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Investigation of the mechanism of fenfluramine-induced pulmonary phospholipidosis in the rat lung modelHassan, Mogamat Shafick January 1993 (has links)
Magister Pharmaceuticae - MPharm / The aim of this study was to investigate the mechanism of fenfluramine-induced pulmonary phospholipidosis, by comparing the profile and levels of induced phospholipids in the rat and the mode of phospholipase inactivation, both relative to that produced by chlorphentermine.
Wistar and BD9 rats were injected with fenfluramine (FF) and chlorphentermine (CP) intra-peritoneally daily over a six week period to induce phospholipidosis. The lungs isolated from such treated and untreated animals, were grouped into unlavaged lungs and lungs to be lavaged and from the latter group the alveolar macrophages were isolated. Small sections of the unlavaged lungs were microscopically examined to verify the induction of phospholipidosis. Further the levels of phosphatidyl choline (PC), spingomyelin (SPM), phosphatidyl ethanolamine (PE), phosphatidyl glycerol (PG), phosphatidyl inositol (PI), phosphatidyl serine (PS) and phosphatidic acid (PA) were determined in both groups of lungs using a TLC method. To assess whether the drug-mediated inactivation of the phospholipases (PL) occurred via direct inhibition of the
enzymes or via the drug-phospholipid complex, the hydrolysis of the above phospholipids by PL-A or PL-C were monitored using colorimetric methods. The feasibility of the phospholipid-drug complex-mediated mechanism was further explored, by assessing the effect the two drugs had on the phase transition temperature of the phospholipids. Electron microscopy revealed the presence of hypertrophied and elevated counts of alveolar macrophages in the treated-Wistar and -BD9 rats. In the FF- and CP treated Wistar and BD9 rats there were, compared to the saline-treated rats, a 200 % and 235 % increase in macrophage counts, respectively, for the FF-treated rats and a 700 % and 965 % increase in macrophage counts, respectively, for the CP treated rats. The levels of all the phospholipids in the unlavaged lungs of both rat
strains were elevated, except that for PG, PS and PA. In both rat strains following the treatment with both drugs the PG levels were not elevated and the PS levels were not elevated following CP treatment. Following the treatment for both drugs, the PA levels were also not elevated in the BD9 rats. Relative to the levels found in the unlavaged lungs of the control rats, the increases ranged from a minimum
of 9 to a maximum of 216 %. In general, Wistar rats appeared to be more susceptible to both FF and CP treatment. In both rat strains, lavaging of the lungs considerably reduced the levels of phospholipids remaining in the lung and the differences between the treated and untreated animals became less striking. The addition of FF or CP, whether directly to the enzyme, or in the form of the drug phospholipid
complex, resulted in significant decreases in the PL-A-mediated or PL-C-mediated hydrolysis of virtualy all the test phospholipids. The average
decrease ranged from 0.811 to 4.04 ,.,.FFAbbb ,.,.1-1sample min-I, for the PL-A activity and 0.023 to 0.827 ,.,.gIp'CC100 ,.,.1-1 sample min-I, for the PL-C activity. In the case of FF, the inhibition of PL-A activity could not be ascribed exclusively to either direct inhibition of the enzyme or reduced susceptibility of the phospholipid substrate-drug complex. The PL-C activity appeared to be inhibited to a greater extent via the phospholipid substrate-drug complex rather than by direct inhibition. On the other hand, CP induced a small, but significantly greater
degree of inhibition of PL-A activity, more via direct inhibition, rather than by the phospholipid substrate-drug complex. The PL-C activity appeared to be inhibited to a greater extent via phospholipid substrate-drug complexation than by direct inhibition. From the above data, considered collectively, it was not possible to declare either of the two possible mechanisms as the more likely one for FF or CP-induced inhibition of the phospholipases. The feasibility of the indirect mode was further explored, by determining the phase transition temperatures for the phospholipid-drug complexes of each drug. The addition of each drug caused a depression of the phase transition temperature of all the phospholipids with a .1T'dd ranging from 0.52 to 15.73 °C. This appears to support the notion that both drugs bind to the phospholipids and the differences in the extent of the phase transition temperature depression of the individual phospholipids may indicate differences in the binding capacities of these drugs. The following major conclusions may be drawn from the results of this investigation. Fenfluramine induces a phospholipidosis syndrome in the lungs of Wistar and BD9 rats that are histologically similar to that induced by CP. It induces the elevation of essentially the same phospholipids as CP, primarily in the alveolar spaces and macrophages, and by implication, most likely via similar mechanisms. For both FF and CP, both direct inhibition and phospholipid-drug complex-mediated inhibition of phospholipases were found to be a viable mechanism for this syndrome. The mechanism for FF-induced pulmonary phospholipidosis thus appears to be similar to that of CP; small quantitative differences in essentially similar mechanisms, may explain the differences in the levels of induced phospholipidosis found in this study.
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Einfluss von Antipsychotika auf die Zytokinproduktion in-vitroSchönherr, Jeremias 15 September 2014 (has links)
Diese Arbeit beschreibt Ergebnisse einer in-vitro Untersuchung der Antipsychotika
Chlorpromazin, Haloperidol, Clozapin, N-Desmethylclozapin und Quetiapin bezüglich ihrer
Wirkung auf die Zytokinproduktion. Dafür wurde Vollblut von gesunden Probandinnen invitro
mit dem Immunmodulator Toxic-Shock-Syndrome-Toxin-1 (TSST-1) stimuliert. Dabei
wurden die Konzentrationen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17 und
Tumornekrosefaktor-α (TNF-α) im unstimulierten Blut und im stimulierten Blut, jeweils mit
und ohne Zusatz der Antipsychotika gemessen.
Es zeigte sich, dass TSST-1 eine signifikante Stimulation der Produktion aller getesteten
Zytokine bewirkte und dass es über diese Stimulation mit TSST-1 hinaus zu einer Erhöhung
von IL-17 unter allen getesteten Antipsychotika kam.
Aufgrund dieser Ergebnisse ist es denkbar, dass Antipsychotika, in Ergänzung zu ihrer
Wirkung an Dopaminrezeptoren, auch über diese immunologische Eigenschaft Wirkungen
und Nebenwirkungen entfalten können. Weiterhin könnte die IL-17-Produktion ein
Biomarker in der Behandlung mit Antipsychotika sein, der wiederum zur individuellen
Vorhersage von Wirkungen und Nebenwirkungen beitragen könnte.
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Characterization And Modulation By Drugs And Other Effectors Of Bovine Liver Microsomal Flavin Monooxygenase (fmo)Baser, Deniz Fulya 01 January 2004 (has links) (PDF)
The flavin-containing monooxygenases (FMO / E.C.1.14.13.8) are microsomal NADPH and oxygen-dependent flavoprotein enzymes that catalyze the oxidation of a wide variety of xenobiotics, including drugs and environmental toxicants. Nucleophiles containing nitrogen, sulfur, phosphorus and selenium heteroatoms are the substrates of FMO.
Bovine liver microsomal FMO enzyme activity was characterized using methimazole as substrate, which is a highly specific substrate for FMO. From 12 different bovine liver samples, microsomes were prepared and the average specific activity of bovine liver microsomal FMO was found to be 2.37 & / #61617 / 0.30 nmol/min/mg (Mean & / #61617 / SE, n=12). The rate of reaction was linear up to 0.5 mg of bovine liver microsomal protein. The maximum FMO enzyme activity was detected at 37 & / #61616 / C and at pH 8.0. Effects of detergents / Triton X-100 and Emulgen 913, on FMO activity were determined and found that enzyme activity increased by the addition of either detergent at all concentrations (0.1%-1.0%). The apparent Vmax and Km values of bovine liver microsomal FMO for methimazole substrate were found as 1.23 nmol/min/mg and 0.11 mM, respectively.
Thermostability of bovine liver microsomal FMO was studied at four different temperatures / 24 & / #61616 / C, 37 & / #61616 / C, 50 & / #61616 / C and 65 & / #61616 / C. The incubation time required for the complete loss of enzyme activity was 5 minutes at 65 & / #61616 / C, 10 minutes at 50 & / #61616 / C and 6.5 hours at 37 & / #61616 / C. 68 % of the activity was still detectable at the end of 53 hours at 24 & / #61616 / C. Bovine liver microsomal activity towards two drug substrates, imipramine and chlorpromazine, was also determined and found to be 3.73 and 3.75 nmol NADPH oxidized/min/mg, respectively. Effects of two drug substrates, imipramine and chlorpromazine, on bovine liver microsomal FMO-catalyzed methimazole oxidation activity was also studied and found that they inhibit FMO activity at all concentrations studied.
Modulation of bovine liver microsomal FMO activity was studied using three different heavy metal ions / Ni+2, Cd+2 and Hg+2. At all other concentrations studied for each heavy metal ion and at all substrate methimazole concentrations (0.1, 0.2, 0.5, 1.0 mM), FMO-catalyzed methimazole oxidation activity decreased compared to control activity. KI values for Ni+2, Cd+2 and Hg+2 were found to be 0.5 mM, 0.085 mM, 4.6 & / #61549 / M, respectively. From the Dixon plot, the pattern of inhibition for three heavy metal ions was observed to be noncompetitive.
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Chlorpromazine Combined with Cidofovir for Treatment of a Patient Suffering from Progressive Multifocal LeukoencephalopathyPöhlmann, Christoph, Hochauf, Kristina, Röllig, Christoph, Schetelig, Johannes, Wunderlich, Olaf, Bandt, Dirk, Ehninger, Gerhard, Jacobs, Enno, Rohayem, Jacques 18 March 2014 (has links) (PDF)
We report on a stem cell-transplanted patient with B cell chronic lymphatic leukemia who presented with a subacute onset of focal neurological deficits, gait abnormalities, emotional lability and dementia. Progressive multifocal leukoencephalopathy was diagnosed by magnetic resonance imaging (MRI) of the brain and detection of JC virus genome in the cerebrospinal fluid. Cidofovir and the 5HT2A receptor antagonist chlorpromazine were subsequently administered. A follow-up MRI of the brain 2 weeks after initiation of the antiviral therapy displayed progress of the demyelination, and the patient died 3 months after onset of the neurological symptoms. This report highlights the need for the development of novel and potent strategies for treatment of progressive multifocal leukoencephalopathy. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Einfluss von Antipsychotika auf die Zytokinproduktion in-vitroSchönherr, Jeremias 07 July 2014 (has links)
Diese Arbeit beschreibt Ergebnisse einer in-vitro Untersuchung der Antipsychotika
Chlorpromazin, Haloperidol, Clozapin, N-Desmethylclozapin und Quetiapin bezüglich ihrer
Wirkung auf die Zytokinproduktion. Dafür wurde Vollblut von gesunden Probandinnen invitro
mit dem Immunmodulator Toxic-Shock-Syndrome-Toxin-1 (TSST-1) stimuliert. Dabei
wurden die Konzentrationen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17 und
Tumornekrosefaktor-α (TNF-α) im unstimulierten Blut und im stimulierten Blut, jeweils mit
und ohne Zusatz der Antipsychotika gemessen.
Es zeigte sich, dass TSST-1 eine signifikante Stimulation der Produktion aller getesteten
Zytokine bewirkte und dass es über diese Stimulation mit TSST-1 hinaus zu einer Erhöhung
von IL-17 unter allen getesteten Antipsychotika kam.
Aufgrund dieser Ergebnisse ist es denkbar, dass Antipsychotika, in Ergänzung zu ihrer
Wirkung an Dopaminrezeptoren, auch über diese immunologische Eigenschaft Wirkungen
und Nebenwirkungen entfalten können. Weiterhin könnte die IL-17-Produktion ein
Biomarker in der Behandlung mit Antipsychotika sein, der wiederum zur individuellen
Vorhersage von Wirkungen und Nebenwirkungen beitragen könnte.
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[pt] EFEITOS DE UM ANTIPSICÓTICO E UM ANTIDEPRESSIVO TRICÍCLICO SOBRE A BOMBA DE SÓDIO E POTÁSSIO, NA+,K+-ATPASE: ESTUDO ATRAVÉS DE FLUORESCÊNCIA / [en] EFFECTS OF AN ANTIPSYCHOTIC AND A TRICYCLIC ANTIDEPRESSANT ON THE SODIUM AND POTASSIUM PUMP NA+,K+ -ATPASE: A FLUORESCENCE STUDYELMER AUGUSTO CUEVA GUEVARA 02 January 2006 (has links)
[pt] A bomba de sódio e potássio Na+,K+-ATPase é uma enzima que
oscila entre
duas conformações principais E1 e E2 durante o ciclo de
transporte dos íons Na+ e
K+ através de membranas. O esteróide cardiotônico ouabaína
é um inibidor
específico que se liga à enzima na conformação E2. A sonda
fluorescente antroilouabaína
(AO) apresenta incremento de fluorescência ao associar-se
ao sítio de
ouabaína da Na+,K+-ATPase. Várias drogas tricíclicas,
incluindo o antipsicótico
clorpromazina (CPZ) e o antidepressivo nortriptilina
(NOR), inibem a atividade
da Na+,K+-ATPase em concentrações clinicamente relevantes.
No presente
trabalho estudaram-se os efeitos de NOR e de CPZ sobre a
fluorescência de AO
associada a Na+,K+-ATPase. A nortriptilina aumentou a
fluorescência de AO,
tendo sido esse efeito dependente da concentração de droga
e da conformação da
enzima. Os resultados permitiram a obter a constante de
associação NOR-
Na+,K+-ATPase e sugeriram que essa associação tende a
estabilizar a
conformação E2. Já a clorpromazina em concentrações abaixo
de 10 µM teve
efeito desprezível sobre a fluorescência de AO. Irradiação
com luz ultravioleta, no
entanto, provocou reações foto-induzidas de CPZ com Na+,K+-
ATPase que
modificaram a cinética de formação dos produtos de
fotodegradação de CPZ,
como demonstrado através da fluorescência desses produtos.
A foto-associação de
CPZ com Na+,K+-ATPase alterou também a estrutura local do
sítio de ouabaína,
provocando aumento considerável do rendimento quântico e
deslocamento do
pico de fluorescência de AO. A fototoxicidade associada à
CPZ indicou potencial
para sua utilização em fotoquimioterapia. / [en] The sodium and potassium pump Na+,K+ -ATPase is an enzyme
that
oscillates between two major conformations E1 and E2
during the ion transport
cycle across membranes. The cardiotonic steroid ouabain
specifically inhibits this
enzyme by binding to the E2 conformation. The fluorescent
label anthroylouabain
(AO) presents increased fluorescence when binding to the
ouabain site of Na+,K+ -
ATPase. Tricyclic drugs such as the antipsychotic
chlorpromazine (CPZ) and the
antidepressant nortriptyline (NOR) inhibit Na+,K+ -ATPase
activity at clinically
relevant concentrations. In the present work the effects
of NOR and CPZ on the
fluorescence properties of AO-bound Na+,K+ -ATPase of
electrocyte membranes
from E. electricus were studied. Nortriptyline was found
to increase the AO
fluorescence in a concentration and conformation-dependent
manner. The
association constant between NOR and Na+,K+ -ATPase was
obtained. The results
suggested that the binding of NOR shifts the conformation
equilibrium of the
enzyme towards E2. CPZ, on the other hand, induced
negligible fluorescence
change up to 10 µM. Ultraviolet irradiation, however,
provoked photo-induced
reactions of CPZ with Na+,K+ -ATPase, which modified the
kinetics of CPZphotodegradation,
as demonstrated by the fluorescent products. The
photolabeling
of Na+,K+ -ATPase with CPZ also modified the local
structure of the ouabain site
inducing a blue shift and a considerable increase of the
AO quantum yield. The
results suggest that CPZ binds to Na+,K+ -ATPase and
photolabels amino-acid
residues near the ouabain binding site. The CPZ-associated
phototoxicity pointed
to its potential use in photochemotherapy.
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Der Einfluss von Clozapin, N-Desmethylclozapin und Chlorpromazin auf die in-vitro-Produktion von ThromboxanSchmidt, Renate Luise 29 July 2014 (has links) (PDF)
Die Hypothese, dass das AP Clozapin, ebenso wie dessen Metabolit NDMC die Produktion von TxA2 beeinfluss könnten, stellten wir nach ausführlicher Literaturrecherche auf. Letztere zeigte, dass bereits beim ersten AP CPZ eine reduzierende Wirkung auf die TxA2-Produktion nachgewiesen werden konnte. TxA2 und die Aktivierung seines Rezeptors modulieren Vasokonstriktion und Thrombozytenaggregation. Weiterhin nehmen sie Einfluss auf dopaminerge und serotonerge Signalwege. In der Pathophysiologie der Schizophrenie spielen eben diese eine bedeutende Rolle und stellen somit Zielstrukturen für APs dar.
Um die Konzentration von TxB2, dem Metaboliten des instabilen Moleküls TxA2 in stimulierten und unstimulierten Blutproben 10 gesunder Probandinnen zu messen, verwendeten wir ein Vollblutverfahren. Um signifikante Ergebnisse zu erhalten, stimulierten wir die Proben mit TSST-1 oder dem monoklonalen Antikörper OKT3 (Muromonab-CD3), der gegen das Oberflächenantigen CD3 gerichtet ist, kombiniert mit dem monoklonalen Antikörper 5C3, der mit dem Protein CD40 interagiert und es stimuliert. Weiterhin versetzten wir das Blut mit den APs CPZ, Clozapin oder NDMC in einer von vier verschiedenen Konzentrationen. Außerdem wurden die Thromboxanspiegel im Blut ohne Zusatz von APs unter verschiedenen Stimulationskonditionen gemessen.
Durch den Zusatz von Clozapin in den verschiedenen Konzentrationen kam es zu einer signifikanten (p<0.05) Verringerung der TxB2-Produktion in den mit TSST-1 und ebenso in den mit OKT3/5C3 versetzen Proben, was wir im Rahmen unserer Studie feststellen konnten. Weiterhin konnten wir zeigen, dass CPZ in sehr niedriger Konzentration die TxB2-Spiegel im unstimulierten und im mit TSST-1 stimulierten Blut reduziert. Daraus lässt sich schlussfolgern, dass Clozapin, NDMC und CPZ auch über eine Modulation der TxA2- und TxB2-Produktion das Neurotransmittersystem beeinflussen könnten. Auch typische Nebenwirkungen der AP, wie zum Beispiel die orthostatische Hypotension, könnten aus den Veränderungen der TxA2- und TxB2-Konzentrationen resultieren.
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Voltametrické stanovení vybraných psychofarmak pomocí uhlíkových elektrod / Voltammetric Determination of Selected Psychopharmaceuticals Using Carbon ElectrodesMatouš, Petr January 2019 (has links)
Differential pulse voltammetry (DPV) was used for developing a method for the determination of phenothiazine derivatives, namely chlorpromazine (CHP) and levomepromazine (LMP), using a glassy carbon electrode (GCE) and a graphite electrode, both with a 2 mm disc diameter. Comparison of quantification limits (LQ) for both substances on both electrodes was performed. After optimizing and processing the results, the optimal conditions for measuring calibrations were as follows: Britton- Robinson (BR) buffer at pH 4.0. Calibration dependences were measured inthe concentration range from 1·10-7 to 1·10-4 mol·dm-3 . There was no need for electrochemical electrode regeneration or matrix pretreatment. The results showed higher measurement sensitivity for CHP, and the graphite electrode also showed higher sensitivity. Although there were measured lower concentrations with the graphite electrode in comparison to the GCE, because of the low repeatability of the measurements in the lower concentration range 1-10·10-7 mol·dm-3 , the LQ is comparable to the results reached on the GCE. Besides to the BR buffer, measurements in other matrices (drinking water and river water) were also made. The following LQ values were achieved: 1.0·10-6 mol·dm-3 (in BR buffer), 1.1·10-6 -1.4·10-6 mol·dm-3 (in drinking water) and...
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Der Einfluss von Clozapin, N-Desmethylclozapin und Chlorpromazin auf die in-vitro-Produktion von ThromboxanSchmidt, Renate Luise 07 July 2014 (has links)
Die Hypothese, dass das AP Clozapin, ebenso wie dessen Metabolit NDMC die Produktion von TxA2 beeinfluss könnten, stellten wir nach ausführlicher Literaturrecherche auf. Letztere zeigte, dass bereits beim ersten AP CPZ eine reduzierende Wirkung auf die TxA2-Produktion nachgewiesen werden konnte. TxA2 und die Aktivierung seines Rezeptors modulieren Vasokonstriktion und Thrombozytenaggregation. Weiterhin nehmen sie Einfluss auf dopaminerge und serotonerge Signalwege. In der Pathophysiologie der Schizophrenie spielen eben diese eine bedeutende Rolle und stellen somit Zielstrukturen für APs dar.
Um die Konzentration von TxB2, dem Metaboliten des instabilen Moleküls TxA2 in stimulierten und unstimulierten Blutproben 10 gesunder Probandinnen zu messen, verwendeten wir ein Vollblutverfahren. Um signifikante Ergebnisse zu erhalten, stimulierten wir die Proben mit TSST-1 oder dem monoklonalen Antikörper OKT3 (Muromonab-CD3), der gegen das Oberflächenantigen CD3 gerichtet ist, kombiniert mit dem monoklonalen Antikörper 5C3, der mit dem Protein CD40 interagiert und es stimuliert. Weiterhin versetzten wir das Blut mit den APs CPZ, Clozapin oder NDMC in einer von vier verschiedenen Konzentrationen. Außerdem wurden die Thromboxanspiegel im Blut ohne Zusatz von APs unter verschiedenen Stimulationskonditionen gemessen.
Durch den Zusatz von Clozapin in den verschiedenen Konzentrationen kam es zu einer signifikanten (p<0.05) Verringerung der TxB2-Produktion in den mit TSST-1 und ebenso in den mit OKT3/5C3 versetzen Proben, was wir im Rahmen unserer Studie feststellen konnten. Weiterhin konnten wir zeigen, dass CPZ in sehr niedriger Konzentration die TxB2-Spiegel im unstimulierten und im mit TSST-1 stimulierten Blut reduziert. Daraus lässt sich schlussfolgern, dass Clozapin, NDMC und CPZ auch über eine Modulation der TxA2- und TxB2-Produktion das Neurotransmittersystem beeinflussen könnten. Auch typische Nebenwirkungen der AP, wie zum Beispiel die orthostatische Hypotension, könnten aus den Veränderungen der TxA2- und TxB2-Konzentrationen resultieren.
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Chlorpromazine Combined with Cidofovir for Treatment of a Patient Suffering from Progressive Multifocal LeukoencephalopathyPöhlmann, Christoph, Hochauf, Kristina, Röllig, Christoph, Schetelig, Johannes, Wunderlich, Olaf, Bandt, Dirk, Ehninger, Gerhard, Jacobs, Enno, Rohayem, Jacques January 2008 (has links)
We report on a stem cell-transplanted patient with B cell chronic lymphatic leukemia who presented with a subacute onset of focal neurological deficits, gait abnormalities, emotional lability and dementia. Progressive multifocal leukoencephalopathy was diagnosed by magnetic resonance imaging (MRI) of the brain and detection of JC virus genome in the cerebrospinal fluid. Cidofovir and the 5HT2A receptor antagonist chlorpromazine were subsequently administered. A follow-up MRI of the brain 2 weeks after initiation of the antiviral therapy displayed progress of the demyelination, and the patient died 3 months after onset of the neurological symptoms. This report highlights the need for the development of novel and potent strategies for treatment of progressive multifocal leukoencephalopathy. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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