Silica and Bacopa effectively detox's from Geoengineering aluminum dispersants

Silica helps aluminum to be excreted via urine but allows essential metals, such as iron and copper, to stay in the body. Furthermore, studies have shown that drinking silica-rich mineral water each day for 12 weeks helps to remove aluminum from the body.

 Studies have shown that drinking silica-rich mineral water each day for 12 weeks helps to remove aluminum from the body.  Preliminary evidence indicates that drinking silica-rich mineral water decreases body levels of aluminum in people with Alzheimer’s disease. In some patients, it simultaneously improves cognitive performance to a significant degree

Supplementing with silica in the form of choline-stabilized ortho-silicic acid, stimulates collagen production and connective tissue function and repair. Because of this, it has been shown to help to increase bone mineral density in osteoporosis and improve the appearance and texture of aging skin, hair, and nails.

Monomethylsilanetriol

Researchers recently discovered that bacopa extract prevents aluminum toxicity in the cerebral cortex of rats. In one study, rats given bacopa extract along with aluminum in their drinking water showed significantly less aluminum-initiated damage to lipids and proteins in brain cells.[10] The bacopa extract also prevented a decline in the normal antioxidant activity associated with aluminum. In another study, aluminum in rats’ drinking water caused significant memory impairment on two different maze tests.[11] However, rats treated with bacopa extract were significantly protected against aluminum-induced memory impairment compared to rats not given bacopa. 

Frankincense Boswellia for arthritis

Some experienced a significant reduction in joint pain by up to 32 percent to 65 percent, which is comparable to prescription medications, showcasing boswellia’s ability as a natural arthritis treatment. (7)


 Boswellia serrata extract is so powerful that today it’s considered comparable to NSAID pain relievers (the leading type of chemical anti-inflammatory medications)


 Frankincense can inhibit certain pro-inflammatory cytokines and mediators that can damage DNA, feed tumor growth and destroy healthy cells.        frankincense boswellia 


 Boswellia seems to lower inflammation and support immune function on multiple levels, including (3):

• interfering with cytokine production that raises inflammation (interferon gamma, interleukin-4 and tumor necrosis factor-alpha)
• delaying reactions to sensitivities
• helping regulate lymphocytes (white blood cells) and T-cells interactions
• regulating production of immunoglobulin G (IgG) antibodies, which protect the body from bacterial and viral infections
• regulating production of immunoglobulin M (igM) antibodies, which are found mainly in the blood and lymph fluid

 

Iproniazid

 (with 15 g,  orally with 150 mg iproniazid) "this was a daily
   treatment given to schizophrenic patients, tryptophan along with an
   antidepressant which is a monoamine oxidase inhibitor. Most showed
   marked changes such as an elevation in mood, an increased
   involvement with other people in their ward, and an increased
   extrovertism. A separate study of this composition with the addition
   of the amino acid L_methionine produced in about half of these
   patients a toxic or deliriod state."

   ...... Tryptophan, a natural and nutritionally essential amino-acid,
   is a centrally active intoxicant and sleep provider in man. It is
   converted metabolicaly to tryptamine, which is a little bit
   psychedelic.  When administered with methionine (another amino-acid
   know to methylate things) it produces methylated tryptamines, the two
   best studied being N-methyltryptamine (NMT) and N,N-dimethytryptamine
   (DMT). The effects that result are hard to categorize, reflecting the
   the diagnostic state of the patient. But something happens. In short,
   tryptophan, alone or in combination with MAO inhibitors or methyl
   donors, is a fabulous tool for exploring brain function...........

A quick Web search turned up some useful information relating to
methionine (again without permission):

   The Cognitive Enhancement Research Institute
   S-adenosylmethionine (SAM)

   One of the essential metabolic functions of the body is active methyl
   donation (cycle A). The active methylation donor is S-adenosyl-
   methionine (SAM), which is produced from methionine by the addition 
   of ATP (adenosine triphosphate). After the methyl group has been 
   donated (reaction 3), homocysteine remains.  Because homocysteine has 
   pro-oxidant properties (elevated levels are associated with cardio-
   vascular disease), it must be detoxified. Two separate mechanisms 
   exist both of which are serine dependent. In the first (reaction 1), 
   homocysteine is re-methylated by methyltetrahydrofolate (Me-THF, or 
   "activated" folic acid) back to methionine, and the SAM cycle is 
   closed.  Under most circumstances, this should be the dominant 
   pathway. In the second mechanism (reaction 2), homocysteine is 
   combined with serine to form cystathionine which is split back apart 
   (slightly differently) to yield cysteine and homoserine. This 
   reaction depends on the enzyme cystathionine beta-synthase which 
   opens up the SAM cycle and results in loss of methionine (and 
   accumulation of cysteine).

   The restoration of the SAM cycle is not solely dependent on
   increasing serine levels. The folate cycle (cycle B) is essential to
   close the SAM cycle and keep methionine available for producing SAM.

   The folate cycle not only requires folic acid, but also vitamins B6
   and B12, and NADH (a vitamin B3-containing reducing agent). NADH is
   now available as a dietary supplement in the US.

So it appears that to be safe methionine should be taken in combination
with vitamins B12, B6 and folic acid. Again on the down side I have read
that methionine has GI side effects such as nausea.

A safe MAOI could be Peganum harmala extract (harmine). With the
exception of tryptophan all the other ingredients are available from
health food stores.

Magnesium allievates muscle cramps, high blood pressue and insomnia.

MAGNESIUM

The extent of magnesium deficiency is currently a controversial subject.  Research is currently underway to examine the hypothesis that magnesium deficiency may be a major health problem in the U.S. and around the world.  In the meantime, some physicians are having success in treating a variety of disorders with supplemental magnesium.
Dr. Jonathan V. Wright, a well-known and successful practitioner of alternative medicine says, "If it spasms . . . try magnesium."  He has had success in treating muscle spasms, bronchial spasms, intestinal spasms and spasms of the esophagus with supplemental magnesium.
Supplemental magnesium has also been used to successfully treat cardiac arrhythmias and mitral valve prolapse.  Magnesium is often quite beneficial in treating asthma.  Magnesium also reduces the chances of complications in individuals who suffer a heart attack.  In many individuals with high blood pressure, supplemental magnesium will cause a noticable blood pressure drop. 
In diabetics, magnesium supplements can slow the progress of diabetic retinopathy.
Too much oral magnesium can cause diarrhea.  Milk of magnesia (magnesium hydroxide) and epsom salts (magnesium sulfate) are commonly used as laxatives.  The chance of a diarrhea problem can be minimized by taking smaller amounts of magnesium spaced throughout the day and by drinking plenty of water.
Severe magnesium deficiency may require magnesium to be given by injection.  Many physicians who specialize in preventive or alternative medicine have had great success with giving their patients magnesium intravenously or by injection.
Moderate amounts of oral magnesium usually do not cause problems.  Magnesium aspartate is the most readily absorbed, but should not be used by those who have experienced problems with aspartame (Nutrasweet) or monosodium glutamate (MSG).  Magnesium citrate is also an easily absorbed form of magnesium, and has become widely available during the past few years.

For further information, check the following reference:
McLean, Robert M.,  "Magnesium and its Therapeutic Uses:  A Review. " American Journal of Medicine.  Vol. 96. pp. 63-75.  January, 1994.

Women need Iron, either by eating Liver or by iron-polysaccharide complexes

Low iron levels are a major health problem, accounting for many undiagnosed cases of lethargy and fatigue.  A routine blood chemistry test will measure many parameters of serum iron and hemoglobin; but many blood tests fail to include a test for ferritin.  Ferritin is the body's primary iron storage protein and is a much more sensitive measure of iron levels.  You may have to specifically request a ferritin test when getting a blood chemistry analysis.  Ferritin will also often detect internal blood loss that may be a very early indication of a potentially major disease.

 The safest iron supplements are probably the iron-polysaccharide complexes:  essentially iron bound up in a complex sugar molecule.  They are sold under brand names such as Niferex, Ferrex-150 and Nu-Iron. 

Chromate chromium for fat loss

Athletes doing weight training taking chromium picolinate at Bemidji State University had a 21 percent greater drop in body fat and a 42 percent greater increase in muscle mass than athletes on the same program not taking the supplement.

Most bioavailable chromium is chromium polynicotinate, or niacin-bound chromium.  It is also a patented substance, and is sold under the tradename Chrome-Mate.  Chromium polynicotinate, niacin-bound chromium is a much safer form of chromium for supplementation.  Some studies have also shown that niacin is necessary for chromium supplements to be of benefit.  Chromium polynicotinate. 

Rats deficient in chromium typically live no more than 24 months.
Chromium is believed to enhance the effectiveness of insulin, a hormone vital for the processing of glucose.  Supplemental chromium reduces blood glucose levels.
High levels of glucose and problems with insulin activity cause glycation, a process that damages vital proteins in the body.

Selegiline Revitalizes your Substantia Nigra for Optimal Dopamine

© 1991-2014 Jerry Emanuelson

DEPRENYL

Deprenyl was developed by Dr. Joseph Knoll of Semmelweis University in Budapest, Hungary during the early 1960's for possible use as an anti-depressant.  The medicine initially showed limited usefulness as a treatment for depression; but more than a decade after its initial development, deprenyl was found to be an effective treatment for Parkinson's Disease
.
Deprenyl acts on an important chemical in the brain called dopamine.  Dopamine is manufactured in the brain from two amino acids that occur naturally in foods: phenylalanine and tyrosine.
To function properly, the human body requires a multitude of chemicals in well-regulated quantities.  For most of these necessary chemicals, the human body has one biological process to manufacture the chemical and another process to break it down.  Dopamine is broken down in the brain by a chemical called MAO-B.  It is important for good health that the manufacture of dopamine from amino acids and the destruction of dopamine by MAO-B is kept in balance.

  If the destruction of dopamine by MAO-B occurs at a faster rate than its production from the amino acids, the brain cells that use dopamine will die.  The loss of dopamine and the resulting brain damage can cause tremors, rigid muscles, loss of coordination, weakness and death.

Beginning at about age 45, the destruction of dopamine in the brain by MAO-B begins increasing.  The amount of dopamine in the typical about human brain begins decreasing by 13 percent every decade.
In about 0.5 percent of the population, the decrease in dopamine takes place much more rapidly than the usual 13 percent every ten years.  When the dopamine content drops to about 30 percent of normal, these individuals develop the tremors and rigid muscles that are typical of Parkinson's Disease.  Parkinson's patients typically experience a decrease in dopamine levels of 30 percent to 90 percent every ten years.  Death usually occurs in Parkinson's patients about the time their brain dopamine content falls to 10 percent of normal.
In the past, the most popular treatment for Parkinson's Disease has been L-Dopa.  L-Dopa is an amino acid that is not present in the ordinary human diet.  The brain can make dopamine much more easily from L-Dopa than from the tyrosine and phenylalanine usually obtained from the human diet.
Deprenyl attacks the other end of the dopamine-preservation process by inhibiting the action of the MAO-B.
During the 1980's, deprenyl, either alone or in combination with L-Dopa, was the most effective known drug treatment for Parkinson's Disease.
Some of the enthusiasm for using deprenyl in Parkinson's Disease has been dampened after it was discovered that the dosage levels used were often too large, and that determining and maintaining the proper dosage in a clinical setting was more difficult that was first thought.
Dr. Knoll claims that deprenyl is also effective in preventing Parkinson's Disease.

According to Dr. Knoll, deprenyl has "proved to be a safe drug in man.  Neither hypertensive reactions nor the need for special dietary care were ever encountered during long-term (2-8 years) daily administration of the drug."  Knoll said that the lethal dose of the drug is more than 1000 times its effective daily dose.  Knoll called this safety margin "remarkable."
Dr. Knoll also said that deprenyl is an effective treatment for aging.
The average life span of the deprenyl-treated rats was 192 weeks.  The researchers considered this to be particularly remarkable since the maximum life span of that strain of laboratory rats is considered to be 182 weeks.
According to Dr. Knoll, similar life-extending results could be expected in humans.  The biological processes deprenyl acts upon to cause its life span extending effects in rats are well-known; and there is general agreement among scientists that deprenyl acts on the same processes in humans.
Dr. Knoll points to the normal decrease in dopamine in the aging brain as an indication of how deprenyl works to increase life span.  He said that it is no coincidence that even the healthiest humans die at about the time the dopamine content of their brain drops below the critical 30 percent level.  According to our present knowledge, the neurons (brain cells) that use dopamine are the most rapidly aging neurons in the human brain.

AGE 45 55 65 75 85 95 105 115 125

DOPAMINE CONTENT 100 percent 87 percent 74 percent 61 percent 48 percent 35 percent 22 percent 11 percent 0

  Deprenyl is broken down in the body to amphetamine and methamphetamine.  London researcher G. P. Reynolds and his associates reported in a British medical journal that even in the larger doses used in Parkinson's Disease, deprenyl is "unlikely to produce any marked degree of central amphetamine-like action." The amphetamine and the methamphetamine breakdown products of deprenyl can show up in urine, though.   In 1987, Dr. Shulman was 62 years-old and so severely afflicted with Parkinson's Disease that he was hardly able to move without help.  He obtained some deprenyl from Europe after hearing about the drug from a neurologist.
In Longevity magazine, Dr. Shulman is quoted as saying that "within 24 hours of taking the drug, I stopped shaking and shuffling, returned to normal, and went back to work."


Dangers of Deprenyl

One of several causes of impaired mental development in Down's syndrome is the excess production of SOD.  The excess SOD destroys some types of free radicals but, in the process, SOD produces more of the dangerous hydroxyl radical than the other antioxidant systems can handle.  There is a possibility that deprenyl, even at low doses, could produce some of the same kind of damage.
Obviously, if we could re-balance the antioxidant systems, the excess SOD activity could be turned from a problem to an advantage.  It will be years before we know the effect of long-term low-dose deprenyl in humans.  In the meantime, here are some things for anyone contemplating low-dose deprenyl for life extension to consider:

• The three major natural antioxidant systems in the body are SOD, catalase, and glutathione peroxidase.  Deprenyl raises SOD activity markedly, catalase activity slightly, and glutathione peroxidase activity none at all.  The nutritional supplement N-Acetyl-Cysteine (NAC) raises glutathione peroxidase levels and should help to re-balance the body's natural antioxidant system in those using deprenyl.
• It is probably unwise for anyone to use deprenyl without rather large doses of supplementary antioxidant vitamins, especially vitamins C and E.
• The increased SOD activity induced by deprenyl is greater in females than males.  The lifespan studies with deprenyl that produced positive results in animals were always done with male animals.  Female animals did not have positive results in lifespan studies.  The ideal dose of deprenyl in women appears to be less than the ideal dose for men.  The use of supplementary antioxidants in women taking deprenyl is correspondingly more important than for men taking deprenyl.

Dosage for Life Extension.


The optimum dose of deprenyl for life extension purposes is unknown.  Extrapolation from animal experiments would indicate that it is about 5 mg. every other day.  Some scientists, though, have suggested that people in their forties begin with 5 mg. per week and gradually increase to about 5 mg. per day by the time they reach their seventies.  Another complicating factor is that the early deprenyl experiments were done only with male animals.  A recent study using male and female rats indicated that the optimal dose for females is much smaller than the optimal dose for males.  Until more research is done, it may be prudent for healthy women under 70 to limit their dosage to 5 mg. per week.
The half-life of deprenyl in the body is only a few hours; but once it enters the brain, its effects are very long-lasting.  The half-life of MAO-B inhibition in humans has been measured to be about 40 days, therefore, deprenyl probably need not be taken daily by persons who do not have a neurological disease.
The successful life extension experiments with deprenyl have been done in rodents, where the half-life of MAO-B inhibition due to deprenyl is 8 to 11 days, as opposed to 40 days in humans.  This indicates that life extension doses extrapolated from rat studies may be 4 to 5 times too high for humans.
(In the study where the half-life of MAO-B inhibition was measured in humans, it was about 38 days in the normal subjects and 43 days for patients with early Parkinson's disease.  The normal subjects were four non-smoking males ages 62 to 69.  The Parkinson's patients were 2 males and 2 females ages 62-70.)

http://www.futurescience.com/hgh.html

Tesamorelin has produced many encouraging results, including a small improvement in glucose levels in most patients.   Human growth hormone often produces a temporary increase in insulin resistance when it is first started, especially in high doses.   Tesamorelin seems to have the opposite effect.

Another long-acting analog of GHRH that looks very promising is CJC-1295, but that product is at least 3 years away from approval by government agencies.  CJC-1295 maintains a much longer half-life in the human body by partially binding to albumin, an important protein that is prevalent in the human bloodstream.

As stated earlier, pharmaceutical companies have produced growth hormone releasing agents that have been shown to be very effective in reversing the decline in HGH production with age.   The one that has consistently worked the best is MK-0677 (ibutamoren mesylate), which is very effective in restoring HGH release in middle-aged and "normally-aging" elderly individuals to the levels of much younger people.   

MK-0677 is an oral medicine that restores the release of HGH in the pulsatile fashion characteristic of HGH release in young people.   

   Restoring HGH in "normally-aging" people is not a function that the Food and Drug Administration (FDA) considers to be a legitimate function of a medicine; therefore, Merck (the pharmaceutical company) stopped all further development of MK-0677.   Other effective oral HGH releasers developed by the pharmaceutical companies have faced a similar fate for similar reasons.

A considerable amount of research has been done on HGH releasers by the pharmaceutical companies, and some very promising substances have been developed, but there is no sign that any of them will be on the market anytime soon.   MK-0677 (ibutamoren mesylate) is a substance, though, that seems to be too good to go away.   It still appears in successful clinical trials from time to time.   It recently completed another successful medical test in normally aging adults, and has been undergoing clinical trials for use in fibromyalgia.

In a free market, MK-0677 (ibutamoren mesylate) would likely have had a revolutionary impact on the health of most people over 40.   In fact, it is possible that MK-0677 could have revolutionized health care, prevented great human suffering, and literally saved trillions of dollars in health care.    Since a free market in pharmaceuticals does not exist, MK-0677 will probably remain a hidden gray market gem for many years.

So DHT via multiple pathways increases nervous system strength, DHT increases epinephrine levels, decreases prolactin (assuming you have enough dopamine production as well), increases GABA, may decrease serotonin and serotonin receptors. All-round this means DHT has positive effects on your chemistry and nerve cells. By reducing prolactin, and estrogen, and subsequently serotonin, and also regulating catecholamines, by this, DHT can definitely increase libido, and alleviate sexual anxiety in most individuals by increasing GABA. DHT is key to many of Testosterone's brain benefits. Keep in mind though, despite positive effects on brain chemistry, this still doesn't give an excuse to OD on aromatase inhibitors, likely, because you need a little bit of estrogen (not much at all), to promote nNOS (neuronal nitric oxide synthase) production. So DHT serves as a great compliment to a little bit of brain estradiol, and a great ratio of DHT to estrogen means optimal sex drive, stamina, charisma and general masculinity.


Let's summarize in Bullets Here.

• DHT regulates alpha and beta adrenergic receptors.
• DHT may increase alpha-1-receptor density.
• DHT may decrease glutamate activity and increases mGLU7 expression (which increases GABA release)
• DHT increases serotonin 5-HT1A receptor density by influencing A1-Adr.Receptors.
• DHT promotes serotonin 5-HT1A/1B activity and may reduce aggression in the presence of serotonin. Although this may easily be over ridden by the pro-adrenergic effects of DHT.
• DHT increases beta-endorphin release by ^ 5-HT1A receptor indirect activation.
• DHT facilitates the release of Epinephrine (adrenaline).
• DHT increases cyclic AMP.
• DHT blocks estrogen-induced prolactin release.
• DHT reduces serotonin and serotonin receptors by inhibiting estrogen influence in the Brain. (but mainly acting to oppose 5-HT2A,2C and 5-HT4 receptors)
• DHT increases Mitogen-Activated-Protein Kinase (MAPK) which leads to a variety of molecular changes and genomic changes as well as neural-changes; decreased serotonin activity in the brain and periphery. 
• DHT increases GABA and GABA-A (neurosteroid-specific) receptor expression. 
• DHT increases NMDA-receptors in the Hippocampus.
• DHT increases Ca3 (Calcium) evoked Acetylcholine Function(AcH release).
• DHT increases nervous system strength and regulates blood pressure.

MK-677 is by Far the Single Most Effective Needle Mover in Sleep Enhancement and Insomnia Treatment by Light Years

 I've discovered that MK-677 works as a capsule , doesn't need refrigeration, dramatically increases deep sleep and effectively restores GH (growth hormone) to youthful levels, effectively treating crippling sleep disorders.

MK-677 Should only be used for 1 week cycles , with 5 weeks off.

MK-677 if used monthly  will shut down your HPA Axis with such serious consequences that your GH levels will plummett to the abyss, and your pituitary simply stops secreting.

Besides cold therapy for sleep, Mk-677 which was also studied for 1 year in the elderly population...  The 1 year clinical trial is free online:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757071

"Daily MK-677 significantly increased GH and IGF-I levels to those of healthy young adults without serious adverse effects."

GH = Healing Injuries Healing Bones, Tendons and Ligaments Extremely restful restorative sleep Protecting muscle tissue

--_---------_--------___________--------_---------______-------

Neuroendocrinology. 1997 Oct;66(4):278-86.

Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man.

Copinschi G1, Leproult R, Van Onderbergen A, Caufriez A, Cole KY, Schilling LM, Mendel CM, De Lepeleire I, Bolognese JA, Van Cauter E.

Author information

• 1Center for the Study of Biological Rhythms (CERB) and Laboratory of Experimental Medicine, Free University of Brussels, Belgium.

Abstract

Previous studies have indicated the existence of common mechanisms regulating sleep and somatotropic activity. In the present study, we investigated the effects of prolonged treatment with a novel, orally active, growth hormone secretagogue (MK-677) on sleep quality in healthy young and older adults. Eight young subjects (18-30 years) followed a double-blind, placebo-controlled, three-period crossover design. Each subject participated in three 7-day treatment periods (with bedtime drug administration), presented in random (Latin square) order, and separated by at least 14 days. Doses were 5 and 25 mg MK-677 and matching placebo. Six older subjects, ages 65-71 years, each participated in two 14-day treatment periods (with bedtime drug administration) separated by a 14-day washout. Doses were 2 and 25 mg MK-677 during the first and second periods, respectively. Baseline sleep and hormonal data were obtained on the 2 days preceding the beginning of the first 14-day treatment period. In young subjects, high-dose MK-677 treatment resulted in an approximately 50% increase in the duration of stage IV and in a more than 20% increase in REM sleep as compared to placebo (p < 0.05). The frequency of deviations from normal sleep decreased from 42% under placebo to 8% under high-dose MK-677 (p < 0.03). In older adults, treatment with MK-677 was associated with a nearly 50% increase in REM sleep (p < 0.05) and a decrease in REM latency (p < 0.02). The frequency of deviations from normal sleep also decreased (p < 0.02). The present findings suggest that MK-677 may simultaneously improve sleep quality and correct the relative hyposomatotropism of senescence.

J Clin Endocrinol Metab. 1996 Dec;81(12):4249-57.

Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects.

Chapman IM1, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, Schilling LM, Cole KY, Skiles EH, Pezzoli SS, Hartman ML, Veldhuis JD, Gormley GJ,Thorner MO.

Author information

• 1Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.

Abstract

Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64-81 yr) were enrolled in a randomized, double blind, placebo-controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 mg/day increasing mean 24-h GH concentration 97 +/- 23% (mean +/- SE; P < 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 +/- 21 microgram/L at baseline, 219 +/- 21 micrograms/L at 2 weeks, and 265 +/- 29 micrograms/L at 4 weeks; P < 0.05). MK-677 produced significant increases in fasting glucose (5.4 +/- 0.3 to 6.8 +/- 0.4 mmol/L at 4 weeks; P < 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23%, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.

Following treatment with 50 mg MK-677, IGF-I concentrations increased 79 ± 9% (84 ± 3 to 150 ± 6 μg/L, P ≤ 0.05 vs. baseline) and 24-h mean GH concentrations increased 82 ± 29% (0.21 ± 0.02 to 0.39 ± 0.04μ g/L, P ≤ 0.05 vs. baseline), respectively - See more at: http://press.endocrine.org/doi/full/10.1210/jcem.82.10.4297#sthash.RPXabxgH.dpuf

Results

Section:

ChooseTop of pageAbstractSubjects and MethodsResults <<DiscussionCITING ARTICLES

Response to treatment

Oral treatment with both 10 mg and 50 mg/day MK-677 was associated with statistically significant increases in circulating concentrations of GH, IGF-I, and IGFBP-3, whereas placebo treatment was without a significant effect on these parameters (Table 2).

GH

- See more at: http://press.endocrine.org/doi/full/10.1210/jcem.82.10.4297#sthash.RPXabxgH.dpuf

Adverse experiences

MK-677 treatment was generally well tolerated and no symptoms developed that were definitely attributed to study drug. There were no serious adverse events during this study, and no subjects were discontinued or had treatment interrupted because of an adverse experience.

- See more at: http://press.endocrine.org/doi/full/10.1210/jcem.82.10.4297#sthash.RPXabxgH.dpuf

The increase in GH concentrations produced by MK-677 treatment was because of an increase in GH pulse, amplitude, and interpeak valley and nadir GH concentrations and not because of increased pulse frequency. - See more at: http://press.endocrine.org/doi/full/10.1210/jcem.82.10.4297#sthash.RPXabxgH.dpuf

This enhancement of GH pulsatility occurs whether these compounds are administered continuously as intravenous infusions or as daily administrations of the long-acting compound MK-677. This suggests that these compounds amplify the normal signals responsible for episodic GH release. This could occur via relief of an inhibitory effect, such as that of somatostatin, enhancement of a stimulatory effect, such as that of GHRH, or a combination of both.

The stimulatory effect of MK-677 on mean GH concentrations in the 8 h after drug administration declined between the first and fourth day of drug administration, although the fourth day value was still significantly greater than baseline. This decline may indicate desensitization to the GH stimulatory effects of the drug and foreshadow an eventual loss of stimulatory effect. Alternately, and probably more likely, it may result from negative feedback effects of IGF-I on GH secretion.

- See more at: http://press.endocrine.org/doi/full/10.1210/jcem.82.10.4297#sthash.RPXabxgH.dpuf

Favorable changes in body composition because of MK-677-induced increases in GH secretion could conceivably counteract any unfavorable effects on insulin resistance. GH therapy in GH-deficient subjects has been reported to increase insulin resistance at 6 weeks, but have a diminished effect at 26 weeks when significant decreases of body fat have occurred (42). - See more at: http://press.endocrine.org/doi/full/10.1210/jcem.82.10.4297#sthash.RPXabxgH.dpuf

Notably, daily oral administration of MK-677 increases plasma GH concentration in healthy elderly subjects and also increases their plasma IGF-I concentration to the normal range of young adults (Chapman et al. 1996).

Among these GH secretagogues (GHSs), MK-677 has been reported to show good oral bioavailability. In addition, chemically synthesized GHSs including GHRP-6 and MK-677 have been reported to show highly potent GHreleasing activity in several species including humans (Walker et al. 1990, Bowers et al. 1992, Hartman et al. 1992, Chapman et al. 1996).

Two-Month Treatment of Obese Subjects with the Oral Growth Hormone (GH) Secretagogue MK-677 Increases GH Secretion, Fat-Free Mass, and Energy Expenditure

J. Svensson, L. Lönn, J.-O. Jansson, G. Murphy, D. Wyss, D. Krupa, K. Cerchio, W. Polvino, B. Gertz, I. Boseaus, L. Sjöström, and B.-Å. Bengtsson

Address all correspondence and requests for reprints to: Dr. Johan Svensson, Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.

DOI: http://dx.doi.org/10.1210/jcem.83.2.4539

Received: June 19, 1997

Accepted: October 14, 1997

First Published Online: July 01, 2013

- See more at: http://press.endocrine.org/doi/abs/10.1210/jcem.83.2.4539#sthash.RAxlYerH.dpuf

ABSTRACT

Obesity is associated with blunted GH secretion, unfavorable body composition, and increased cardiovascular mortality. The objective of this study was to investigate the effects of oral treatment with the GH secretagogue MK-677 on GH secretion and body composition in otherwise healthy obese males. The study was randomized, double blind, parallel, and placebo controlled. Twenty-four obese males, aged 18–50 yr, with body mass indexes greater than 30 kg/m² and waist/hip ratios greater than 0.95, were treated with MK-677 25 mg (n = 12) or placebo (n = 12) daily for 8 weeks.

Serum insulin-like growth factor I (IGF-I) increased approximately 40% with MK-677 treatment (P < 0.001 vs. placebo). Serum IGF-binding protein-3 was also significantly increased (P ≤ 0.001 vs. placebo). GH and PRL (peak and area under the curve values) were significantly increased after the initial dose of MK-677. Significant increases, with the exception of peak PRL, persisted at 2 and 8 weeks of treatment. The increases in GH and PRL after the initial dose were significantly greater than the increase seen after multiple doses. Serum and urinary concentrations of cortisol were not increased at 2 and 8 weeks (P = NS, vs. placebo). Fat-free mass increased significantly in the MK-677 treatment group when determined with dual energy x-ray absorptiometry (P < 0.01) or using a four-compartment model (P < 0.05). Total and visceral fat were not significantly changed with active therapy. The basal metabolic rate was significantly increased at 2 weeks of MK-677 treatment (P = 0.01) but not at 8 weeks (P = 0.1). Fasting concentrations of glucose and insulin were unchanged, whereas an oral glucose tolerance test showed impairment of glucose homeostasis at 2 and 8 weeks.

We conclude that 2-month treatment with MK-677 in healthy obese males caused a sustained increase in serum levels of GH, IGF-I, and IGF-binding protein-3. The effects on cortisol secretion were transient. Changes in body composition and energy expenditure were of an anabolic nature, with a sustained increase in fat-free mass and a transient increase in basal metabolic rate. Further studies are needed to evaluate whether a higher dose of MK-677 or a more prolonged treatment period can promote a reduction in body fat.

Affiliations

• Research Centre for Endocrinology and Metabolism (J.S., J.-O.J., B.-Å.B.), Departments of Radiology (L.L.), Clinical Nutrition (I.B.), and Internal Medicine (L.S.), Sahlgrenska University Hospital, Göteborg, Sweden; and Merck Research Laboratories (G.M., D.W., D.K., K.C., W.P., B.G.), Rahway, New Jersey 07065

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J Clin Endocrinol Metab. 1996 Aug;81(8):2776-82.

Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men.

Copinschi G1, Van Onderbergen A, L'Hermite-Balériaux M, Mendel CM, Caufriez A, Leproult R, Bolognese JA, De Smet M, Thorner MO, Van Cauter E.

Author information

• 1Center for the Study of Biological Rhythms, Université Libre de Bruxelles, Belgium.

A central enigma in neuroendocrine pathophysiology is the virtually uniform, but mechanistically incompletely explicable, attenuation of secretory and trophic activity of the growth hormone (GH)—insulin-like growth factor type I (IGF-I) axis in healthy aging in mammalian species, including the primate and human. Indeed, in humans, the calculated daily GH secretion rate falls approximately 50% every 7 years beginning at age 18 to 21, but this diminution in GH secretion is approximately twofold less rapid in premenopausal women. In contrast, the magnitude of relative GH deficiency appears to be similar in individuals of older (e.g., postmenopausal) age of either gender. Interpreting the mechanisms that underlie such marked attenuation of secretory activity of the GH-IGF-I axis is confounded by endocrinemetabolic covariates that accompany healthy aging, such as an accumulation of (visceral) adiposity, a decline in physical fitness, a reduction in sex steroids, disruption of slow-wave sleep, and concurrent illness and medications. Available clinical investigations point to a partial endogenous GHRH deficiency state, in this so-called somatopause. An important additional age-related fall in brain cholinergic activity (which regulates somatostatin secretion) is likely, thus arguing for combined hypothalamic somatostatin excess and GHRH, GHRP, or both deficiency. This article also evaluates the novel hypothesis that the GH impoverishment of aging is marked by disrupted network function of the GH-IGF-I feedback axis. Given this background, available and new technologies applied in patient-oriented investigations will likely unravel further the presumptively multiple mechanisms that subserve the hyposomatotropism of healthy aging, and begin to address the relative risks and benefits of restoring secretory activity of the aging GH-IGF-I axis.

MK-677, an Orally Active Growth Hormone Secretagogue, Reverses Diet-Induced Catabolism

M. G. Murphy, L. M. Plunkett, B. J. Gertz, W. He, J. Wittreich, W. M. Polvino ² , and D. R. Clemmons

Address all correspondence and requests for reprints to: M. Gail Murphy, Merck Research Laboratories, Building 10, Sentry Parkway, Bluebell, Pennsylvania 19422.

DOI: http://dx.doi.org/10.1210/jcem.83.2.4551

Received: May 14, 1997

Accepted: October 28, 1997

First Published Online: July 01, 2013

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Abstract

The reversal of diet-induced negative nitrogen balance by GH suggests a possible therapeutic role for GH treatment in catabolic patients. A double-blind, randomized, placebo-controlled, two-period, cross-over study was designed to investigate whether MK-677, an orally active nonpeptide mimic of GH-releasing peptide, can reverse diet-induced protein catabolism. Eight healthy volunteers (ages 24–39 yr) were calorically restricted (18 kcal/kg·day) for two 14-day periods. During the last 7 days of each diet period, subjects received either oral MK-677 25 mg or placebo once daily. There was a 14- to 21-day washout interval between periods. During the first week of caloric restriction (i.e. diet alone), daily nitrogen losses were similar for both treatment groups (mean ± se; MK-677 group −2.67 ± 0.40 g/day vs. placebo group− 2.83 ± 0.26 g/day). During the second week (diet and study drug), mean daily nitrogen balance was 0.31 ± 0.21 g/day in the MK-677 treatment group compared with −1.48 ± 0.21 g/day in the placebo group (P < 0.01). MK-677 improved nitrogen balance integrated over the 7 days of treatment; area under the curve day 8–14 nitrogen balance response was +2.69 ± 5.0 (se) for MK-677 and −8.97 ± 5.26 g·day for placebo (P < 0.001). MK-677 produced a peak GH response of 55.9 ± 31.7 μg/L after single dose (day 1 of treatment) and 22.6 ± 9.3 μg/L after a week of dosing compared with placebo treatment peak GH values of approximately 9 (treatment day 1) and approximately 7 μg/L (treatment day 7). Following the initial 7-day caloric restriction, insulin-like growth factor-I (IGF-I) declined from 232 ± 25 to 186 ± 19 ng/mL in the MK-677 group and from 236 ± 19 to 174 ± 23 ng/mL in the placebo group. Mean IGF-I concentration increased significantly during MK-677 to 264 ± 31 ng/mL (mean for the last 5 days of treatment) compared with 188 ± 19 ng/mL with placebo (P < 0.01). No significant difference in IGF binding protein-2 was found between the MK-677 and placebo treatments. However, the mean in IGF binding protein-3 for the last 5 days of MK-677 treatment was also significantly increased to 3273 ± 330 ng/mL (mean ± se) compared with placebo 2604 ± 253 ng/mL (P < 0.01). Neither the serum cortisol nor the PRL response was significantly greater after 7 days of MK-677 dosing compared with 7 days of placebo. MK-677 (25 mg) was generally well tolerated and without clinically significant adverse experiences. In conclusion, MK-677 reverses diet-induced nitrogen wasting, suggesting that if these short-term anabolic effects are maintained in patients who are catabolic because of certain acute or chronic disease states, it may be useful in treating catabolic conditions.

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Abstract

The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK-677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double-blind, parallel, placebo-controlled study. Twenty-four healthy obese males, 19–49 years of age, with body mass index > 30 kg/m² were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK-677 increased markers of bone formation; a 23% increase in the carboxy-terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK-677 treatment (p < 0.01 and p = 0.001 vs. placebo, respectively) while a 15% increase in serum levels of osteocalcin was not detected until 8 weeks of treatment (p < 0.01 vs. placebo). Markers of bone resorption were induced within 2 weeks of treatment with MK-677; serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen were increased 26% at 8 weeks (p = 0.001 vs. placebo), and urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% (p < 0.05 vs. placebo) and 46% (p < 0.05 vs placebo), respectively. MK-677 increased serum insulin-like growth factor binding protein-5 (IGFBP-5) by 43–44% after 2–8 weeks of treatment (p < 0.01 vs. placebo). Serum IGFBP-4 was increased by 25% after 2 weeks of treatment (p < 0.001 vs. placebo) but no significant change from baseline was observed after 8 weeks of treatment. Plasma interleukin-6 was not significantly changed by active treatment. In conclusion, short-term treatment of healthy obese male volunteers with the GH secretagogue MK-677 increases markers of both bone resorption and formation. Large increases in serum levels of IGF-I and IGFBP-5 and a transient increase in serum IGFBP-4 were found. Future long-term studies are needed to investigate if prolonged treatment with MK-677 increases bone mass.

Abstract

To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a randomized, double blind, three-period cross-over comparison of orally administered placebo and 5- and 25-mg doses of MK-677. Each period involved bedtime administration of the drug for 7 consecutive days. At the end of each period, plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured at 0745 h, and 24-h profiles of plasma GH and cortisol were obtained at 15-min intervals together with the 24-h urinary excretion of free cortisol. Profiles of plasma free cortisol were calculated at hourly intervals. The amounts of GH secreted were similar in all three conditions, but GH pulse frequency was increased with both dosages of the drug, primarily because of an increase in the number of low amplitude pulses. Plasma IGF-I levels were increased in a dose-dependent manner, whereas IGFBP-3 levels were increased only with the highest dosage. There was a positive relationship between GH pulse frequency and IGF-I increase. Except for an advance in the nocturnal nadir and in the morning elevation, MK-677 had no effect on cortisol profiles. In particular, 24-h mean levels of plasma total and free cortisol and urinary excretion of free cortisol were similar under all conditions. The present data suggest that the use of MK-677 for the treatment of relative somatotropic deficiency, particularly in older adults compromised by such deficiency, deserves further investigation.

Studies have found that in general, the optimal temperature for sleep is quite cool, around 60 to 68 degrees Fahrenheit. For some, temperatures that fall too far below or above this range can lead to restlessness.

Temperatures in this range, it seems, help facilitate the decrease in core body temperature that in turn initiates sleepiness. A growing number of studies are finding that temperature regulation plays a role in many cases of chronic insomnia. Researchers have shown, for example, that insomniacs tend to have a warmer core body temperature than normal sleepers just before bed, which leads to heightened arousal and a struggle to fall asleep as the body tries to reset its internal thermostat.

. Studies show that for troubled sleepers, a cool room and a hot-water bottle placed at the feet, which rapidly dilates blood vessels, can push the internal thermostat to a better setting.

THE BOTTOM LINE insomniacs tend to have a warmer core body temperature than normal sleepers just before bed, which leads to heightened arousal.