Biomedical subjects

Frank Larsen

Publications and source records attributed to Frank Larsen.

4 recordsLinked to original sources

PubMed2006

Mechanistic model of acute autoinhibitory feedback action after administration of SSRIs in rats: application to escitalopram-induced effects on brain serotonin levels.

This study presents the development and evaluation of a feedback turnover model that mimics drug-induced effects on brain extracellular levels of serotonin (5-HT) after acute administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram (S-citalopram) in rats. The extracellular 5-HT output in the hippocampus was continuously monitored by intracerebral microdialysis in conjunction with serial arterial blood sampling for evaluation of escitalopram pharmacokinetics. 5-HT levels were significantly increased following administration of 2.5, 5 and 10 mg/kg of escitalopram and the 5-HT levels gradually declined to its baseline value within 360 min. However, at 5 and 10 mg/kg, the response-time curves were almost identical. This might be explained by activation of serotonergic autoreceptors exerting negative feedback, leading to a reduced release of new 5-HT into the synapse. The dynamics of escitalopram-evoked changes of 5-HT response was characterized by a turnover model, which included an inhibitory feedback moderator component. Thus, the response acted linearly on the production of the moderator, which acted inversely on the production of response. The plasma kinetics served as input to an inhibitory function acting on the loss of response. Simultaneous fitting of the model after three constant rate infusions demonstrated the flexibility of the system. The efficacy (I(max)) and potency (IC(50)) of inhibition of reuptake were 0.9+/-0.03 and 4.4+/-1.4 ng/ml, respectively, corresponding to an EC(50) of escitalopram about 30 ng/ml. In conclusion, the model lends itself to 'what-if' predictions at different drug exposure scenarios, and has potential for extrapolation of the pharmacodynamics of SSRIs in man.

Animals↗

PubMed2006

The pharmacokinetics of escitalopram in patients with hepatic impairment.

The effect of hepatic impairment on the pharmacokinetics of escitalopram was determined by means of nonlinear mixed effect modeling, considering both the Child-Pugh classification (and its components) and cytochrome P450 2C19 (CYP2C19) activity. Twenty-four subjects were grouped according to their Child-Pugh score as healthy, with mild hepatic impairment or with moderate hepatic impairment. The subjects were administered a single oral dose of escitalopram 20 mg, and blood was sampled up to 168 hours after dosage. The serum concentration of escitalopram was determined and the pharmacokinetics assessed by nonlinear mixed effect modeling. The CYP2C19 activity was measured from the urinary excretion ratio of S/R-mephenytoin. All subjects tolerated the treatment well, and no serious adverse events were reported. Predicted mean area under the curve from zero to infinity (AUC(inf)) values were 51% and 69% higher for patients with mild and moderate hepatic impairment (Child-Pugh classification), respectively, compared with healthy subjects. The best-fitting model showed an influence of CYP2C19 activity on clearance and body weight on the volume of distribution for escitalopram. CYP2C19 activity is a better predictor of escitalopram clearance than is Child-Pugh classification.

Adult↗

PubMed2002

A human CpG island randomly inserted into a plant genome is protected from methylation.

In vertebrate genomes the dinucleotide CpG is heavily methylated, except in CpG islands, which are normally unmethylated. It is not clear why the CpG islands are such poor substrates for DNA methyltransferase. Plant genomes display methylation, but otherwise the genomes of plants and animals represent two very divergent evolutionary lines. To gain a further understanding of the resistance of CpG islands to methylation, we introduced a human CpG island from the proteasome-like subunit I gene into the genome of the plant Arabidopsis thaliana. Our results show that prevention of methylation is an intrinsic property of CpG islands, recognized even if a human CpG island is transferred to a plant genome. Two different parts of the human CpG island - the promoter region/ first exon and exon 2-4 - both displayed resistance against methylation, but the promoter/ exon1 construct seemed to be most resistant. In contrast, certain sites in a plant CpG-rich region used as a control transgene were always methylated. The frequency of silencing of the adjacent nptII (KmR) gene in the human CpG constructs was lower than observed for the plant CpG-rich region. These results have implications for understanding DNA methylation, and for construction of vectors that will reduce transgene silencing.

Arabidopsis↗

PubMed2000

Citalopram.

Citalopram is a selective serotonin (5-HT) reuptake inhibitor (SSRI) developed by H. Lundbeck A/S in Denmark. It is the most selective serotonin antidepressant with proven efficacy, a favourable pharmacokinetic profile and a low potential for interactions with other concomitant medication. The drug has a low incidence of side effects, even when compared to the other SSRIs and good patient compliance and satisfaction is a feature of this drug. These factors make the drug a good choice for depressed patients who require continuation and long-term treatment, as well as for elderly patients. Copyright 2000 John Wiley & Sons, Ltd.

Journal Article↗