Intranasal administration is a method of delivering therapeutic agents to the central nervous system (CNS). It is non-invasive and allows large molecules that do not cross the blood-brain barrier ...access to the CNS. Drugs are directly targeted to the CNS with intranasal delivery, reducing systemic exposure and thus unwanted systemic side effects. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways via an extracellular route and does not require drug to bind to any receptor or axonal transport. Intranasal delivery is a widely publicized method and is currently being used in human clinical trials. Intranasal delivery of drugs in animal models allows for initial evaluation of pharmacokinetic distribution and efficacy. With mice, it is possible to administer drugs to awake (non-anesthetized) animals on a regular basis using a specialized intranasal grip. Awake delivery is beneficial because it allows for long-term chronic dosing without anesthesia, it takes less time than with anesthesia, and can be learned and done by many people so that teams of technicians can dose large numbers of mice in short periods. Efficacy of therapeutics administered intranasally in this way to mice has been demonstrated in a number of studies including insulin in diabetic mouse models and deferoxamine in Alzheimer's mouse models. The intranasal grip for mice can be learned, but is not easy and requires practice, skill, and a precise grip to effectively deliver drug to the brain and avoid drainage to the lung and stomach. Mice are restrained by hand using a modified scruff in the non-dominant hand with the neck held parallel to the floor, while drug is delivered with a pipettor using the dominant hand. It usually takes 3-4 weeks of acclimating to handling before mice can be held with this grip without a stress response. We have prepared this JoVE video to make this intranasal delivery technique more accessible.
Introduction
Intranasal deferoxamine (IN DFO) has been shown to decrease memory loss and have beneficial impacts across several models of neurologic disease and injury, including rodent models of ...Alzheimer's and Parkinson's disease.
Methods
In order to assess the mechanism of DFO, determine its ability to improve memory from baseline in the absence of a diseased state, and assess targeting ability of intranasal delivery, we treated healthy mice with IN DFO (2.4 mg) or intraperitoneal (IP) DFO and compared behavioral and biochemical changes with saline‐treated controls. Mice were treated 5 days/week for 4 weeks and subjected to behavioral tests 30 min after dosing.
Results
We found that IN DFO, but not IP DFO, significantly enhanced working memory in the radial arm water maze, suggesting that IN administration is more efficacious as a targeted delivery route to the brain. Moreover, the ability of DFO to improve memory from baseline in healthy mice suggests a non‐disease‐specific mechanism of memory improvement. IN DFO treatment was accompanied by decreased GSK‐3β activity and increased HIF‐1α activity.
Conclusions
These pathways are suspected in DFO's ability to improve memory and perhaps represent a component of the common mechanism through which DFO enacts beneficial change in models of neurologic disease and injury.
Intranasal deferoxamine (IN DFO) decreases memory loss and has beneficial impacts across several models of neurologic disease and injury. We show that IN DFO improves memory from baseline in normal healthy mice while modifying GSK‐3β and HIF‐1α, suggesting these pathways may be involved in a common mechanism through which DFO enacts beneficial change.
ABSTRACTLongitudinal myelitis secondary to an acute flare of systemic lupus erythematosus has been reported in the literature. There have been few published cases of complete functional recovery in ...patients with systemic lupus erythematosus–related longitudinal myelitis (systemic lupus erythematosus–related longitudinal myelitis). Of those cases, none have described in detail the rehabilitation course of treatment. In the current case, intensive rehabilitation was coupled with aggressive pharmaceutical treatment resulting in almost full functional recovery. A 23-yr-old African American woman with a history of systemic lupus erythematosus was originally admitted as an inpatient for flank pain. Overnight, she progressed rapidly to complete flaccid paraplegia classified as T3 American Spinal Injury Association Impairment Scale A based on the International Standards for Neurological Classification of Spinal Cord Injury. Throughout the next year, she participated in acute inpatient rehabilitation, followed by outpatient rehabilitation (physical, occupational, and aquatic therapies). A year after her initial hospital admission, she progressed to full community ambulation T3 American Spinal Injury Association Impairment Scale D. This case illustrates the importance of proper medical treatment and a comprehensive rehabilitation program, which improved functional outcomes for a patient with a complete spinal cord injury due to systemic lupus erythematosus–related longitudinal myelitis.
Feasibility Trial of a 10-Week Adaptive Hall, Sara F; Wiering, Bethany A; Erickson, Lauren O ...
Pain management nursing,
08/2019, Letnik:
20, Številka:
4
Journal Article
Recenzirano
This study assessed the feasibility of implementing a yoga intervention adapted for participants diagnosed with chronic pain in a large Midwest neuroscience pain clinic. Although conducted using a ...small convenience sample, this was a novel program in that it was led by an advanced practice nurse certified in pain management and to teach yoga. She was therefore uniquely qualified to tailor the yoga practice to suit individual needs of study participants.
The intervention consisted of a weekly 1-hour class for 10 weeks. Feasibility measures included patient recruitment, program adherence, patient satisfaction, global impression of change, and likelihood of continuing yoga practice. In addition, it was hypothesized that the program would positively affect participants' pain interference, physical function, pain intensity, pain behavior, mood, sleep, and pain medication usage.
Survey measurements were conducted 10 weeks before class start, immediately before the first class, and immediately after the last class.
Although there is a strong body of research supporting the benefits of yoga for chronic pain conditions, our experience highlights some of the challenges of implementing an adaptive yoga program. Our study found that recruitment of patient through physician referral was highly feasible; however, retention rates for participants were very low. Program adherence is a barrier for research on yoga in chronic pain, as well as for clinical practice. A slight reduction in pain interference and physical function over time and trend toward improvement in all exploratory outcomes was identified. None of these trends were statistically significant, likely because of small sample size.
Deferoxamine, a metal chelator, has been shown to be neuroprotective in animal models of ischemic stroke, traumatic brain injury and both subarachnoid and intracerebral hemorrhage. Intranasal ...deferoxamine (IN DFO) has also shown promise as a potential treatment for multiple neurodegenerative diseases, including Parkinson’s and Alzheimer’s. However, there have been no attempts to thoroughly understand the dynamics and pharmacokinetics of IN DFO. We developed a new high-performance liquid-chromatography electrospray-tandem mass spectrometry (HPLC/ESI-MS2) method to quantify the combined total levels of DFO, ferrioxamine (FO; DFO bound to iron), and aluminoxamine (AO; aluminum-bound DFO) in brain tissue using a custom-synthesized deuterated analogue (DFO-d 7, Medical Isotopes Inc., Pelham NH) as an internal standard. We applied our method toward understanding the pharmacokinetics of IN DFO delivery to the brain and blood of rats from 15 min to 4 h after delivery. We found that IN delivery successfully targets DFO to the brain to achieve concentrations of 0.5–15 μM in various brain regions within 15 min, and decreasing though still detectable after 4 h. Systemic exposure was minimized as assessed by concentration in blood serum. Serum concentrations were 0.02 μM at 15 min and no more than 0.1 μM at later time points. Compared to blood serum, brain region-specific drug exposure (as measured by area under the curve) ranged from slightly under 10 times exposure in the hippocampus to almost 200 times exposure in the olfactory bulb with IN DFO delivery. These findings represent a major step toward future method development, pharmacokinetic studies, and clinical trials for this promising therapeutic.
Retraction of distal sensory axons is a prominent feature in diabetic peripheral neuropathy (DPN), a process amenable to insulin therapy. Nevertheless, diabetic patients and long-term diabetic mice ...develop motor deficits after longer durations of DPN, a process that may be related to insulin deficiency. To compare the efficacy of intranasal delivery of insulin (IN-I) and subcutaneous insulin (Subc-I) in preventing motor deficits in a long-term mouse model of DPN, IN-I or Subc-I, 0.87 IU daily or placebo was delivered in separate cohorts of diabetic and nondiabetic CD1 mice for 8 months. Radiolabeled detection was used to assess insulin delivery and biodistribution. Biweekly behavioral tests and monthly electrophysiological and multipoint quantitative studies assessed motor function deficits. Morphometric analysis of spinal cord, peripheral nerve, muscle innervation, and specific molecular markers were evaluated at and before the end point. Despite progressive distal axonal terminal loss, numbers and caliber ofmotor neurons were preserved. There were no differences in glycemia between IN-I and Subc-I-treated mice. Intranasal delivery of insulin and, to a lesser extent, Subc-I, protected against electrophysiological decline, loss of neuromuscular junctions, and loss of motor behavioral skills. Intranasal delivery of insulin was associated with greater preservation of the phosphatidylinositol 3-kinase signaling pathway involving Akt, cyclic AMP response element binding protein,and glycogen synthase kinase 3β but did not alter extracellular signal-regulated kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase, or c-Jun amino-terminal kinase. Thus, direct delivery of insulin to the nervous system might prevent motor deficit in human type 1 diabetes by preservation of the phosphatidylinositol 3-kinase-Akt pathway rather than only affecting glycemic levels; the effects of insulin on other signaling pathways may, however, play additional roles.
Here we provide the first evidence that therapeutic levels of a lysosomal enzyme can bypass the blood–brain barrier following intranasal administration. α-l-iduronidase (IDUA) activity was detected ...throughout the brains of IDUA-deficient mice following a single intranasal treatment with concentrated Aldurazyme® (laronidase) and was also detected after intranasal treatment with an adeno-associated virus (AAV) vector expressing human IDUA. These results suggest that intranasal routes of delivery may be efficacious in the treatment of lysosomal storage disorders.
►A novel non-invasive route of delivery for lysosomal enzyme to the CNS. ►Delivery of IDUA to the brain by intranasal administration of laronidase. ►Delivery of IDUA to the brain by intranasal administration of an AAV vector.
Radiation-induced sarcomas in the brain are extremely rare, usually occur with an average latency of 9 years, and are associated with poor outcomes. Latency periods shorter than 1 year may indicate a ...genetic predisposition such as Li-Fraumeni syndrome. A 34-year-old man underwent initial tumor resection and radiation therapy for a World Health Organization (WHO) Grade II Astrocytoma. Within 6 months, the tumor recurred as WHO Grade III and was treated with temozolomide and then bevacizumab. Despite the patient’s apparent improving condition, MRI revealed new dural-based lesions 10 months after radiation therapy and identified as high-grade sarcoma. The patient resumed bevacizumab, began NovoTTF treatment for progressing glioma, and ifosfamide/doxorubicin for the sarcoma. Genetic testing revealed no pathogenic mutation in the TP53 gene. Ultimately, treatment was unsuccessful and the patient succumbed to glioma and sarcoma within 2 years of initial diagnosis. This case was unique due to the rapidly progressing glioma and sudden appearance of a high-grade sarcoma. It is unusual to have two separate intracranial primary cancers with each requiring a different chemotherapy regimen. We discuss the difficulty of simultaneously treating with separate chemotherapy regimens. It remains unclear whether the sarcoma was induced by the radiation treatment or a genetic predisposition.
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