressant-treated subjects had been treated with a heterogeneous variety of antidepressant drugs. The results should be understood in the context of suicide victims with depression. CONCLUSIONS: These results show the up-regulation of brain α2- and β1-adrenoceptors in depression and suggest that the regulation induced by chronic antidepressant treatment would be altered in these subjects.

Enantiomeric antidepressant drugs should be considered on individual merit

Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug-drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression.

Cytochrome P-450 activities in human and rat brain microsomes.

The role of cytochrome P450 in the metabolism of dextromethorphan, amitriptyline, midazolam, S-mephenytoin, citalopram, fluoxetine and sertraline was investigated in rat and human brain microsomes. Depending on the parameters, the limit of quantification using gas chromatography-mass spectrometry methods was between 1.6 and 20 pmol per incubation, which generally contained 1500 microg protein. Amitriptyline was shown to be demethylated to nortriptyline by both rat and human microsomes. Inhibition studies using ketoconazole, furafylline, sulfaphenazole, omeprazole and quinidine suggested that CYP3A4 is the isoform responsible for this reaction whereas CYP1A2, CYP2C9, CYP2C19 and CYP2D6 do not seem to be involved. This result was confirmed by using a monoclonal antibody against CYP3A4. Dextromethorphan was metabolized to dextrorphan in rat brain microsomes and was inhibited by quinidine and by a polyclonal antibody against CYP2D6. Only the addition of exogenous reductase allowed the measurement of this activity in human brain microsomes. Metabolites of the other substrates could not be detected, possibly due to an insufficiently sensitive method. It is concluded that cytochrome P450 activity in the brain is very low, but that psychotropic drugs could undergo a local cerebral metabolism which could have pharmacological and/or toxicological consequences.

An index of 5-HT synthesis changes during early antidepressant treatment: α-[11C]methyl-l-tryptophan PET study

The antidepressant selective serotonin transporter inhibitors (SSRIs) are clinically active after a delay of several weeks. Indeed, the rapid increase of serotonin (5-HT) caused by SSRIs, stimulates the 5-HT1A autoreceptors, which exert a negative feedback on the 5-HT neurotransmission. Only when autoreceptors are desensitized, can SSRIs exert their therapeutic activity. The 5-HT1A receptor antagonist pindolol has been used to accelerate the clinical effects of antidepressant by preventing the negative feedback. Using the a-[11C]methyl-L-tryptophan/positron emission tomography (PET), the goal of the present double-blind, randomized study was to compare the changes in a-[11C]methyl-L-tryptophan trapping, an index of serotonin synthesis, in patients suffering from unipolar depression treated with the SSRI citalopram (20 mg/day) plus placebo versus patients treated with citalopram plus pindol (7.5 mg/day). PET and Hamilton depression rating scale (HDRS-17) were performed at baseline, and after 10 and 24 days of antidepressant treatment. Results show that the combination citalopram plus pindol, compared to citalopram alone shows a more rapid and greater increase of an index of 5-HT synthesis in prefrontal cortex (BA 9). This research is the first human PET study demonstrating that, after 24 days, the combination SSRIs plus pindolol produces a greater increase of the metabolism of serotonin in the prefrontal cortex, an area associated to depressive symptoms.

Enantiomers' potential in psychopharmacology--a critical analysis with special emphasis on the antidepressant escitalopram

Stereochemistry is now influencing most areas of pharmacotherapy, with a growing awareness in the field of psychiatry and, more specifically, depression. This is due to the fact that the enantiomers of many chiral drugs may have distinct pharmacological, pharmacokinetic and/or pharmacogenetic profiles. Consequently, in some instances there may be an advantage in using a single enantiomer over the racemic form-thus providing a basis for the development of new therapeutic agents, as well as the potential to improve current treatments. This review highlights some of the potential advantages and disadvantages that using single enantiomers might offer. The principles are exemplified through reference to the stereoselective properties of several established chiral psychotropic drugs, including thioridazine, methadone, trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. Emphasis is given to the treatment of depression and how the potential of one pure enantiomer-escitalopram, the S-enantiomer of the selective serotonin reuptake inhibitor citalopram-appears to be fulfilling its preclinical promise in the clinic.

Simultaneous quantification of selective serotonin reuptake inhibitors and metabolites in human plasma by liquid chromatography-electrospray mass spectrometry for therapeutic drug monitoring.

A simple and sensitive liquid chromatography-electrospray ionization mass spectrometry method was developed for the simultaneous quantification in human plasma of all selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their main active metabolites (desmethyl-citalopram and norfluoxetine). A stable isotope-labeled internal standard was used for each analyte to compensate for the global method variability, including extraction and ionization variations. After sample (250μl) pre-treatment with acetonitrile (500μl) to precipitate proteins, a fast solid-phase extraction procedure was performed using mixed mode Oasis MCX 96-well plate. Chromatographic separation was achieved in less than 9.0min on a XBridge C18 column (2.1×100mm; 3.5μm) using a gradient of ammonium acetate (pH 8.1; 50mM) and acetonitrile as mobile phase at a flow rate of 0.3ml/min. The method was fully validated according to Société Française des Sciences et Techniques Pharmaceutiques protocols and the latest Food and Drug Administration guidelines. Six point calibration curves were used to cover a large concentration range of 1-500ng/ml for citalopram, desmethyl-citalopram, paroxetine and sertraline, 1-1000ng/ml for fluoxetine and fluvoxamine, and 2-1000ng/ml for norfluoxetine. Good quantitative performances were achieved in terms of trueness (84.2-109.6%), repeatability (0.9-14.6%) and intermediate precision (1.8-18.0%) in the entire assay range including the lower limit of quantification. Internal standard-normalized matrix effects were lower than 13%. The accuracy profiles (total error) were mainly included in the acceptance limits of ±30% for biological samples. The method was successfully applied for routine therapeutic drug monitoring of more than 1600 patient plasma samples over 9 months. The β-expectation tolerance intervals determined during the validation phase were coherent with the results of quality control samples analyzed during routine use. This method is therefore precise and suitable both for therapeutic drug monitoring and pharmacokinetic studies in most clinical laboratories.

Mirtazapine in drug-induced excessive sweating.

Excessive sweating is a well-known side effect of a selective serotonin reuptake inhibitor treatment, but little is known about the impact of sweating on treatment discontinuation or the general quality of life of patients. In this case report, we present a patient suffering from excessive sweating induced by escitalopram. When mirtazapine was administered as an additional treatment, a dose-dependent reduction of drug-induced excessive sweating was observed. Taking into account the particular serotonin antagonistic properties of mirtazapine, its eventual influence on the regulation of body temperature and diaphoresis in the central nervous system is discussed.

Increased trimipramine plasma levels during fluvoxamine comedication.

A depressive patient, a non-responder to trimipramine (TRI), was comedicated first with citalopram (CIT) and then with fluvoxamine (FLUV). Both the TRI-CIT and TRI-FLUV combination treatments led to a worsening of the depressive state and to the appearance of panic attacks. The addition of FLUV to TRI resulted in a twofold increase of the plasma levels of TRI and to a slight increase of its N-demethylated and 2-hydroxylated metabolites. These results suggest that the interaction between FLUV and TRI occurred at the level of cytochrome P-450IID6 and cytochrome P-450meph in this patient, phenotyped as an extensive metabolizer of both dextromethorphan and mephenytoin. The adverse effects were possibly due to (a) a pharmacokinetic interaction between CIT and FLUV with TRI and/or (b) alterations in serotonergic and/or dopaminergic neurotransmission.

Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients.

Five selective serotonin reuptake inhibitors (SSRIs) have been introduced recently: citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Although no therapeutic window has been defined for SSRIs, in contrast to tricyclic antidepressants, analytical methods for therapeutic drug monitoring of SSRIs are useful in several instances. SSRIs differ widely in their chemical structure and in their metabolism. The fact that some of them have N-demethylated metabolites, which are also SSRIs, requires that methods be available which allow therapeutic drug monitoring of the parent compounds and of these active metabolites. most procedures are based on prepurification of the SSRIs by liquid-liquid extraction before they are submitted to separation by chromatographic procedures (high-performance liquid chromatography, gas chromatography, thin layer chromatography) and detection by various detectors (UV, fluorescence, electrochemical detector, nitrogen-phosphorus detector, mass spectrometry). This literature review shows that most methods allow quantitative determination of SSRIs in plasma, in the lower ng/ml range, and that they are, therefore, suitable for therapeutic drug monitoring purposes of this category of drugs.

Métabolisme d'antidépresseurs dans différentes espèces : aspects méthodologiques et pharmacogénétiques, perspectives cliniques

Résumé pour large public Unité de Biochimie et Psychopharmacologie Clinique, Centre de neurosciences Psychiatrique, Département de Psychiatrie Adulte, Faculté de Biologie et de Médecine, Université de Lausanne Lors de la prise d'un médicament, celui-ci va passer par différentes étapes que sont l'absorption, la distribution, le métabolisme et enfin l'élimination. Ces quatre étapes sont regroupées sous le nom de pharmacocinétique. A noter que ces quatre paramètres sont dynamiques et en constante évolution. Durant cette thèse, nous avons investigué différents aspects de la pharmacocinétique, tout d'abord par une revue de la littérature sur la glycoprotéine-P (Pgp). Récemment découverte, cette protéine de membrane est située aux endroits stratégiques de l'organisme comme la barrière hématoencéphalée, le placenta ou les intestins où elle influencera l'entrée de différentes substances, en particulier les médicaments. La Pgp serait impliquée dans les phénomènes de résistances aux agents thérapeutiques en oncologie. La Pgp influence donc l'absorption des médicaments, et son impact en clinique, en termes d'efficacité de traitement et de toxicité prend chaque jour plus d'importance. Ensuite nous avons mis au point une méthode d'analyse quantitative d'un antidépresseur d'une nouvelle génération : la mirtazapine (Remeron®). La nouveauté réside dans la façon dont la mirtazapine interagit avec les neurotransmetteurs impliqués dans la dépression que sont la sérotonine et la noradrénaline. Cette méthode utilise la chromatographie liquide pour séparer la mirtazapine de ses principaux métabolites dans le sang. La spectrométrie de masse est utilisée pour les détecter et les quantifier. Les métabolites sont des substances issues de réactions chimiques entre la substance mère, la mirtazapine, et généralement des enzymes hépatiques, dans le but de rendre cette substance plus soluble en vue de son élimination. Cette méthode permet de quantifier la mirtazapine et ses métabolites dans le sang de patients traités et de déterminer la variation des taux plasmatiques chez ces patients. Puis nous avons étudié le métabolisme d'un autre antidépresseur, le citalopram, qui a un métabolisme complexe. Le citalopram est un racémate, c'est-à-dire qu'il existe sous forme de deux entités chimiques (R-(-) et S-(+) citalopram) qui ont le même nombre d'éléments mais arrangés différemment dans l'espace. La voie métabolique cérébrale du citalopram est sous le contrôle d'une enzyme, la monoamine oxydase (MAO), conduisant à une forme acide du citalopram (l'acide propionique du citalopram). La MAO existe sous deux formes : MAO-A et MAO-B. Nous avons utilisé des souris déficientes d'un gène, celui de la MAO-A, pour mieux en comprendre le métabolisme en les comparants à des souris sauvages (sans déficience de ce gène). Nous avons utilisé le citalopram et deux de ses métabolites (le déméthylcitaloprarn et le didéméthyícitalopram) comme substrats pour tester la formation in vitro de l'acide propionique du citalopram. Nos résultats montrent que la MAO-A favorise la formation de l'entité R-(-) et présente une plus grande affinité pour le citalopram, tandis que la MAO-B métabolise préférentiellement l'entité S-(+) et a une plus grande affinité pour les deux métabolites déméthylés. De plus, la déficience en MAO-A est partiellement compensée parla MAO-B chez les souris déficientes du gène de la MAO-A. Enfin, nous avons étudié une deuxième voie métabolique du citalopram qui s'est avérée toxique chez le chien Beagle. Celle-ci est catalysée par une autre famille d'enzymes, les cytochromes P-450, et mène aux métabolites déméthylés et didéméthylés du citalopram. Nous avons utilisé des tissus hépatiques de chiens Beagle. Plusieurs cytochromes P-450 sont impliqués dans le métabolisme du citalopram menant à sa forme déméthylée, ceci tant chez l'homme que chez le chien. Par contre, dans le métabolisme de la forme déméthylée menant à 1a forme didéméthylée, un seul cytochrome P-450 serait impliqué chez l'Homme, tandis qu'ils seraient plusieurs chez le chien. L'activité enzymatique produisant la forme didéméthylée est beaucoup plus importante chez le chien comparé à l'homme. Cette observation soutien l'hypothèse que des taux élevés de la forme didéméthylée participent à la toxicité spécifique du citalopram chez le chien. Nous pouvons conclure que plusieurs famille d'enzymes sont impliquées tant au niveau cérébral qu'hépatique dans la métabolisation de médicaments psychotropes. Sachant que les enzymes peuvent être stimulées ou inhibées, il importe de pouvoir suivre au plus prés les taux plasmatiques des différents psychotropes et de leurs métabolites. Résumé Unité de Biochimie et Psychopharmacologie Clinique, Centre de neurosciences Psychiatrique, Département de Psychiatrie Adulte, Faculté de Biologie et de Médecine, Université de Lausanne La plupart des médicaments subissent une transformation enzymatique dans l'organisme. Les substances issues de cette métabolisation ne sont pas toujours dotées d'une activité pharmacologique. Il s'est avéré par conséquent indispensable de suivre les taux plasmatiques d'une substance et de ses métabolites et d'établir ou non l'existence d'une relation avec l'effet clinique observé. Ce concept nommé « therapeutic drag monitoring » (TDM) est particulièrement utile en psychiatrie ou un manque de compliance des patients est fréquemment observé. Les médicaments psychotropes ont un métabolisme principalement hépatique (cytochromes P-450) et parfois cérébral (monoamines oxydases), comme pour le citalopram par exemple. Une méthode stéréosélective de chromatographie liquide couplée à la spectrométrie de masse a été développée pour analyser les énantiomères R-(-) et S-(+) d'un antidépresseur agissant sur les récepteurs noradrénergiques et sérotoninergiques, la mirtazapine et de ses métabolites déméthylmirtazapine et 8-hydroxymirtazapine. Les données préliminaires obtenues dans les plasmas dosés suggèrent que les concentrations de R-(-)-mirtazapine sont plus élevées que celles de S-(+)-mirtazapine, à l'exception des patients qui auraient comme co-médication des inhibiteurs du CYP2D6, telle que la fluoxétine ou la thioridazine. Il y a une enantiosélectivité du métabolisme de la mirtazapine. En particulier pour la 8-hydroxymirtazapine qui est glucuroconjuguée et pour laquelle le ratio S/R varie considérablement. Cette méthode analytique présente l'avantage d'être utilisable pour le dosage stéréosélectif de la mirtazapine et de ses métabolites dans le plasma de patients ayant d'autres substances en co-médication. La glycoprotéine P fonctionne comme une pompe transmembranaire transportant les xénobiotiques depuis le milieu intracellulaire vers le milieu extracellulaire. Son induction et son inhibition, bien que moins étudiées que pour les cytochromes P-450, ont des implications cliniques importantes en termes d'efficacité de traitement et de toxicité. Cette glycoprotéine P a fait l'objet d'une recherche bibliographique. Nous avons étudié le métabolisme du citalopram, un antidépresseur de la classe des inhibiteurs spécifiques de la recapture de la sérotonine chez la souris et chez le chien. Cette substance subit un métabolisme complexe. La voie de métabolisation conduisant à la formation de l'acide propionique du citalopram, catalysée par les monoamines oxydases, a été étudiée in vitro dans les mitochondries cérébrales chez la souris déficiente du gène de la MAO-A (Tg8). La monoamine oxydase A catalyse la formation de l'énantiomère R-(-) et présente une plus grande affinité pour les amines tertiaires, tandis que la monoamine oxydase B favorise la formation de la forme S-(+) et a une affinité plus marquée pour les amines secondaires et primaires. L'étude du citalopram chez la souris Tg8 adulte a montré que la monoamine oxydase B compense la déficience de la monoamine oxydase A chez ces souris génétiquement modifiées. Une autre voie de métabolisation du citalopram conduisant à la formation de didéméthylcitalopram, catalysée par les cytochromes P-450, a été étudiée in vitro dans des microsomes hépatiques de chiens Beagle. Nos études ont montré que les cinétiques de N-déméthylation du citalopram sont biphasiques chez le chien. Les orthologues canins impliqués dans la première N-déméthylation semblent être identiques aux cytochromes P-450 humains. Par contre, dans la deuxième Ndéméthylation, un seul cytochrome P-450 semble être impliqué chez l'homme (CYP2D6), tandis qu'on retrouve jusqu'à cinq orthologues chez le chien. Le CYP2D15, orthologue canin du CYP2D6, est majoritairement impliqué. De plus, l'activité enzymatique, reflétée par les clairances intrinsèques, dans la première N-déméthylation est jusqu'à 45 fois plus élevée chez le chien comparé à l'homme. Ces différentes observations soutiennent l'hypothèse que des taux élevés de didéméthylcitalopram sont responsables de la toxicité du citalopram chez le chien. Nous pouvons conclure que plusieurs famille d'enzymes sont impliquées tant au niveau cérébral qu'hépatique dans la métabolisation de médicaments psychotropes. Sachant -que les enzymes peuvent être induits ou inhibés, il importe de pouvoir suivre au plus près les taux plasmatiques des différents psychotropes et de leurs métabolites. Summary Most of the drugs are metabolized in the organism. Substances issued from this metabolic activity do not always show a pharmacological activity. Therefore, it is necessary to monitor plasmatic levels of drugs and their metabolites, and establish the relationship with the clinical effect. This concept named therapeutic drug monitoring is very useful in psychiatry where lack of compliance is commonly observed. Antidepressants are mainly metabolized in the liver (cytochrome P-450) and sometimes in the brain (monoamine oxidase) like the citalopram, for exemple. A LC-MS method was developed, which allows the simultaneous analysis of R-(-) and S-(+) enantiomers of mirtazapine, an antidepressant acting specifically on noradrenergic and serotonergic receptors, and its metabolites demethylmirtazapine and 8-hydroxymirtazapine in plasma of mirtazapine treated patients. Preliminary data obtained suggested that R-(-) mirtazapine concentrations were higher than those of S-(+) mirtazapine, except in patients comedicated with CYP2D6 inhibitors such as fluoxetine or thioridazine. There is an enantioselectivity in the metabolism of mirtazapine. In particular for the 8-hydroxymirtazapine, which is glucuroconjugated and S/R ratio varies considerably. Therefore this method seems to be suitable for the stereoselective assay of mirtazapine and its metabolites in plasma of patients comedicated with mirtazapine and other drugs for routine and research purposes. P-glycoprotein is working as an efflux transporter of xenobiotics from intracellular to extracellular environment. Its induction or inhibition, although less studied than cytochrome P-450, has huge clinical implications in terms of treatment efficacy and toxicity. An extensive literature search on P-glycoprotein was performed as part of this thesis. The study of citalopram metabolism, an antidepressant belonging to the class of selective serotonin reuptake inhibitors. This substance undergoes a complex metabolism. First metabolization route leading to citalopram propionic acid, catalyzed by monoamine oxidase was studied in vitro in mice brain mitochondria. Monoamine oxidase A catalyzed the formation of R-(-) enantiomer and showed greater affinity for tertiary amines, whereas monoamine oxidase B triggered the formation of S-(+) enantiomer and demonstrated higher affinity for primary and secondary amines. citalopram evaluation in adult Tg8 mice showed that monoamine oxidase B compensated monoamine oxidase A deficiency in those genetically transformed mice. The second metabolization route of citalopram leading to didemethylcitalopram and catalyzed by cytochrome P-450 was studied in vitro in Beagle dog's livers. Our results showed that citalopram N-demethylation kinetics are biphasic in dogs. Canine orthologs involved in the first N-demethylation seemed to be identical to human cytochromes P-450. However, in the second N-demethylation only one cytochrome P-450 seemed to be involved in human (CYP2D6), whereas up to five canine orthologs were found in dogs. CYP2D15 canine ortholog of CYP2D6 was mainly involved. In addition, enzymatic activity reflected by intrinsic clearance in the first N-demethylation was up to 45 fold higher in dogs compared to humans. Those observations support the assumption that elevated rates of didemethylcitalopram are responsible for citalopram toxicity in dogs. We can conclude that several enzymes groups are involved in the brain, as well as in the liver, in antidepressant metabolization. Knowing that enzymes may be induced or inhibited, it makes sense to closely monitor plasmatic levels of antidepressants and their metabolites.

Gériatrie [Review in geriatric medicine 2014].

Several studies contributed to improving the diagnostic and prognostic assessment of delirium in hospitalized older patients. Direct patient education proved efficient in benzodiazepines withdrawal. A position statement of the American Geriatrics Society does not recommend tube feeding when eating difficulties arise in older persons suffering from advanced dementia. Several studies emphasized once again the potential importance of preventative interventions (in particular physical activity) to prevent or delay dementia occurrence. Two randomized controlled trials of monoclonal antibodies that bind amyloid did not show benefit in patients with mild-to-moderate Alzheimer's dementia (AD). In contrast, vitamin E reduced functional decline in these patients, and citalopram reduced agitation among AD patients as well as their caregiver's stress.

Lääkepatentit - suojauksen merkitys lääkkeen elinkaaren aikana

Lääkemarkkinat ovat rahassa mitattuna erittäin merkittävät markkinat. Siksi suojauksen merkityksen tarkastelu lääkkeen elinkaaren vaiheissa on mielenkiintoista. Kulutushyödyke- ja lääkemarkkinat ovat luonteeltaan erilaiset lääkemarkkinoiden voimakkaan sääntelyn takia. Myös tutkimus- ja tuotekehityskulut lääkevalmisteilla ovat poikkeuksellisen suuria. Lääkekeksintöjä suojataan patenteilla. Lääkevalmisteen suoja-ajan umpeuduttua myyntihinta putoaa yleensä merkittävästi ja hyvin nopeasti. Lääkeyritysten keinoja välttää suoja-ajan päättymisen mukanaan tuomat myyntitulojen alenemiset ovat muun muassa kokonaan uusien innovaatioiden keksiminen, olemassa olevan lääkevalmisteen ominaisuuksien parantaminen sekä oman geneerisen valmisteen tuominen markkinoille. Tutkimuksen päätarkoituksena oli selvittää, kuvata ja analysoida kolmen kansantaloudellisesti hyvin merkittävän lääkeaineen elinkaaren vaiheita Suomessa. Tutkimuksessa tarkasteltiin suojauksen merkitystä lääkkeiden myyntiin ja kulutukseen sekä kilpailevien valmisteiden osuuteen markkinoilla. Tutkitut lääkeaineet olivat simvastatiini, bisoprololi ja sitalopraami. Tutkimuksessa pohdittiin lääkkeiden suojamekanismin merkitystä ja riittävyyttä eri sidosryhmille. Tutkimuksessa selvitettiin myös patentoinnin merkitystä lääkkeiden myynnin kehittymiseen ja kilpailevien lääkevalmisteiden lukumääriin elinkaaren eri vaiheissa. Tutkittujen valmisteiden patenttien umpeutuessa geneerisiä valmisteita tulee markkinoille pian ja lukumääräisesti paljon. Rinnakkaistuontivalmisteet eivät juuri alentaneet alkuperäislääkkeiden hintoja. Geneeriset valmisteet alensivat hintoja selvästi jopa useita kymmeniä prosentteja. Hintojen romahdus oli keskimäärin noin 75 %. Hintakilpailun takia alkuperäislääkkeen elinkaaren loppupuolella tukkumyynnin arvo koko ajan pieneni kulutuksen kasvaessa tasaisesti. Lisääntynyt hintakilpailu on lisännyt viranomaisille jätettävien hintahakemusten määrää oleellisesti. Hintakilpailusta hyötyvät sekä yhteiskunta ja kuluttajat alkuperäisvalmistajien ja apteekkien kustannuksella. Yhden maan myynnillä ei käytännössä ole nykyisillä suojamekanismeilla mahdollisuutta kattaa lääkkeen kehittämiseen käytettyjä kuluja. Tähän vaaditaan kansainvälisiä markkinoita.

Cardiac Toxicity in Selective Serotonin Reuptake Inhibitor Users.

Several classes of recreational and prescription drugs have been associated with an increased risk of cardiovascular disease and the occurrence of arrhythmias, which may be involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart, which may be caused by selective serotonin reuptake inhibitor use and their possible role in the occurrence of sudden cardiac death. A total of 40 cases were included in the study and were divided evenly into 2 groups: 20 cases of patients treated with selective serotonin reuptake inhibitors and 20 cases of sudden deaths involving patients void of any drug treatment. The first group included 16 patients treated with citalopram and 4 with sertraline. Autopsies, histology, biochemistry, and toxicology were performed in all cases. Pathological changes in selective serotonin reuptake inhibitor users consisted of various degrees of interstitial and perivascular fibrosis as well as a small degree of perineural fibrosis within the myocardium of the left ventricle. Within the limits of the small number of investigated cases, the results of this study seem to confirm former observations on this topic, suggesting that selective serotonin reuptake inhibitors may play a potential, causative role in the pathogenesis of sudden deaths in chronic users even at therapeutic concentrations.