High-dose Injection Research Articles

New approach for quantification of left ventricular function from low-dose gated bloodpool SPECT: Validation and comparison with conventional methods in patients

BackgroundPlanar equilibrium radionuclide angiocardiography (ERNA) has been used as the gold standard for assessment of left ventricular (LV) function for over three decades. However, this imaging modality has recently gained less favor due to growing concerns about radiation exposure. We developed a novel approach that involves integrating short axis slices of gated bloodpool SPECT for quantification of LV function with improved signal-to-noise ratio and reduced radioactive dose while maintaining image quality and quantitative precision. MethodsTwenty patients referred for ERNA underwent standard in vitro 99mTc-labeling of red blood cells (RBC), and were initially imaged following a low-dose (~ 8 mCi) injection using a dedicated cardiac SPECT camera, and then had planar imaging following a high-dose (~ 25 mCi) injection. Four different quantification methods were utilized to assess the LV function and were compared for quantitative precision and inter-observer reproducibility of the quantitative assessments. ResultsThe Yale method resulted in the most consistent assessment of LV function compared with the gold standard high-dose ERNA method, along with excellent inter-observer reproducibility. ConclusionsThe new low-dose 99mTc-RBC imaging method provides precise quantification of LV function with a greater than 67% reduction in dose and may potentially improve assessment of regional function.

Curcumin-Alleviated Osteoarthritic Progression in Rats Fed a High-Fat Diet by Inhibiting Apoptosis and Activating Autophagy via Modulation of MicroRNA-34a.

PurposeThe mechanism underlying curcumin’s protective effect on osteoarthritis (OA) has not been clarified. This study aimed to determine whether curcumin exerts a chondroprotective effect by inhibiting apoptosis via upregulation of E2F1/PITX1 and activation of autophagy via the Akt/mTOR pathway by targeting microRNA-34a (miR-34a).MethodsMale Sprague–Dawley rats were fed a normal diet (ND) or high-fat diet (HFD) for 28 weeks. Five rats from each diet group were selected randomly for histological analysis of OA characteristics. Rats fed a HFD were given a single intra-stifle joint injection of the miR-34a mimic agomir-34a or negative control agomir (NC), followed by weekly low-dose (200 μg/kg body weight) or high-dose (400 μg/kg body weight) curcumin intra-joint injections from weeks 29 to 32. The rats’ stifle joints were submitted to histological analysis and to an apoptotic assay. Expression of miR-34a was detected using a real-time RT-PCR. E2F1 and PITX1 protein levels were determined by Western blot analysis, and the expressions of Beclin1, LC3B, p62, phosphorylated (p)-Akt, and p-mTOR were measured using immunofluorescence analysis.ResultsWe found that rats fed a HFD had OA-like lesions in their articular cartilage and had increased apoptosis of chondrocytes and decreased autophagy compared to rats fed a ND. Curcumin treatment alleviated OA changes, inhibited apoptosis, and upregulated autophagy. Agomir-34a treatment reduced E2F1, PITX1, Beclin1, and LC3B expression and increased p62, p-Akt, and p-mTOR expression in HFD-fed rats given low- or high-dose curcumin. Greater numbers of apoptotic cells, lesser expression of p62, p-Akt, and p-mTOR, and greater expression of E2F1, PITX1, and LC3B were observed in the agomir-34a and high-dose curcumin-treated group than in agomir-34a and low-dose curcumin-treated group.ConclusionCurcumin’s chondroprotective effect was mediated by its suppression of miR-34a, apparently by reducing apoptosis, via upregulation of E2F1/PITX1, and by augmenting autophagy, likely via the Akt/mTOR pathway.

Effects of Long-Acting Testosterone Undecanoate on Behavioral Parameters andNa + , K+-ATPase mRNA Expressionin Mice with Alzheimer`s Disease.

Previous studies have shown that testosterone attenuates stress-induced mood dysfunction and memory deterioration. However, the exact mechanism is still unknown. This study was conducted to investigate the role of long-term testosterone undecanoateonthe behavioral responsesinAD induced by AlCl3 + D-galactoseadministrationand the possible alteration of the gene expression level of the Na/K ATPase pump. Adult male mice received AlCl3 in drinking water(10mg/kg/day)and (D-gal 200mg/kg/day), subcutaneously for 90 consecutive days, then received a single intramuscular (I.M) injection of castor oil (vehicle) on day 91, while treated groups received a single I.M injection of either low (100mg/kg/45days) or high dose (500mg/kg/45days) respectively of long-acting testosterone undecanoate on day 91. The time spent in the interaction zoneduring the open field test, preference index to novel objectsin the novel object recognition test, spontaneous alternation percentage (SAP)in Y-maze test,and escape latency timein the Morris water maze testwere used to measure the locomotor activity, long-term memory, and spatial memory in mice, respectively. The results showed that testosterone undecanoate treatment improved locomotor activity, improved preference to novel objects, improved spatial memory, and reversed anxiety and depression induced by AlCl3 + D-galactose administration in male mice, suggesting the enhancement of behavioral and memory functions brought by testosterone treatment. Moreover, testosterone undecanoate treatment did alter gene expression levels of Na/K ATPase isoforms in the brain hippocampus. In most cases, altered gene expression was significant and correlated with the observed behavioral changes. Taken together, our findings provide new insight into the effects of long-acting testosterone undecanoate administration on locomotor activity, long-term memory, anxiety, and spatial memory in male mice with Alzheimer's disease.

The effect of intra-amygdalar leptin administration on anxiety, depression and learning behaviors in rats

Leptin is released by adipose tissue. Leptin can cross the blood–brain barrier and bind to receptors on neurons in brain areas to exert its biological function when released into circulation. This study aimed to determine the influences of intra-amygdalar administration of high and low doses of leptin on anxiety, depression, learning behaviors of rats. In the experimental protocol I, intra-amygdalar injection of high and low doses of leptin (0.1 and 1 μg/ kg) and saline were administered 30 min before the behavioral tests. Then, the animals were exposed to open field, elevated plus maze, Porsolt and Morris water maze tests for measuring of behaviors. In experimental protocol 2, the cerebrospinal fluids of all groups of experimental protocol 1 were collected by microdialysis method and then were analyzed by HPLC. The effect of the low dose of leptin was significant on the open field. The effect of the high and low dose of leptin was significant on the elevated plus maze test. The effect of the low dose of leptin was significant on mobility in the center of the Porsolt. A high dose of leptin group had spent less time around the platform than controls in the Morris water maze test. HPLC analysis showed that the amount of serotonin and glutamate in the amygdala region increased after low dose leptin administration. Intra-amygdalar injection of low doses of leptin may decrease anxiety and depression-like behavior in rats by increasing serotonin and glutamate levels in the amygdala.

Intra-articular drug depots for controlled release of heavy chain only antibodies blocking joint inflammation

Purpose: In many inflammation-driven diseases, blocking IL-1 signaling can be a potential strategy to help restore normal homeostasis. The modified recombinant version of IL-1RA, known by the name Anakinra, which competes with IL-1β is seen as a potential disease modifying osteoarthritis drug (DMOAD). However, as with many therapeutic proteins it shows a short half-life and loss of bioactivity. Currently, this problem is addressed by frequent injections of high doses of therapeutic proteins that is associated with unwanted side effects and patient morbidity.

Current Nanocarrier Strategies Improve Vitamin B12 Pharmacokinetics, Ameliorate Patients' Lives, and Reduce Costs.

Vitamin B12 (VitB12) is a naturally occurring compound produced by microorganisms and an essential nutrient for humans. Several papers highlight the role of VitB12 deficiency in bone and heart health, depression, memory performance, fertility, embryo development, and cancer, while VitB12 treatment is crucial for survival in inborn errors of VitB12 metabolism. VitB12 is administrated through intramuscular injection, thus impacting the patients’ lifestyle, although it is known that oral administration may meet the specific requirement even in the case of malabsorption. Furthermore, the high-dose injection of VitB12 does not ensure a constant dosage, while the oral route allows only 1.2% of the vitamin to be absorbed in human beings. Nanocarriers are promising nanotechnology that can enable therapies to be improved, reducing side effects. Today, nanocarrier strategies applied at VitB12 delivery are at the initial phase and aim to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients’ lives. The safety of nanotechnologies is still under investigation and few treatments involving nanocarriers have been approved, so far. Here, we highlight the role of VitB12 in human metabolism and diseases, and the issues linked to its molecule properties, and discuss how nanocarriers can improve the therapy and supplementation of the vitamin and reduce possible side effects and limits.

Systemic methylprednisolone for hearing preservation during cochlear implant surgery: A double blinded placebo-controlled trial

AimTo assess whether a single, peri-operative, high dose of methylprednisolone can improve the preservation of residual acoustic hearing following cochlear implantation (CI). MethodsThis was a double blinded placebo-controlled trial, performed in a tertiary academic centre. The hypothesis was that methylprednisolone would improve the preservation of hearing, and lower electrode impedances. Adult patients (18–85 years) with hearing at 85 dB or better at 500 Hz in the ear to be implanted were randomly allocated to either treatment (methylprednisolone, 1g administered intravenously upon induction of anaesthesia) or control (normal saline infusion). As per standard clinical practice, all patients received a routine dose of dexamethasone (8 mg intravenously) on induction of anaesthesia. Implantation was undertaken with a slim and flexible lateral wall electrode via the round window. Surgical technique was routine, with adherence to soft surgical principles. The primary outcome was hearing preservation within 20 dB at 500 Hz, 12 months following cochlear implantation. Secondary outcomes included hearing preservation at 6 weeks and 3 months, monopolar electrode impedance, and Consonant-Vowel-Consonant (CVC) Phoneme scores at 3 and 12 months after surgery. ResultsForty-five patients were enrolled into the control group and 48 patients received the steroid. The number of patients achieving hearing preservation at 12 months did not differ significantly between those receiving methylprednisolone treatment and the controls. There were no differences in hearing preservation at any frequency at either 6 weeks or 3 months after implantation. Neither CVC phoneme scores nor electrode impedances differed between the groups. ConclusionsThis paper demonstrates that high-dose local steroid injection at surgery was not effective in preventing a loss of residual hearing, improving speech perception, or lowering electrode impedances. The findings were contrary to the experimental literature, and emerging clinical evidence that steroid elution from implant electrodes influences cochlear biology in humans. We found no evidence to support the widely-held practice of administering intravenous steroids in the perioperative period, in an attempt to preserve residual hearing.

A clinically derived guinea pig dosing model of cisplatin ototoxicity

The guinea pig is a commonly-used animal model in hearing research, as their audible frequency range is similar to that of humans, and they possess comparatively large cochleae among rodents. Numerous studies have investigated the ototoxic effects of cisplatin in guinea pigs, but these have been mostly limited to single high-dose bolus injections of cisplatin. This method of drug administration is not consistent with human treatment schedules, and therefore lacks translational value to clinical applications. We tested several different cisplatin dosing schedules in guinea pigs based on common research based and clinical regimens, measuring the resulting hearing loss and morbidity (weight loss). We propose a dosing paradigm of once-weekly 4 mg/kg cisplatin injections for three weeks to best mimic clinical treatment schedules. This method resulted in a configuration of hearing loss similar to what is observed in humans along with minimal changes in weight.

Abnormal electrophysiological phenotypes and sleep deficits in a mouse model of Angelman Syndrome

BackgroundAngelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal-specific loss of expression of UBE3A (ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (> 80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS.MethodsWe used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported in Ube3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light–dark cycles, sleep stages and sleep spindles in Ube3a-del and WT mice.ResultsUbe3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated that Ube3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model.LimitationsThis study was limited to the exon 2 deletion mouse model, and future work will investigate the rat model of AS, containing a complete Ube3a deletion and pair EEG with behavior.ConclusionsOur data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing.

Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia.

Background:It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia.Objective:To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes).Methods:We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200–600 pmol/L). We used multivariable Cox regression to compute 0–15-year hazard ratios for dementia.Results:For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia.Conclusion:We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.

Single high-dose vitamin D3 injection and clinical outcomes in brain tumor resection: A randomized, controlled clinical trial

Vitamin D is known as a neuroprotective hormone with anti-inflammatory and immune-modulatory properties. We evaluated the effect of vitamin D3 injection on vitamin D status and clinical outcomes in patients with low serum levels of 25-hydroxyvitamin D [25(OH)D] undergoing craniotomy for brain tumor resection. Patients with benign brain tumors and serum 25(OH)D levels ≤20ng/mL were randomized to two groups with an equal number of subjects. The study group (n=30) received intramuscular injection of 300,000 IU vitamin D3 prior to surgery. The control group (n=30) was left without intervention, and both groups underwent routine therapies. On day 5 after craniotomy, the serum 25(OH)D levels increased significantly in the study group (P= <0.001). The length of ICU and hospital stay was significantly lower in the study group compared to the control group (P=0.01 and P=0.008, respectively). It was true when the age, tumor size, tumor type, Karnofsky Performance Scale (KPS) score, and calcium and albumin levels at baseline entered the logistic regression model (OR=0.17 (95%CI=0.04-0.72, P=0.01), and OR=0.19 (95%CI=0.04-0.82, P=0.02), respectively). With and without the application of logistic regression analysis, there was no significant difference in perioperative complications. Intramuscular injection of 300,000 IU of vitamin D3 in patients with low serum levels of 25(OH)D undergoing craniotomy, could rise safely the serum 25(OH)D level. This intervention, significantly reduced the length of ICU stay and hospitalization. Clinicaltrials.gov.identifier no: NCT03248544. Date: 8/14/2017.

Case Report: Refractory Hypotension of GABA B Receptor Autoimmune Encephalitis

Introduction: With the development of antibody detection technology, Gamma-Aminobutyric Acid (GABA) B receptor encephalitis is a known autoimmune disease. This paper describes a patient with refractory hypotension who suffered GABA B receptor autoimmune encephalitis.Case Report: We describe a 63-year-old man with GABA B receptor autoimmune encephalitis who had hypotension on day 17 of the disease onset. Despite two rounds of immunoglobulin administration, high-dose intravenous steroid injections and immunosuppressive therapy on day 35 of hospitalization, psychiatric symptoms and seizures were significantly improved; however, the patient's blood pressure remained low.Conclusion: This case study and literature review investigated the impairment of autonomic nerve function and its subsequent management in patients with GABA B receptor autoimmune encephalitis.

Kupffer cell release of platelet activating factor drives dose limiting toxicities of nucleic acid nanocarriers

This work establishes that Kupffer cell release of platelet activating factor (PAF), a lipidic molecule with pro-inflammatory and vasoactive signaling properties, dictates dose-limiting siRNA nanocarrier-associated toxicities. High-dose intravenous injection of siRNA-polymer nano-polyplexes (si-NPs) elicited acute, shock-like symptoms in mice, associated with increased plasma PAF and consequently reduced PAF acetylhydrolase (PAF-AH) activity. These symptoms were completely prevented by prophylactic PAF receptor inhibition or Kupffer cell depletion. Assessment of varied si-NP chemistries confirmed that toxicity level correlated to relative uptake of the carrier by liver Kupffer cells and that this toxicity mechanism is dependent on carrier endosome disruptive function. 4T1 tumor-bearing mice, which exhibit increased circulating leukocytes, displayed greater sensitivity to these toxicities. PAF-mediated toxicities were generalizable to commercial delivery reagent in vivo-jetPEI® and an MC3 lipid formulation matched to an FDA-approved nanomedicine. These collective results establish Kupffer cell release of PAF as a key mediator of siRNA nanocarrier toxicity and identify PAFR inhibition as an effective strategy to increase siRNA nanocarrier tolerated dose.

The method and effect of rapid establishment of a mild cognitive impairment model

To further the exploration of the pathogenesis of mild cognitive impairment (MCI), we aimed to determine the appropriate dose for a rapidly established MCI rat model using D-galactose (D-gal), with lasting cognitive effects. In Experiment 1, we evaluated various D-gal concentrations (100-2,000 mg/kg/day), and determined that, compared with saline injections of the same volume. In Experiment 2, we evaluated the duration of the effect of 1,000 mg/kg/day D-gal injections for 1 week, with MWM testing initiated at 1 day, 1 month, and 3 months after completion of the injection regime in three model groups, respectively. In Experiment 1, D-gal injections at a concentration of 1,000 mg/kg/day for 1 week was adequate to induce a significantly worse Morris water maze (MWM) test performance and pathomorphologic changes in the hippocampus, with MWM testing initiated 1 day after completion of the injection regime. In Experiment 2, Before modeling, the overall condition (fur, mental state, foraging behavior, and activity level), body weight, swimming speed, and swimming time did not significantly differ between the control (saline injections) and model groups (D-gal injections). After modeling, MWM test performance was considerably worse (longer escape latencies and fewer platform crossings within 90 seconds) in the model groups than in the control group, without significant differences among model groups. Furthermore, movement trajectories were similar among model groups. These results demonstrate that subcutaneous injections of D-gal 1,000 mg/kg/day for 1 week produce changes consistent with the characteristics and pathological processes of MCI. Thus, high-dose D-gal injection allows the rapid establishment of an MCI model that is effective and sustainable.

Therapeutic plasma exchange vs conventional treatment with intravenous high dose steroid for neuromyelitis optica spectrum disorders (NMOSD): a systematic review and meta-analysis.

Therapeutic plasma exchanges (TPE) has been recommended for neuromyelitis optica spectrum disorders (NMOSD) as a rescue therapy after nonresponding from the high-dose steroid and as an early therapy in severe attacks. We performed a systematic review to evaluate whether therapeutic plasma exchange (TPE) is better than conventional intravenous methylprednisolone (IVMP) in neuromyelitis optica spectrum disorders (NMOSD) patients. Systematic search was conducted in five databases: PubMed, Embase, Scopus, Web of Science, and CENTRAL for randomized controlled trials and observational studies of TPE compared to intravenous steroid in NMOSD patients with neurological or visual outcomes in English without publication date restriction. Quality assessment was performed using ROB2 and ROBINS-I. The meta-analysis was done using a random-effects model. Pooled risk ratio (RR) or mean difference with a 95% CIs of efficacy outcomes included the Expanded Disability Status Scale (EDSS), visual acuity, and LogMAR were measured. Of 3439 potential studies, seven were included in the systematic review (1211 attacks; 433 patients) and three studies were included in the meta-analysis. Compared to high dose steroid alone, the add-on TPE increases a chance for the returning of EDSS to baseline at discharge (RR 3.02, 95% CI 1.34-6.81) and last follow-up (RR 1.68, 95% CI 1.01-2.79) as well as improves visual acuity at last follow-up. TPE as an add-on therapy to high-dose steroid injection during an acute attack in NMOSD patients is associated with returning to baseline EDSS at discharge and last follow-up, and a trend to have a lower disability at 6-12months.

Efficacy and safety of high-dose Xueshuantong injection (lyophilised) in reducing the incidence of major adverse cardiovascular events in patients with unstable angina: a protocol of a randomised, parallel-arm, controlled, double-blind and multicentre clinical trial based on dual antiplatelet therapy

IntroductionUnstable angina (UA), referred to as acute coronary syndrome (ACS), causes unexpected chest pain. Xueshuantong injection (lyophilised) (XST) is a traditional Chinese herbal injection having the potential to treat ACS....

Avidin grafted dextran nanostructure enables a month-long intra-discal retention

Low back pain is often the direct result of degeneration of the intervertebral disc. A wide range of therapeutics including anti-catabolic, pro-anabolic factors and chemo-attractants that can stimulate resident cells and recruit endogenous progenitors are under consideration. The avascular nature and the dense matrix of this tissue make it challenging for systemically administered drugs to reach their target cells inside the nucleus pulposus (NP), the central gelatinous region of the intervertebral disc (IVD). Therefore, local intra-discal injection of therapeutic drugs directly into the NP is a clinically relevant delivery approach, however, suffers from rapid and wide diffusion outside the injection site resulting in short lived benefits while causing systemic toxicity. NP has a high negative fixed charge density due to the presence of negatively charged aggrecan glycosaminoglycans that provide swelling pressures, compressive stiffness and hydration to the tissue. This negative fixed charge density can also be used for enhancing intra-NP residence time of therapeutic drugs. Here we design positively charged Avidin grafted branched Dextran nanostructures that utilize long-range binding effects of electrostatic interactions to bind with the intra-NP negatively charged groups. The binding is strong enough to enable a month-long retention of cationic nanostructures within the NP following intra-discal administration, yet weak and reversible to allow movement to reach cells dispersed throughout the tissue. The branched carrier has multiple sites for drug conjugation and can reduce the need for multiple injections of high drug doses and minimize associated side-effects, paving the way for effective clinical translation of potential therapeutics for treatment of low back pain and disc degeneration.

Central serous chorioretinopathy associated with high-dose follistatin-344: a retrospective case series.

To present 11 bodybuilding athletes who developed central serous chorioretinopathy (CSCR) following high-dose subcutaneous follistatin-344, a peptide-based performance and image enhancing drug, injections to increase muscle mass. This is a retrospective case series from one institution. Demographic and clinical data of 11 patients who were admitted to our clinic with decreased visual acuity after high-dose follistatin-344 injections and optical coherence tomography (OCT) findings consistent with CSCR were analyzed. All 11 patients were male, and the mean age was 36.8 ± 8.1years. All patients had a history of injecting complete 1mg vials of follistatin-344 subcutaneously in the abdomen. There was a history of a single previous high-dose follistatin-344 injection in eight patients and multiple previous injections in three patients. At the time of diagnosis, ten patients had unilateral CSCR findings and one had bilateral CSCR findings. In all eight patients with a history of only one injection, subretinal fluid completely disappeared after an average of 2.3 ± 0.7months and symptoms regressed. Recurrent CSCR developed in three patients with a history of multiple follistatin-344 injections. Follistatin-344 injection can be considered as a risk factor for CSCR. To take medical history from CSCR patients including follistatin-344 use may be important to reveal the CSCR etiology.

Blood clearance kinetics and organ delivery of medium-chain triglyceride and fish oil-containing lipid emulsions: Comparing different animal species

Medium-chain triglycerides (TG) (MCT) and fish oil (FO) TG are incorporated as the core TG component into intravenous (IV) lipid emulsions for infusion in parenteral nutrition. Bolus injections of IV emulsions, on the other hand, have emerged as a novel therapeutic approach to treat various acute disorders. However, intravascular metabolism and organ delivery of acute IV injection of emulsions containing both MCT and FO are not fully defined, nor have they been characterized across common experimental animal models. We characterized and compared blood clearance kinetics and organ distribution of bolus injections of MCT/FO emulsions among different animal species. We also examined whether sex differences or feeding status can affect catabolic properties of MCT/FO lipid emulsions. Blood clearance rates of lipid emulsions with specific TG composition were compared in rats IV injected with [3H]cholesteryl hexadecyl ether labeled pure n-6 long-chain (LCT) and n-3 FO TG lipid emulsions, or emulsions containing MCT and FO at different ratios (wt/wt), which include 8:2 (80% MCT: 20% FO), 5:4:1 (50% MCT: 40% LCT: 10% FO) and SMOF (30% LCT: 30% MCT: 25% olive oil: 10% FO). Dose-response effects (0.016mg-1.6mgTG/g body weight) of the MCT/FO 8:2 emulsions on blood clearance properties and organ delivery were determined in both mice and rats. Blood clearance kinetics and organ uptake of MCT/FO 8:2 emulsions were compared between male and female rats and between fed and fasted rats. Changes in plasma lipid profiles after acute injections of MCT/FO 8:2 lipid emulsion at different doses (0.043, 0.133, and 0.4mgTG/g body weight) were characterized in non-human primates (Cynomolgus monkeys). MCT/FO 8:2 emulsion was cleared faster in rats when compared with other emulsions with different TG contents. Mice had faster blood clearance and higher fractional catabolic rates (FCR) when compared with the rats injected with MCT/FO 8:2 emulsions regardless of the injected doses. Mice and rats had similar plasma TG and free fatty acid (FFA) levels after low- or high-dose injections of the MCT/FO emulsion. Tissue distribution of the MCT/FO 8:2 lipid emulsion are comparable between mice and rats, where liver had the highest uptake per recovered dose among all organs (>60%). Feeding status and sex differences did not alter the blood clearance rate of the MCT/FO 8:2 emulsion in rats. In a nonhuman primate model, dose-response increases in plasma TG and FFA were observed after IV injection of MCT/FO 8:2 emulsions within the 1st 10min. A lipid emulsion containing both MCT and FO TG is cleared rapidly in blood and readily available for organ uptake in rodent and primate animal models. Characterization of the blood clearance properties of the MCT/FO 8:2 emulsion administered in various animal models may provide further insight into the safety and efficacy profiles for future therapeutic use of bolus injections of MCT/FO emulsions in humans.

A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts

BackgroundCyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents. ObjectiveTo evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT. Design, setting, and participantsRESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy. Outcome measurements and statistical analysisCoprimary endpoints were >50% decline in PSA from baseline (PSA50) responses to BAT and following AR-targeted therapy rechallenge. Outcomes in the post-abiraterone cohort are presented, as well as updated results from the post-enzalutamide cohort and an exploratory AR-V7 analysis. Results and limitationsNo statistically significant difference in PSA50 response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA50 responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005). ConclusionsBAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone. Patient summaryBAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7–positive patients.