Drug Concentrations In Brain Tissue Research Articles

Brain targeting efficacy of novel drug delivery system in the treatment of Alzheimer's disease.

Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group. Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration. The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration. This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.

Phase 1b/2a safety and tolerability study of bemcentinib (BEM) with pembrolizumab/carboplatin/pemetrexed in first line (1L) advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) without/with a STK11 mutation.

TPS9154 Background: The combination of platinum, pemetrexed, and pembrolizumab (CIT) has become the standard of care in 1L non–oncogene addicted NSCLC. Despite an initial improvement in response rate and survival, the 5-year survival of NSCLC remains approximately 20-30%, due to the emergence of primary and acquired resistance. Additionally, the presence of brain metastases occurs in ˜30-50% of NSCLC patients and confers a poor prognosis. Among the currently non-actionable mutations, STK11/LKB1 mutations (STK11m) are common (˜20%) in NSCLC. Recent evidence suggests that STK11m NSCLC patients have a minimal response to checkpoint inhibitors and to chemo-immunotherapy in the first line setting. STK11m tumors are characterized by an immune-suppressed phenotype which is highly associated with AXL signalling. BEM, a first-in-class, oral, selective AXL inhibitor, has demonstrated the ability to prevent chemoresistance, re-sensitize STK11m NSCLC tumors to pembrolizumab, and enhance efficacy of CIT in preclinical lung models. Moreover, following oral administration, BEM readily distributes in brain tumour tissue in recurrent glioblastoma patients, with a 25.9 mean ratio of drug concentration in brain tissue to plasma. Therefore, the addition of BEM to CIT has the potential to improve 1L treatment outcomes in NSCLC overall and particularly in STK11m tumors. Methods: This is an open-label, multi-center, phase 1b/2a study to assess the safety, tolerability, and preliminary anti-tumor activity of BEM + CIT as 1L treatment in patients with advanced (Stage IIIb/IIIc) or metastatic (Stage IV) non-squamous NSCLC without actionable mutations. Patients with stable brain metastases are eligible to participate. Phase 1b follows a 3+3 design and will explore CIT in combination with one of 3 BEM dose levels: Cohort 1 = 75mg; Cohort 2 = 100 mg; or Cohort 3 = 150 mg. BEM is administered orally once/day on Day 1 of each 21-day treatment cycle. After 4 cycles of CIT + BEM, maintenance with BEM + pemetrexed + pembrolizumab is administered for up to 2 years. An independent data safety monitoring board will assess the safety data at the end of the dose-limiting toxicity period (the first 21 days of treatment for each patient, i.e. cycle 1) of each cohort and will recommend the BEM dose for the phase 2a expansion. In the phase 2a, up to 40 patients harboring a STK11m (regardless of their co-mutational status), in the absence of driver mutations will be enrolled. The study will include extensive co-mutational analyses via next-generation sequencing to identify potential sub-groups of patients deriving particular benefit. The trial is open to patient enrolment in phase1b in the US; recruitment for phase 2a is planned to open in Q2 2023 in Europe and US. EudraCT 2019‐003806‐28/NA/124645. Clinical trial information: NCT05469178 .

CTNI-07. ABTC-1701: PILOT SURGICAL PK STUDY OF BGB324 (BEMCENTINIB) IN RECURRENT GLIOBLASTOMA PATIENTS – RESULTS FROM INTERIM FUTILITY ANALYSIS

Abstract BACKGROUND Glioblastoma often can relapse as mesenchymal (MES) tumors, indicating a phenotypic shift during clinical progression. Glioma spheres, when they gain MES phenotypes, develop dependence on AXL for their growth both in vitro and in vivo. The first-in-class orally bioavailable AXL kinase inhibitor bemcentinib has IC50 of 14 nM and is > 100-fold selective for AXL over other kinases. Bemcentinib is currently under evaluation as a monotherapy and in combination with other treatments across various PhII trials in several oncology indications. METHODS This is an open-label, multicenter, intratumoral pharmacokinetic study of bemcentinib in patients with recurrent glioblastoma for whom a surgical resection is medically indicated. All subjects must have had histological confirmation of glioblastoma by either biopsy or resection that is progressive or recurrent following radiation therapy ± chemotherapy. Intratumoral drug levels were analyzed by LC/MS. RESULTS A planned analysis after the first 5 patients were enrolled with glioblastoma (4 IDH WT and 1 IDH-mutant), (3m, 2f, median age 57, KPS 80). Bemcentinib concentration in contrast enhancing brain tissue ranged from 3.1 to 43.0 uM with a geometric mean concentration of 11.1 uM (% CV, 132.1). The drug concentration in contrast enhancing tumor tissue exceeded the 1.0 uM threshold in all 5 patients, satisfying the criteria of the protocol to enroll an additional 15 patients into the surgical study. Total drug levels were approximately 2-fold greater in contrast enhancing tissue as compared to tissue from a non-enhancing region of the tumor (geometric mean, 5.8 uM; % CV, 187.7). The mean ratio of the drug concentration in brain tissue to plasma was 25.9 (% CV, 92.7) for contrast enhancing tissue and 13.4 (% CV, 126.8) for non-enhancing tissue. CONCLUSIONS Bemcentinib readily distributes in brain tumor tissue following oral administration. The study continues to complete accrual for the remaining 15 patients.

Antiretroviral drug concentrations in brain tissue of adult decedents.

Determine concentrations of antiretroviral therapy (ART) drugs in the human brain. Cohort study of persons with HIV who consented to antemortem assessment and postmortem autopsy. Eleven persons with HIV who were taking ART at the time of death and had detectable concentrations of at least one ART drug in intracardiac aspirate at autopsy were evaluated. Autopsies were performed within 24 h of death and brain tissue was stored at -80 °C. Concentrations of 11 ART drugs were measured in three brain regions (globus pallidus, cortical gray matter, white matter) by HPLC tandem mass spectrometry with a lower limit of quantification of 25 ng/ml. Participants were mostly men (82%) with a mean age of 40.4 years. Drug concentrations in brain tissue were highly variable and exceeded published concentrations in cerebrospinal fluid for several drugs, including for tenofovir, efavirenz, and lopinavir. Drug concentrations correlated most strongly between cortical gray matter and globus pallidus (rho = 0.70) but less well between globus pallidus and white matter (rho = 0.43). Combining all drugs and brain regions (n = 89), higher drug concentrations in brain were associated with longer estimated duration of HIV infection (P = 0.015), lower HIV RNA in plasma (P = 0.0001), lower nadir CD4 T-cell count (P = 0.053), and worse neurocognitive performance (P = 0.017). This is the first analysis of ART drug concentrations in human brain tissue. Concentrations of several drugs in this analysis were similar to published concentrations in cerebrospinal fluid but others exceeded published concentrations. The association between higher drug concentrations in the brain and worse neurocognitive performance may indicate ART neurotoxicity.

Brain tissue: a viable postmortem toxicological specimen.

Brain tissue may be a valuable specimen in interpretation of postmortem toxicology. The protected and isolated position of the brain eliminates or at least attenuates many of the interpretive challenges with postmortem blood specimens. This study presents data for 30 drug and drug metabolites in cases submitted to the Sedgwick County Regional Forensic Science Center for autopsy examination from 2007 to 2014. Drug concentration in heart and femoral blood is compared with the drug concentration in brain tissue. There is a positive correlation of blood to brain concentrations, thus providing another tool for the toxicologist or pathologist to utilize in case interpretation.

Study of amphotericin B magnetic liposomes for brain targeting

This study aims to prepare amphotericin B magnetic liposomes (AmB-MLPs), which may improve drug concentration in brain, enhance magnetic targeting for brain and reduce drug toxicity in the presence of magnetic field. AmB-MLPs were prepared by means of film dispersion–ultrasonication, and their physical properties were characterized. In vivo, the magnetic targeting for brain by carotid artery administration was investigated. The particle size of AmB-MLPs was 240±11nm, the encapsulation efficiency was 79.32±2.03%, and the saturation magnetization was 32.54memug−1 at room temperature, which had good magnetic responsiveness. The group of AmB injection was delivered by carotid artery, nevertheless they all died after 20min. AmB-MLPs were injected by carotid artery, and the drug concentration in brain tissue was obviously increased in presence of magnetic field than that of in absence of magnetic field (P<0.05). The Prussian blue staining in brain of SD rats showed that the density of blue staining-positive particles in brain tissue of applying magnetic field group was higher than that of non magnetic field group. These results suggested that AmB-MLPs could reinforce brain targeting and reduce drug toxicity when they were injected by carotid artery under the effect of magnetic field.

Strategy to Assess the Role of (Inter)active Metabolites in Pharmacodynamic Studies In-vivo: a Model Study with Heptabarbital

The purpose of this investigation was to develop a universal experimental strategy by which the role of (inter)active metabolites in in-vivo pharmacodynamic studies can be examined. Heptabarbital was chosen as a model drug and several pharmacokinetic variables which may affect in-vivo concentration-pharmacological response relationships were examined. Adult female rats received an i.v. infusion of the drug at one of three different rates (0.225-1.50 mg min-1) until the animals lost their righting reflex (after 11 +/- 1 to 88 +/- 8 min of infusion). The serum concentration of the drug at onset of loss of righting reflex (LRR) increased slightly with increasing infusion rate. The drug concentrations in brain tissue and cerebrospinal fluid (CSF), (mean +/- s.d.: 67 +/- 5 mg kg-1 and 24 +/- 4 mg L-1, respectively, for the lowest infusion rate) were not affected by the infusion rate. The possible contribution of (inter)active metabolites to the pharmacological response of heptabarbital was determined by administration of different i.v. bolus doses (14.1-22.5 mg) resulting in widely differing sleeping-times (7 +/- 3 to 119 +/- 20 min). The concentrations of heptabarbital in serum, brain tissue and CSF at offset of LRR (mean +/- s.d.: 77 +/- 8 mg L-1, 76 +/- 7 mg kg-1 and 29 +/- 5 mg L-1, respectively, for the highest dose) were not affected by the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Aripiprazole brain concentration is altered in P-glycoprotein deficient mice

P-glycoprotein (P-gp) is a transporter that mediates the tissue disposition of numerous drugs. To evaluate the role of P-glycoprotein (P-gp) in aripiprazole tissue distribution and penetration across the blood-brain barrier, mice deficient in the P-gp gene (Abcb1a/b−/−) were dosed intraperitoneally with 2 µg/g mouse of the antipsychotic drug aripiprazole. Wildtype FVB mice were administered the same dose as transgenic animals. At one, two, and three hours after dosing, blood and tissue samples were collected and assayed for aripiprazole concentration by HPLC. Deficiency of P-gp did not result in significantly altered plasma drug concentrations but had dramatic effects on drug concentrations in brain tissue. At 1, 2, and 3 h after dosing, aripiprazole brain concentrations in the Abcb1a/b−/− mice were 4.6-, 4.1- and 3.0-fold higher, respectively ( P < 0.01), compared with the wildtype mice. Increases in drug concentration were also observed in testes and muscle in Abcb1a/b −/− mice. All other tissues including gut, lung, heart, kidney, liver, and spleen did not show significant differences between the two groups. These data provide evidence that aripiprazole is a transportable substrate of P-gp. Thus, factors influencing P-gp activity within the blood brain barrier in humans may have implications for the therapeutic effects and tolerability of aripiprazole.

P-Glycoprotein Contributes to the Blood-Brain, but Not Blood-Cerebrospinal Fluid, Barrier in a Spontaneous Canine P-Glycoprotein Knockout Model

P-glycoprotein is considered to be a major factor impeding effective drug therapy for many diseases of the central nervous system (CNS). Thus, efforts are being made to gain a better understanding of P-glycoprotein's role in drug distribution to brain parenchyma and cerebrospinal fluid (CSF). The goal of this study was to validate and introduce a novel P-glycoprotein-deficient (ABCB1-1Delta) canine model for studying P-glycoprotein-mediated effects of drug distribution to brain tissue and CSF. CSF concentrations of drug are often used to correlate efficacy of CNS drug therapy as a surrogate for determining drug concentration in brain tissue. A secondary goal of this study was to investigate the validity of using CSF concentrations of P-glycoprotein substrates to predict brain tissue concentrations. Loperamide, an opioid that is excluded from the brain by P-glycoprotein, was used to confirm a P-glycoprotein-null phenotype in the dog model. ABCB1-1Delta dogs experienced CNS depression following loperamide administration, whereas ABCB1 wild-type dogs experienced no CNS depression. In summary, we have validated a novel P-glycoprotein-deficient canine model and have used the model to investigate transport of the P-glycoprotein substrate (99m)Tc-sestamibi at the blood-brain barrier and blood-CSF barrier.

Transient and controllable opening of the blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats.

The blood-brain barrier hinders progress in the chemotherapy of brain tumors due to insufficient penetration of anticancer drugs into the brain tissue. Short-chain alkylglycerols affect the physicochemical properties of biological membranes. The enhancement of the blood-brain barrier permeability by intra-arterial administration of alkylglycerols was investigated in tumor-free and C6 astroglioma bearing rats. The antineoplastic agents cisplatin and methotrexate and the antibiotics vancomycin and gentamicin were selectively injected into the right internal carotid artery in the absence and presence of various alkylmono-, alkyldi-, and alkyltriglycerols. In normal rats the intra-arterial administration of the drugs without alkylglycerols resulted in low drug concentrations in brain tissue. In the presence of alkylglycerols (0.01-0.3 M) a reversible (within minutes) and concentration-dependent enrichment of the coinjected agents was found, preferentially in the ipsilateral hemisphere. The extent of drug accumulation in the brain was modified by changes in the chemical structure of the alkylglycerols. The effect increased with the chain length of the alkyl group, decreased with the number of glycerols, and varied from 2- to more than 230-fold compared to controls. In rats with C6 tumors 1-O-pentylglycerol increased the delivery of methotrexate 18-fold in the tumor, 28-fold in the surrounding brain, 18-fold in the contralateral brain, and 19-fold in the cerebellum compared to controls with methotrexate in the absence of pentylglycerol. In conclusion, the intra-arterial administration of alkylglycerols represents a novel and well controllable method for enhanced drug delivery to the brain and to brain tumors.

Ciprofloxacin and sparfloxacin penetration into human brain tissue and their activity as antagonists of GABAA receptor of rat vagus nerve

Patients undergoing elective surgery for removal of brain tumors, aneurysms, or other vascular malformations were administered a single oral dose of sparfloxacin (400 mg; 16 patients) or ciprofloxacin (750 mg; 5 patients) either 3 to 5 h or 22 to 26 h before surgery. Serum samples were taken from all patients at 0, 1, 3 to 5, 7 to 9, and 22 to 26 h after dosing; an additional serum sample was obtained at 48 h from patients who received sparfloxacin. A single sample of brain tissue was taken from all patients; a sample of cerebrospinal fluid (CSF) uncontaminated with blood was obtained from five patients. Serum and brain tissue samples were assayed by high-pressure liquid chromatography. Drug concentrations in brain tissue exceeded those in CSF by 1.8- to 19.4-fold. Kinetic modeling suggested that peak sparfloxacin concentrations in brain tissue may have occurred later than 3 to 5 h and that actual peak concentrations may therefore have been higher (up to 10 micrograms/g of tissue). The activities of ciprofloxacin and sparfloxacin as antagonists of the gamma-aminobutyric acid antagonist (GABAA) receptor were measured with the rat vagus nerve preparation. The 50% inhibitory concentration (IC50) of ciprofloxacin was 250 microM (95.25 micrograms/ml), but in the presence of biphenyl acetic acid (BPAA), the IC50 of ciprofloxacin was only 0.6 microM (0.23 microgram/ml). In contrast, the IC50 of sparfloxacin alone or in the presence of BPAA was > 300 microM (> 100 micrograms/ml). We conclude that the concentrations of ciprofloxacin and sparfloxacin in brain tissue may exceed serum drug concentrations and cannot be predicted from the concentrations in CSF. Sparfloxacin does not have any activity as a GABA antagonist, either alone or in the presence of BPAA, at the concentrations which are likely to be reached in human brain tissue.

Distribution of disulfiram in brain after carotid ligation in gerbils

Aiming whether intraperitoneal administration of disulfiram (tetraethyl thiuram disulfide, DS) achieves potentially therapeutic drug concentrations in brain tissue, the behaviour of blood-brain barrier (BBB) to 14C-labelled DS in cerebral ischemia with and without simultaneous adminisration of dimethylsulfoxide (DMSO) was studied in Mongolian gerbils subjected to left common carotid artery (CCA) occlusion. The results indicated that: (a) the permeability of DS through the BBB was significantly enhanced in the ischemic brain during the initial 30 min duration after DS administration; (b) administration of DMSO increased the entry of DS into the ischemic brain five-fold during the first 30 min and it was significantly higher even at the 60 min sampling period; (c) in general, the content of DS in the brain was quickly reduced with time.