Evaluation of safety and efficacy of rapamycin-eluting balloon in patients with intracranial atherosclerotic stenosis: a cohort study.

OBJECTIVE: The safety and efficacy of drug-eluting balloon on the treatment of intracranial atherosclerotic stenosis (ICAS) remain unclear. Here, we present our observation in a cohort study on the safety and efficacy of rapamycin-eluting balloon for patients with ICAS. METHODS: A total of 80 ICAS patients with stenosis degree of 70-99% were included. All patients were treated with rapamycin-eluting balloon and were followed up for 12 months after operation. RESULTS: All patients were successfully treated, where the mean stenosis severity reduced from 85.1 ± 7.6 to 6 ± 4.9%. 8 patients experienced immediate post-operational complications. Two patients passed away during the first month of the follow-up period. Recurrent ischemic syndrome and angiographic restenosis only appeared 7 days after operation. During later follow-up period, none of the patients had clinical angiographic restenosis or needed target vessel revascularization. CONCLUSION: Our data suggest that intracranial stenting with rapamycin-eluting balloon seems to be safe and effective, although more clinical data are needed to support this notion.

Effectiveness of Guiding Catheter Retrieval Balloon Technique in the Treatment of Acute Anterior Circulation Tandem Occlusion: A Retrospective Study.

BACKGROUND: Tandem occlusion accounts for 10%-20% of all large vessel occlusion strokes and often yields a poor recanalization rate. The endovascular treatment of tandem lesions is still controversial. This study uses an endovascular treatment strategy, "guided catheter recovery balloon (GRB)" for the treatment of acute anterior circulation tandem occlusion. METHODS: A retrospective design was adopted. The population included patients with acute tandem occlusion who received emergency GRB endovascular treatment. And the choice of stenting was made based on intraoperative radiography imaging. Recanalization was evaluated by the thrombolysis in cerebral infarction score after the operation. Three-month modified Rankin Scale follow-up results were recorded, and modified Rankin Scale ≤2 was considered favorable recovery. RESULTS: A total of 55 patients aged 66.9 ± 8.5 years were enrolled, 37 of whom received stenting. The mean overall recanalization time was 46 minutes. Fifty (90.9%) patients achieved successful recanalization with a thrombolysis in cerebral infarction score of 2b-3. At the 3-month follow-up, the number of patients with favorable functional recovery was 28 (50.9%). The presence of hypertension was correlated with a favorable recovery outcome: 82.1% of the favorable recovery population had hypertension, and 55.6% of the unfavorable outcome population had hypertension (P = 0.033). There was no statistically significant association between stent application and favorable recovery outcomes (P = 0.504). CONCLUSIONS: GRB technique showed a high recanalization rate when applied to the treatment of acute anterior circulation tandem occlusion.

Posterior cerebral artery embolism resulting in bilateral paramedian thalamic infarction: A case report.

RATIONALE: Bilateral thalamic infarcts are not easily recognized, it have diverse clinical manifestations and relatively severe symptoms. It may leave long-term drowsiness, cognitive impairment, and speech impairment. We report a case of bilateral paramedian thalamic infarction with impaired consciousness as the main symptom. The digital subtraction angiography suggested that the left superior cerebellar artery and posterior cerebral artery (PCA) were occluded. PATIENTS CONCERN: A previously 67-year-old man was taken to our hospital after 9.5 hours of acute dizziness and loss of consciousness. DIAGNOSIS: The cranial DWI + MRA suggested acute cerebral infarction in bilateral thalamus and bilateral midbrain, and the left posterior cerebral artery was not clearly visualized. The patient was diagnosed with posterior cerebral artery embolism. INTERVENTIONS: A mechanical thrombectomy was performed. OUTCOME: The patient's symptoms did not completely improve after revascularization, followed by fluctuating consciousness. LESSONS: Recurrent lethargy in patients after endovascular treatment may be a clinical manifestation of damage to thalamic structures or due to the presence of ineffective recanalization.

Brain activity alterations in patients with Parkinson's disease with cognitive impairment based on resting-state functional MRI.

OBJECTIVE: This study aimed to investigate the differences in regional homogeneity (ReHo) values in patients with Parkinson's disease (PD) with cognitive impairment (PD-CI) and thus explore the neuropathological mechanism of PD-CI. METHODS: Resting-state functional magnetic resonance imaging scans were obtained from 36 patients with PD and 20 healthy controls (HCs) in this study. The PD group comprised 20 patients with PD-CI and 16 patients with PD with normal cognitive function (PD-NC). The data were analyzed using ReHo analysis to observe the changes in brain activity in patients with PD-CI and PD-NC. Statistical comparison was performed using covariance analysis and post hoc t tests. RESULTS: The patients in the PD-CI group were older than those in the PD-NC and HC groups. Compared with the HC group, the PD-CI group showed that the ReHo value decreased in the right supplementary motor area, left lingual gyrus, left thalamus, and left precuneus, but increased in the left fusiform gyrus. Compared with the HC group, the PD-NC group showed that the ReHo value decreased in the right cerebellum_6, but increased in the left inferior temporal gyrus, left orbital inferior frontal gyrus, and left precentral gyrus. Compared with the PD-NC group, the PD-CI group showed that the ReHo value decreased in the right precuneus, left triangular inferior frontal gyrus, left middle frontal gyrus, right opercular inferior frontal gyrus, left orbital inferior frontal gyrus, left supramarginal gyrus, left angular gyrus, left inferior temporal gyrus, and right cerebelum_7b, but increased in the left precentral gyrus and left fusiform gyrus. CONCLUSIONS: Age was a risk factor for cognitive decline in patients with PD. The ReHo value in the default mode network (DMN) was closely related to PD cognitive function, and the DMN was affected before CI and continuously deteriorated with disease progression. The disorder of visual conduction pathway was involved in CI in patients with PD, but these patients could recruit cognitive resources by improving visual-spatial ability. The cognitive function in such patients was related to the dopaminergic, cholinergic, and noradrenergic systems. The information transmission efficiency of the cerebellum-thalamus-cortex loop was reduced and involved in the cognitive decline process in patients with PD.

Expression of Bcl-2 and Bad in hippocampus of status epileptic rats and molecular mechanism of intervened recombinant human erythropoietin.

Injury of hippocampal neurons in status epilepticus (SE) SD rats kindled by pentylenetetrazol (PTZ) were studied, and the changes of apoptosis neurons, protein expression of Bad and Bcl-2 alone and combined application of phosphatidyl inositol 3-kinase (PI3K) inhibitor LY294002 and recombinant human erythropoietin (rHuEpo) were evaluated for the possible mechanisms of rHuEpo. The SE rats kindled by the PTZ were randomly divided into normal control group [normal saline (NS)], model group (PTZ + NS), rHuEpo treated group (PTZ + rHuEpo), LY294002 treated group (PTZ + LY294002 + rHuEpo) and LY294002 control group (rHuEpo + PTZ + DMSO). Apoptosis of hippocampal neurons was detected by TUNEL method; expression of phosphorylation protein kinase B (p-PKB/p-Akt), Bcl-2 and Bad were detected by immunohistochemistry; the expression of Bcl-2 mRNA, Bad mRNA in hippocampal neurons of rats were detected through reverse transcription polymerase chain reaction (RT-PCR); the expression of Akt, p-Akt and Bcl-2, Bad protein in hippocampal neurons of rats were detected by western blotting. The amount of apoptotic neurons was less in the rHuEpo treated group and the LY294002 control group than in the LY294002 treated group (P<0.05). The expression of p-Akt protein and Bcl-2 protein increased while the Bad protein decreased significantly in the rHuEpo treated group and the LY294002 control group compared with the LY294002 treated group (P<0.05). The expression of Bad protein and Bad mRNA in hippocampus increased while the p-Akt, Bcl-2, Bcl-2 mRNA decreased significantly in the LY294002 treated group compared with the rHuEpo treated group (P<0.05). The PI3K/Akt signaling pathway is one of the pathways of rHuEpo neuroprotective effects and was confirmed from both the of positive and negative aspects. rHuEpo regulates the expression of mitochondrial apoptotic pathway related factors Bad and Bcl-2 to inhibit apoptosis and promotes neuronal survival.

The impact of sialic acids on the pharmacokinetics of a PEGylated erythropoietin.

Erythropoietin (EPO) is an important molecule in the erythropoiesis and various forms of EPO have been marketed in managing anemia in humans. Long acting EPOs for less frequent dosing have been generated either by increasing the number of glycosylation sites of the EPO molecule or by linking it to a polyethylene glycol (PEG). We have generated recombinant human EPO (rhEPO) using glycoengineered Pichia pastoris strains and evaluated the pharmacokinetics (PK) in rats of this molecule linked to a 40 kDa PEG (PEGylated rhEPO), in relation to its glycosylation patterns. As expected, the PEGylated rhEPO exhibited a significant improvement in half-life of serum when compared with the non-PEGylated version. Interestingly, the PK properties of the PEGylated rhEPO molecule were also significantly influenced by the glycosylation profile. Specifically, PEGylated rhEPO with a significantly higher sialic acid content in the biantennary structure (high A2) exhibited lower systemic clearance and higher systemic exposure than those with a lower sialic acid content (low A2) following either intravenous or subcutaneous administrations. These results suggest that A2 content may be one of the important criteria for release in manufacturing PEGylated rhEPO to ensure consistent PK.

Lymphatic transport and catabolism of therapeutic proteins after subcutaneous administration to rats and dogs.

The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ∼70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2- to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.

Evaluation of two ELISA methods to detect therapeutic anti-IGF1R antibodies in clinical study samples of dalotuzumab.

BACKGROUND: Dalotuzumab (MK 0646), an anti-IGF1R antibody intended for cancer therapy, has progressed to Phase III clinical trials. To evaluate pharmacokinetic properties, we developed and compared two ELISAs to measure dalotuzumab in human serum and validated the second method following regulatory guidelines for ligand-binding assays. RESULTS: After an IGF1R-mediated capture step, dalotuzumab was detected by either an antihuman IgGFc- or by an antihuman IgG1-specific antibody. The assay range was 20 to 2000 ng/ml with mean inter-day accuracy of controls ranging from 97 to 108% (method A) and 83 to 97% (method B), respectively. Mean assay precision was ≤20% CV both intra- and inter-day. Other parameters that were validated included dilution linearity, stability, interferences and incurred sample reanalysis. In addition, application of both assay formats to clinical sample analysis was demonstrated establishing time-concentration curves. CONCLUSION: As the methods rely on commercial reagents, they may be applicable to other anti-IGF1R antibodies and facilitate the development of new therapeutics.

Pharmacokinetic immunoassay methods in the presence of soluble target.

Soluble targets represent a special challenge when employing ligand binding assays to support pharmacokinetic analysis of monoclonal therapeutics. Target-engaged antibody is not available for binding in immunoassays employing anti-idiotype-specific antibodies or target for capture. We investigated several formats of total antibody assays that show reduced interference of soluble targets: direct target capture, indirect target capture and acid dissociation. While indirect target capture worked well for a regular affinity antibody against DKK1, a high affinity antibody against PCSK9 required an additional acid dissociation step. The choice of a suitable format was antibody and target dependent. Our results offer several choices to approach immunoassay development for soluble targets.