Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-10-07
2001-05-15
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S578000
Reexamination Certificate
active
06232346
ABSTRACT:
BACKGROUND
Organ Failure and Nutrition
There are four critical organ systems that are especially likely to fail in aging and critical illness. They are the cardiovascular, central nervous, musculoskeletal and immune systems.
Relationship of Malnutrition to Mitochondrial Function
Protein-calorie malnutrition contributes to both skeletal and cardiac
1
muscle dysfunction in patients with cardiac failure. Muscle is composed of water, minerals, nitrogen and glycogen
2,3
. Feeding wasted individuals results in a gain of the multiple elements in lean tissue
4
including potassium. Body potassium, has been used as an index of body cell mass
5
, the metabolically active component of the lean tissue. In contrast to body nitrogen, body potassium responds rapidly to feeding by both oral and intravenous routes
6,7,8,9,10
. It has been shown that in malnutrition there is a change in muscle membrane potential resulting in reduced intracellular ionic potassium. The reduced cellular potassium cannot be simply corrected by giving potassium but requires restitution of nutrition. The above mentioned observations suggest that cell ion uptake, an energy dependent process, occurs earlier than protein synthesis during nutritional support. This concept has received experimental support by two studies using
31
P-NMR which showed that malnutrition was associated with a reduced rate of oxidative phosphorylation, suggesting a mitochondrial abnormality
11,12
.
Cell energetics are also important for muscle activity and it has been shown
13,14,15,16,17,18,19,20,21,22
that skeletal muscle function, including that of the diaphragm, can be rapidly altered by nutrient deprivation and restored by refeeding. Also the changes in muscle function are specific to alterations in the nutritional status and are not influenced by sepsis, trauma, renal failure and steroid administration
15,17
. Christie and Hill indicated that nutritional support improves muscle, including diaphragmatic function before any increase in body protein or body mass
20
. Windsor and Hill
21
demonstrated that the functional effects of nutrition are more important than subnormal body protein as an index of surgical risk. Hanning and her colleagues
22
demonstrated the ability of stimulated muscle function as demonstrated by a slow relaxation rate and an altered force-frequency curve to predict the ability of patients with cystic fibrosis to grow as an outcome measure. In contrast, body composition, protein biochemistry, muscle power on an ergometer or use of supplements did not predict growth potential. Among the macronutrients, Castenada et al
23
have shown that protein deficiency can profoundly alter muscle function even when energy intake is sufficient to meet requirements.
The data given above indicate that it is critical to correct protein-calorie malnutrition, with an emphasis on protein repletion, in order to obtain the maximum functional benefits of administering skeletal muscle specific micronutrients. Current diet supplementing strategies for correcting protein-calorie malnutrition focus on giving supplements of protein and energy (carbohydrates and fats). No supplement to date has addressed the cascading series of metabolic abnormalities that can lead to mitochondrial dysfunction.
SUMMARY OF THE INVENTION
We have found that nutrition can be used to prevent or delay the onset of cardiac failure and thereby, promote recovery in disease states affecting the heart. Similar considerations apply to diseases of the other organ systems indicated above.
We have found that the central effect of nutrition in all these systems can be unified into its influence on mitochondrial energetics. That is: inadequate nutitional substrate is a cause of impaired cell energetics. This has led us to invent a composition for the improvement of mitochondrial energetics.
We have shown that in the skeletal muscle protein-calorie malnutrition profoundly reduces mitochondrial oxidative phosphorylation and reduces calcium cycling in cardiac muscle
1
. We have found that there is profound reduction of respiratory chain complex I, II and IV activity in animals given a protein-calorie deficient diet. In addition, complex I activity is similarly reduced in lymphocyte mitochondria showing that these effects are not cardiac specific but apply to mitochondria in other tissues, and protein feeding rapidly restored the abnormality when it was simply due to protein-energy malnutrition (unpublished data).
In addition, certain micronutrients and amino acids also influence mitochondrial function in general. For example, carnitine improves mitochondrial DNA transcription and translation in aged animals
24
. A specific acyl derivative of carnitine, acetyl-carnitine has been used for mitochondrial DNA synthesis based on findings observed in patients treated with anti-retroviral agents
25
. Coenzyme Q can alter immune function
26
and may protect the central nervous system from injury and neurodegeneration
27
. On the basis of the above considerations, a nutritional supplement that could maintain or restore mitochondrial function will prevent cardiac failure or aid recovery from cardiac disease. In addition it could also aid in the management of neurodegenerative, musculoskeletal including the muscular abnormality in chronic obstructive lung disease (COPD)
16
and immune disorders.
Heart Failure
Congestive heart failure has emerged as a major health problem during the past two decades. Its morbidity and mortality have shown a steady increase since 1970
28
; heart failure now affects approximately 1% of the population of the United States and Canada. These data reflect both the aging of our population and the success of modern cardiovascular medicine in converting acute, often previously fatal, cardiac disease into a more chronic process.
The underlying abnormality in congestive heart disease is myocardial dysfunction leading to inadequate blood flow to peripheral tissues. Although there have been considerable advances in our understanding of the pathogenesis of heart failure in recent years, critical questions remain about the evolution of cardiac dysfunction to terminal failure. The importance of elucidating the mechanisms responsible for the evolution of maladaptive hypertrophy to cardiac failure is emphasized by the fact that in spite of our advances, no presently available therapeutic intervention has been shown to substantially improve the long-term survival of patients with dilated cardiomyopathy and congestive heart failure. The underlying heart disease is relentlessly progressive in almost all patients who develop symptoms of overt failure and mortality continues to be unacceptably high; for example, in a recent heart failure trial, SOLVD, 40% of patients in the symptomatic treated group were dead within 4 years
29
. Heart transplantation appears to be the only prospect to improve long term survival for many patients.
The reason for this dismal outcome despite modern advances lies in the fact that several metabolic abnormalities have been found in the failing myocardium which together as indicated below result in progressive loss of cardiac myocytes (muscle).
There is a progressive accumulation of calcium in the muscle, which in turn results in increased calcium in the mitochondria. The progressive increase in mitochondrial calcium as well as the basic cardiac disease (ischemic, viral, toxic, genetic) decrease myocyte energy production and increase oxidative stress resulting in free radical damage. The combined result of these three processes promotes myocyte dysfunction and death. In addition these processes also influence skeletal muscle and contribute to fatigue and disability.
The modern pharmacological therapy of heart failure has focused on the amelioration of fluid overload and hemodynamic abnormalities and has not addressed the fundamental fact that if there is progressive loss of cardiac muscle then the patient will inevitably succumb. That is: the inexorable myocyte loss by apoptosis that occurs in heart failure is the key factor responsible for myocardial deco
Jeejeebhoy Khursheed N.
Sole Michael J.
Nields, Lemack & Dingman
Reamer James H.
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