X-Message-Number: 31297
Date: Tue, 23 Dec 2008 18:43:22 -0800 (PST)
From: 
Subject: An Anti-frailty Pill For Seniors?


An Anti-frailty Pill For Seniors? New Drug Increases Muscle Mass In Arms And 
Legs Of Older Adults

ScienceDaily (Nov. 5, 2008) - Researchers at the University of Virginia Health 
System report that a daily single oral dose of an investigational drug, MK-677, 
increased muscle mass in the arms and legs of healthy older adults without 
serious side effects, suggesting that it may prove safe and effective in 
reducing age-related frailty.


Published in the November 4, 2008 issue of Annals of Internal Medicine, the 
study showed that levels of growth hormone (GH) and of insulin-like growth 
factor I (IGF- I) in seniors who took MK-677 increased to those found in healthy
young adults. The drug restored 20 percent of muscle mass loss associated with 
normal aging.


"Our study opens the door to the possibility of developing treatments that avert
the frailty of aging," explains Dr. Michael O. Thorner, a nationally recognized
researcher of growth hormone regulation and a professor of internal medicine 
and neurosurgery at UVA. "The search for anti-frailty medications has become 
increasingly important because the average American is expected to live into his
or her 80s, and most seniors want to stay strong enough to remain independent 
as they age."


Funded by the National Institutes of Health, the two-year, double-blind, 
placebo-controlled, modified-crossover study involved 65 men and women ranging 
in age from 60 to 81.


The study drug, MK-677, mimics the action of ghrelin, a peptide that stimulates 
the growth hormone secretagogue receptor (GHSR). Drug developers are focusing on
GHSR because it plays an important role in the regulation of growth hormone and
appetite. They think it may prove to be an excellent treatment target for 
metabolic disorders such as those related to body weight and body composition.


According to Dr. Thorner, the UVA research was a "proof-of-concept" study that 
sets the stage for a larger and longer clinical trial to determine whether 
MK-677 is effective in people who are frail and to assess its long term safety.

Adapted from materials provided by University of Virginia Health System.


Ann Intern Med. 2008 Nov 4;149(9):601-11.Effects of an oral ghrelin mimetic on 
body composition and clinical outcomes in healthy older adults: a randomized 
trial.

    Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, 
    Heymsfield SB, Bach MA, Vance ML, Thorner MO. the University of Virginia, 
    Charlottesville, Virginia; Vanderbilt University School of Medicine, 
    Nashville, Tennessee; University of Kentucky, Lexington, Kentucky; and Merck
    Research Laboratories, Rahway, New Jersey.

    BACKGROUND: Growth hormone secretion and muscle mass decline from midpuberty
    throughout life, culminating in sarcopenia, frailty, decreased function, 
    and loss of independence. The decline of growth hormone in the development 
    of sarcopenia is one of many factors, and its etiologic role needs to be 
    demonstrated. OBJECTIVE: To determine whether MK-677, an oral ghrelin 
    mimetic, increases growth hormone secretion into the young-adult range 
    without serious adverse effects, prevents the decline of fat-free mass, and 
    decreases abdominal visceral fat in healthy older adults. DESIGN: 2-year, 
    double-blind, randomized, placebo-controlled, modified-crossover clinical 
    trial. SETTING: General clinical research center study performed at a 
    university hospital. PARTICIPANTS: 65 healthy adults (men, women receiving 
    hormone replacement therapy, and women not receiving hormone replacement 
    therapy) ranging from 60 to 81 years of age. INTERVENTION: Oral 
    administration of MK-677, 25 mg, or placebo once daily. MEASUREMENTS: Growth
    hormone and insulin-like growth factor I levels. Fat-free mass and 
    abdominal visceral fat were the primary end points after 1 year of 
    treatment. Other end points were body weight, fat mass, insulin sensitivity,
    lipid and cortisol levels, bone mineral density, limb lean and fat mass, 
    isokinetic strength, function, and quality of life. All end points were 
    assessed at baseline and every 6 months. RESULTS: Daily administration of 
    MK-677 significantly increased growth hormone and insulin-like growth factor
    I levels to those of healthy young adults without serious adverse effects. 
    Mean fat-free mass decreased in the placebo group but increased in the 
    MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 
    to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by
    intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, 
    -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were 
    observed in abdominal visceral fat or total fat mass; however, the average 
    increase in limb fat was greater in the MK-677 group than the placebo group 
    (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 
    1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 
    group (P = 0.003). Fasting blood glucose level increased an average of 0.3 
    mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity 
    decreased. The most frequent side effects were an increase in appetite that 
    subsided in a few months and transient, mild lower-extremity edema and 
    muscle pain. Low-density lipoprotein cholesterol levels decreased in the 
    MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to
    -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no 
    differences between groups were observed in total or high-density 
    lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 
    to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients
    (P = 0.020). Changes in bone mineral density consistent with increased bone
    remodeling occurred in MK-677 recipients. Increased fat-free mass did not 
    result in changes in strength or function. Two-year exploratory analyses 
    confirmed the 1-year results. Limitation: Study power (duration and 
    participant number) was insufficient to evaluate functional end points in 
    healthy elderly persons. CONCLUSION: Over 12 months, the ghrelin mimetic 
    MK-677 enhanced pulsatile growth hormone secretion, significantly increased 
    fat-free mass, and was generally well tolerated. Long-term functional and, 
    ultimately, pharmacoeconomic, studies in elderly persons are indicated.
PMID: 18981485

Curr Opin Investig Drugs. 2008 Sep;9(9):983-92.

The effects of growth hormone and insulin-like growth factor-1 on the aging 
cardiovascular system and its progenitor cells.

    Devin JK, Young PP. University of Texas MD Anderson Cancer Center, 
    Department of Endocrine Neoplasia and Hormonal Disorders, Houston, TX 77030,
    USA.

    Aging is a major risk factor for the development of cardiovascular disease. 
    Aging is also associated with a decline in the growth hormone (GH) and 
    insulin-like growth factor-1 (IGF-1) axis. This axis impacts endothelial and
    vascular smooth muscle cell biology, as well as cardiac function. The 
    number of endothelial progenitor cells (EPCs) also decreases with age and is
    emerging as a surrogate measurement of vascular senescence. Studies suggest
    that EPCs impact vascular health by modulating vascular repair and 
    function. Current evidence demonstrates that EPC number and function is 
    restored with a GH-mediated increase in serum IGF-1. Modulation of the GH 
    and IGF-1 system may therefore provide a useful therapy in the prevention of
    age-associated changes in the cardiovascular system and in future 
    regenerative cell-based therapies.
PMID: 18729005

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