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Use of inhibitors of the renin-angiotensin system

a technology of angiotensin and inhibitors, which is applied in the direction of biocide, plant growth regulators, biochemistry apparatus and processes, etc., can solve the problems of increased mortality, wasting in the affected territory, and generalised weight loss, and achieves the effect of increasing blood flow and glucose uptak

Inactive Publication Date: 2005-09-01
TRIZELL LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent text describes the discovery of a new method for improving metabolic efficiency and mechanical performance of tissues by down-regulating the activity of the renin-angiotensin system (RAS) and promoting the activity of kinins. This method can be used to treat and prevent various disorders such as wasting, cardiovascular and cardiac diseases, and hypoxia. It can also be used to enhance physical fitness, promote cardiovascular and cardiorespiratory fitness, and improve performance in environments with low oxygen supply or reduced oxygen demand. The invention offers a new approach to the treatment and prevention of these disorders and can be used in both sporting applications and in the treatment of individuals at risk of these disorders."

Problems solved by technology

To deal first with generalised wasting, many disease processes can lead to aggressive generalised weight loss through either the inability to consume sufficient nutrients and energy sources, through their loss from the body (either enterally or in the form of cellular matter), or through an inability to absorb them.
This weight loss may at best be disabling, and at worst associated with an increased mortality.
In localised wasting, disuse of any given muscle group (for instance due to musculoskeletal or neurological injury) may lead to wasting in the affected territory.
There are currently no available treatments which are routinely used to slow or limit such wasting, nor which have been shown to accelerate the reversal of such wasting with appropriate exercise or after the cessation of the initiating disease state.
Most such interventions are either currently unproven, or have been shown to have no or only modest influence.
However, these treatments may be associated with an unacceptable side-effect profile and also suffer from the disadvantage that they have to be parenterally administered (usually by intramuscular injection).
Pharmacological manipulations are not currently available.
None is available for routine clinical practice.

Method used

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  • Use of inhibitors of the renin-angiotensin system
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Examples

Experimental program
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Effect test

example 1

[0121] This Example demonstrates that ACE inhibitors increase the mitochondrial membrane potential of cardiomyocytes. It is based on observation of the potential difference (ΔΨm) across the inner mitochondrial membrane that is generated by the extrusion of protons to the outside of the mitochondrion during the transport of electrons from electron-carrying coenzymes to molecular oxygen. Part of the energy stored in ΔΨm is utilised to support the synthesis of most of the ATP derived from aerobic metabolism. Thus, ΔΨm is an indicator of the energisation state of the mitochondrion, and also of the efficiency of oxygen utilisation to generate chemical energy. To investigate whether some of the therapeutic properties of ACE inhibitors could be accounted for by an increase in ΔΨm, this parameter was examined in rat cardiomyocytes, following pre-treatment with the ACE inhibitor lisinopril.

[0122] More particularly, cardiomyocytes were isolated from new-born Sprague-Dawley rats hearts and ma...

example 2

[0127] Ninety military recruits were studied before and after military training of 12 weeks duration. These were randomised to receive the AT1-receptor antagonist Losartan or placebo.

[0128] There was a consistent trend for the recruits to improve their VO2max at anaerobic threshold, although a distinction was observed, according to genotype. The results shows a gain of 2.1±6.8 ml / min for II genotype on placebo vs. −1.1±6.5 ml / min for DD genotype on placebo, and a gain of 0.3±6.3 ml / min for II on losartan vs. −1.8±6.3 ml / min for DD on Losartan. When combined, the difference in gain was 1.3±6.6 ml / min for II on vs. −1.4±6.4 ml / min for DD: p 0.07).

[0129] The data for VO2max showed a similar trend, as did measures of muscle fatigue. These data are consistent with an enhanced ability, especially for those of II genotype (and thus lower ACE activity) to achieve higher workloads, before reaching anaerobic threshold, and therefore to be more resistant to fatigue in situations of moderate ...

example 3

[0130] The bioactive element of the renin angiotensin system (RAS) is angiotensin II (AT II). Elevations of AT II in plasma or in local tissue would indicate conditions in which inhibition of the RAS may have significant therapeutic benefit even where partial inhibition of the RAS has been achieved (such as by therapy with ACE inhibitors).

[0131] ATT II was measured as follows: Blood samples were collected after supine rest of at least 10 minutes. An antecubital polyethylene catheter was inserted and 10 ml of venous blood were drawn. After immediate centrifugation, aliquots (EDTA plasma sample) were stored at −70° C. until analysis. Angiotensin II was measured using a commercially available radioimmunoassay (IBL, Hamburg, Germany, sensitivity 1.5 pg / ml). After extraction of the plasma samples, AT II is assayed by a competitive radioimmunoassay. This radioimmunoassay is using a rabbit anti-AT II antiserum and a radio-iodinated AT II tracer. Bound and free phases are separated by a se...

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Abstract

It has been found that inhibitors of the rennin-angiotensin system are useful for the treatment or prevention of conditions associated with hypoxia or impaired metabolic function or efficiency. In particular, they may be used in connection with therapy of stroke or its recurrence, the acute treatment of myocardial infarction, and the treatment or prevention of wasting or cachexia, and are thus useful in treatment of the symptoms and signs of aging. These inhibitors may also be used to enhance function in healthy subjects.

Description

FIELD OF THE INVENTION [0001] This invention relates to the use of inhibitors of the renin-angiotensin system. BACKGROUND OF THE INVENTION [0002] Wasting diseases may be categorised into generalised and localised wasting diseases. To deal first with generalised wasting, many disease processes can lead to aggressive generalised weight loss through either the inability to consume sufficient nutrients and energy sources, through their loss from the body (either enterally or in the form of cellular matter), or through an inability to absorb them. Other diseases are associated with marked weight loss quite out of proportion to any reduction in nutrient absorption or increase in nutrient loss. Such weight loss may have a metabolic origin. Severe cardiac failure as well as renal, hepatic and malignant disease processes are all associated with such inappropriate weight loss. Some neurological diseases, such as Parkinson's disease and syndrome are similarly related, as are conditions associa...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K45/00A61K31/00A61K31/22A61K31/223A61K31/40A61K31/401A61K31/403A61K31/405A61K31/407A61K31/41A61K31/415A61K31/417A61K31/4178A61K31/4184A61K31/44A61K31/472A61K31/519A61K31/55A61K31/551A61K31/554A61K31/66A61K31/662A61K38/00A61P3/00A61P7/00A61P9/10A61P25/00A61P37/04A61P43/00C08G61/08C12Q1/00
CPCA61K31/00A61K45/06A61K31/223A61K31/40A61K31/401A61K31/403A61K31/405A61K31/407A61K31/41A61K31/415A61K31/417A61K31/4178A61K31/4184A61K31/44A61K31/472A61K31/519A61K31/55A61K31/551A61K31/554A61K31/66A61K31/662C08G61/08A61K31/22A61P1/16A61P11/00A61P13/12A61P19/04A61P25/00A61P29/00A61P3/00A61P31/04A61P31/18A61P35/00A61P3/06A61P37/04A61P37/06A61P43/00A61P7/00A61P7/02A61P9/00A61P9/04A61P9/10A61P9/12A61P3/10
Inventor MONTGOMERY, HUGH EDWARDMARTIN, JOHN FRANCISERUSALIMSKY, JORGE DANIEL
Owner TRIZELL LTD
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