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New novel drug delivery method has potential to treat Alzheimer’s

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Japanese scientists have developed a novel drug delivery framework which could one day be used in the treatment of neurodegenerative diseases such as Alzheimer’s. 

Researchers at the Tokyo University of Science in Japan, have developed a novel concept of a nose-to-brain system for the clinical application of neuropeptides.

They developed a derivative of glucagon-like peptide-2 and found that when administered intranasally (through the nose), it is efficiently delivered through the trigeminal nerve to the site of action and exhibits antidepressant-like effects. 

This is the first demonstration in the world that intranasally administered neuropeptides reach the brain (hippocampus and hypothalamus) via neurons.

Those behind it say this framework could be applied to drug design for neurodegenerative diseases with high, unmet medical demand like Alzheimer’s disease.

What is intranasal administration?

Intranasal administration has been garnering increasing popularity as a non-invasive approach to deliver drugs directly to the brain. This approach involves the respiratory or olfactory epithelia of the nasal mucosa through which the drugs reach the central nervous system (CNS). 

Transport from the respiratory epithelium via the trigeminal nerve is considerably slower than transport from the olfactory epithelium route via the olfactory bulb (OB) or cerebrospinal fluid (CSF). 

However, only a small portion of the nasal mucosa in humans is made up of olfactory epithelium, propelling researchers to focus on improving intranasal drug delivery time through the predominant respiratory epithelium.

To facilitate this, a team of researchers including Professor Chikamasa Yamashita, developed a novel drug to test its uptake efficacy by the CNS.

“In a previous study, we combined functional sequences (namely, a membrane permeability-promoting sequence [CPP] and an endosomal escape-promoting sequence [PAS]) to glucagon-like peptide-2 (GLP-2), which is effective against treatment-resistant depression, so that it can be efficiently taken up by neurons,” explains Professor Yamashita.

“Using this, we aimed to construct a nose-to-brain system mediated by the trigeminal nerve in the respiratory epithelium.”

What the research shows

While studying the uptake, the team noted that its anti-depressant effects via intranasal (in) administration remained on par with intracerebroventricular (icv) administration at identical doses. 

When they performed intracerebroventricular and intranasal administration of PAS-CPP-GLP-2 into mice, the amount of drug transferred to the whole brain was quantified by enzyme-linked immunosorbent assay (ELISA).

The ELISA revealed that a much smaller amount of intranasally administered PAS-CPP-GLP-2 reached the brain than icv administered PAS-CPP-GLP-2. However, both icv and in. administration showed efficacy at the same dose.

Professor Yamashita explains: “This suggests that the peptide delivered to the site of action by icv. administration is present in large amounts in the brain but only in very small amounts, as it remains in the perivascular space. On the other hand, intranasally administered PAS-CPP-GLP-2, unlike icv. administration, may be transferred to the site of action without passing through the CSF or perivascular space.”

It was then discovered that the migration of PAS-CPP-GLP-2 via nerve transit was the reason behind its pharmacological activity despite its low levels in the brain in administration.

Potential for future treatments

“This is the world’s first drug delivery system that allows intranasally administered peptides to be delivered to the central nervous system via nerve cells, delivering peptides to the site of action with the same efficiency as icv administration,” adds Professor Yamashita.

“Current data suggests the possibility of extending the use of this system from treating depression to delivering drugs in patients with Alzheimer’s disease. It is therefore expected to be applied to neurodegenerative diseases with high, unmet medical demand.”

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Air pollution linked to increased hospital admission for heart and lung diseases

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Exposure to fine particulate matter (PM2.5) air pollution is linked to an increased risk of hospital admission for major heart and lung diseases, find two large US studies, published by The BMJ.

Together, the results suggest that no safe threshold exists for heart and lung health.

According to the Global Burden of Disease study, exposure to PM2.5 accounts for an estimated 7.6% of total global mortality and 4.2% of global disability adjusted life years (a measure of years lived in good health).

In light of this extensive evidence, the World Health Organization (WHO) updated the air quality guidelines in 2021, recommending that an annual average PM2.5 levels should not exceed 5 μg/m3 and 24 hour average PM2.5 levels should not exceed 15 μg/m3 on more than 3-4 days each year.

In the first study, researchers linked average daily PM2.5 levels to residential zip codes for nearly 60 million US adults (84 per cent white, 55 per cent women) aged 65 and over from 2000 to 2016. They then used Medicare insurance data to track hospital admissions over an average of eight years.

After accounting for a range of economic, health and social factors, average PM2.5 exposure over three years was associated with increased risks of first hospital admissions for seven major types of cardiovascular disease – ischemic heart disease, cerebrovascular disease, heart failure, cardiomyopathy, arrhythmia, valvular heart disease, and thoracic and abdominal aortic aneurysms.

Compared with exposures of 5 μg/m3 or less (the WHO air quality guideline for annual PM2.5), exposures between 9 and 10 μg/m3, which encompassed the US national average of 9.7 μg/m3 during the study period, were associated with a 29% increased risk of hospital admission for cardiovascular disease.

On an absolute scale, the risk of hospital admission for cardiovascular disease increased from 2.59% with exposures of 5 μg/m3 or less to 3.35% at exposures between 9 and 10 μg/m3.

“This means that if we were able to manage to reduce annual PM2.5 below 5 µg/m3, we could avoid 23% in hospital admissions for cardiovascular disease,” say the researchers.*

These cardiovascular effects persisted for at least three years after exposure to PM2.5, and susceptibility varied by age, education, access to healthcare services, and area deprivation level.

The researchers say their findings suggest that no safe threshold exists for the chronic effect of PM2.5 on overall cardiovascular health, and that substantial benefits could be attained through adherence to the WHO air quality guideline.

“On February 7, 2024, the US Environmental Protection Agency (EPA) updated the national air quality standard for annual PM2.5 level, setting a stricter limit at no more than 9 µg/m3. This is the first update since 2012. However, it is still considerably higher than the 5 µg/m3 set by WHO. Obviously, the newly published national standard was not sufficient for the protection of public health,” they add.*

In the second study, researchers used county-level daily PM2.5 concentrations and medical claims data to track hospital admissions and emergency department visits for natural causes, cardiovascular disease, and respiratory disease for 50 million US adults aged 18 and over from 2010 to 2016.

During the study period, more than 10 million hospital admissions and 24 million emergency department visits were recorded.

They found that short term exposure to PM2.5, even at concentrations below the new WHO air quality guideline limit, was statistically significantly associated with higher rates of hospital admissions for natural causes, cardiovascular disease and respiratory disease, as well as emergency department visits for respiratory disease.

For example, on days when daily PM2.5 levels were below the new WHO air quality guideline limit of 15 μg/m3, an increase of 10 μg/m3 in PM2.5 was associated with 1.87 extra hospital admissions per million adults aged 18 and over per day.

The researchers say their findings constitute an important contribution to the debate about the revision of air quality limits, guidelines, and standards.

Both research teams acknowledge several limitations such as possible misclassification of exposure and point out that other unmeasured factors may have affected their results. What’s more, the findings may not apply to individuals without medical insurance, children and adolescents, and those living outside the US.

However, taken together, these new results provide valuable reference for future national air pollution standards.

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Home health care linked to increased hospice use at end-of-life – study

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Patients who had previously received home health care had a higher likelihood of accessing hospice care at the end of their life, according to a new study.

Researchers, whose findings are published in the Journal of Palliative Medicine, examined the home health care and hospice care experiences of more than two million people.

Using Medicare data, researchers found when individuals received home health care before the last year of their life, they had higher odds of using hospice care than those who had never received home health care.

Researchers said this association underscores the potential benefits of receiving end-of-life care in the comfort of one’s home.

As the aged population increases, the findings also show the need for more resources in the health care sector and staff training in end-of-life care.

Home health care services including skilled nursing, therapy, social work and aide services are used to maintain functioning or slow decline in health. Hospice care provides similar services but is intended for those with life expectancies of six months or less and is focused on pain relief, minimising hospital visits and providing comfort and support. Both services provide patients the opportunity to receive more personalised care in their home.

Researchers say home-based care also encourages greater involvement of family caregivers in the caregiving process.

Olga Jarrín, senior author of the study, the Hunterdon Professor of Nursing Research at the Rutgers School of Nursing and director of the Community Health and Aging Outcomes Laboratory within the Rutgers Institute for Health, Health Care Policy and Aging Research, commented: “In addition to benefits for the patient, hospice care also provides resources and support to help family caregivers cope with the physical, emotional and practical challenges of caring for a loved one at the end of life.”

Hyosin (Dawn) Kim, research assistant professor at Oregon State University and first author of the study, added: “By providing personalised care, reducing hospitalisations, fostering family involvement and support, and improving symptom management, home-based care can enhance the quality of end-of-life experiences for patients with terminal illnesses and their families.”

 

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Sleep programme shows promise in those with memory problems – study

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A new study has shown promising results in improving sleep and quality of life in individuals living with memory problems.

A group of researchers from Penn Nursing, Penn Medicine, Rutgers School of Nursing, and Drexel University’s College of Nursing and Health Professions, have delved into the efficacy of a non-pharmacological approach in a trial known as the Healthy Patterns Sleep Program.

The study involved 209 pairings of community-residing individuals with memory problems and their care partners. Participants were assigned to either the Healthy Patterns Sleep Program, which consisted of one-hour home activity sessions administered over four weeks, or a control group that received sleep hygiene training, plus education on home safety and health promotion.

The Healthy Patterns Sleep Program trained care partners in timed daily activities such as reminiscence in the morning, exercise in the afternoon and sensory activities in the evening that can decrease daytime sleepiness and improve nighttime sleep quality.

Nancy Hodgson, PhD, RN, FAAN, the Claire M. Fagin Leadership Professor in Nursing and Chair of Department of Biobehavioral Health Sciences, who led the study, said: “The results from this study provide fundamental new knowledge regarding the effects of timing activity participation and can lead to structured, replicable treatment protocols to address sleep disturbances. Overall, the Healthy Patterns program resulted in improved QOL compared to an attention-control group.”

The findings also indicate that, compared to a control group, the four-week Healthy Patterns program improved sleep quality among persons living with memory issues who had depressive symptoms or poor sleep quality.  The study indicates the Healthy Patterns Intervention might need a longer dose to induce improvements in other sleep-wake activity metrics.

The study’s significance lies in its confirmation of the effectiveness of behavioural interventions in not only improving quality of life and addressing sleep quality issues in this population, but also potentially reducing care partner burden and overall care costs for persons living at home with memory problems.

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