| 1. |
- Yusof, Siti R, et al.
(författare)
-
Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution : the missing link in pharmacodynamic studies
- 2019
-
Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 24:5, s. 935-945
-
Tidskriftsartikel (refereegranskat)abstract
- Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.
|
|
| 2. |
- Fridén, Markus, 1978-
(författare)
-
Development of Methods for Assessing Unbound Drug Exposure in the Brain : In vivo, in vitro and in silico
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The blood-brain barrier is formed by tightly joined capillary cells with transporter proteins and acts as to regulate the brain concentration of nutrients as well as many drugs. When developing central nervous system drugs it is necessary to measure the unbound drug concentration in the brain, i.e. the unbound brain exposure. This is to ensure that the drug reaches the site of action. Furthermore, when designing new drugs it is extremely valuable to be able to predict brain exposure from a tentative drug structure. Established methods to measure total drug concentrations are of limited (if any) utility since the pharmacologically active, unbound, concentration is not obtained. The aim of the conducted research was to develop an efficient methodology to measure unbound drug in the brain and to generate a dataset for developing computational prediction models describing the relationship between drug structure and unbound brain exposure. First it was demonstrated that unbound brain exposure can be efficiently assessed using a combination of total drug concentrations in the brain and separate measurements of drug binding in the brain slices. The in vitro brain slice method was refined and made high-throughput. Improvements were also made to the in vivo measurements of total concentrations by introducing an appropriate correction for drug in residual blood. Modeling of a 43-drug dataset in the rat showed that unbound brain exposure is related to the drug hydrogen bonding potential and not to lipid solubility, which contrasts the common understanding. Further, the drug concentrations in cerebrospinal fluid approximated unbound concentrations in the brain (r2=0.80) and were also correlated with corresponding measurements in humans (r2=0.56). Therefore, rat-derived prediction models can be used when designing drugs for humans. This thesis work has provided drug industry and academia with efficient tools to obtain and to use relevant estimates of drug exposure in the brain for evaluating drugs candidates.
|
|
| 3. |
- Loryan, Irena, 1977-, et al.
(författare)
-
In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions : link to spatial receptor occupancy
- 2016
-
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:11, s. 1527-1536
-
Tidskriftsartikel (refereegranskat)abstract
- The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2A receptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.
|
|
| 4. |
- Hammarlund-Udenaes, Margareta
(författare)
-
In vivo approaches to assessing the blood-brain barrier
- 2014
-
Ingår i: The blood-brain barrier (BBB). - Heidelberg New York Dordrecht London : Springer. - 9783662437865 ; , s. 21-48
-
Bokkapitel (refereegranskat)abstract
- Methods for in vivo assessment of blood-brain barrier (BBB) transport are presented, with their advantages and disadvantages. The methods described are brain uptake index, the i.v. injection technique, in situ brain perfusion, brain efflux index, % injected dose, microdialysis, CSF sampling and positron emission tomography, and the combinatorial mapping of unbound drug partitioning across the BBB. The methods are put into a pharmacokinetic context by delineating the type of readings that they give, be it the rate of transport across the BBB or the extent of transport of total drug (unbound and bound), or of the unbound drug.
|
|
| 5. |
- Loryan, Irena, 1977-, et al.
(författare)
-
Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development
- 2017
-
Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:12, s. 4362-4373
-
Tidskriftsartikel (refereegranskat)abstract
- Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.
|
|
| 6. |
- Alenius, Malin, et al.
(författare)
-
Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
- 2008
-
Ingår i: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956 .- 1879-1379. ; 42:11, s. 884-893
-
Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.
|
|
| 7. |
|
|
| 8. |
- Lundquist, Pinelopi, et al.
(författare)
-
Validation studies on the 5-hydroxy-L-[beta-11C]-tryptophan/PET method for probing the decarboxylase step in serotonin synthesis
- 2006
-
Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 59:8, s. 521-531
-
Tidskriftsartikel (refereegranskat)abstract
- The two-tissue compartment model, including irreversible trapping in the second compartment (2TCM) is used to describe the kinetics of 5-Hydroxy-L-[beta-(11)C]-tryptophan ([(11)C]HTP), a radioligand used in positron emission tomography (PET) for probing the second enzymatic step in the biosynthesis of serotonin. In this study, we examined the capacity of the model to track pharmacological changes in this biological process. We also investigated the potential loss of [(11)C]HTP-derived radioactivity during a PET study, since loss should be negligible not to alter quantification. Six rhesus monkeys were investigated using bolus [(11)C]HTP/PET methodology before and after pharmacological intervention. The second enzymatic step in serotonin synthesis was inhibited using the aromatic L-amino acid decarboxylase inhibitor NSD1015 (10 mg/kg). The extent of [(11)C]-derived radioactivity loss from the brain was studied by inhibition of the enzyme responsible for formation of the tissue metabolite, monoamine oxidase A, using clorgyline (2 mg/kg). After NSD1015, the uptake of [(11)C]HTP-derived radioactivity was increased in all the investigated brain regions, while the parameter used to reflect decarboxylase activity, the net accumulation rate constant (K(acc)), was decreased by 37% in the striatum, compared with baseline. Pretreatment with clorgyline did not change the brain uptake of [(11)C]HTP-derived radioactivity or K(acc). This study demonstrates that the 2TCM for [(11)C]HTP/PET is able to detect changes occurring during alteration of the biological process (i.e., the conversion of HTP to serotonin). Elimination of the radiotracer metabolite [(11)C]HIAA from the brain may be considered negligible if the PET study is limited to 60 min.
|
|
| 9. |
- Alassaad, Anna, 1977-
(författare)
-
Improving the Quality and Safety of Drug Use in Hospitalized Elderly : Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization.
|
|
| 10. |
- Bengtsson, Jörgen, et al.
(författare)
-
The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep
- 2009
-
Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 157:6, s. 1085-1096
-
Tidskriftsartikel (refereegranskat)abstract
- Background and purpose The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied. Experimental approach Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg.kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated. Key results Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups. Conclusions and implications The morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.
|
|
