WO2008104861A1 - Method for the treatment of an individual having a vascular deficiency in the upper part of the body especially a cerebral vascular deficiency or an ocular vascular disorder - Google Patents
Method for the treatment of an individual having a vascular deficiency in the upper part of the body especially a cerebral vascular deficiency or an ocular vascular disorder Download PDFInfo
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- WO2008104861A1 WO2008104861A1 PCT/IB2008/000425 IB2008000425W WO2008104861A1 WO 2008104861 A1 WO2008104861 A1 WO 2008104861A1 IB 2008000425 W IB2008000425 W IB 2008000425W WO 2008104861 A1 WO2008104861 A1 WO 2008104861A1
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- therapeutic agent
- individual
- positive pressure
- deficiency
- vascular deficiency
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
- A61H23/00—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms
- A61H23/04—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms with hydraulic or pneumatic drive
Definitions
- Cerebral ischemia is the second etiology for death in western countries. It is also the first cause of acquired handicap in adult and the second cause of dementia after Alzheimer disease (WHO report 1999). As a consequence, cerebral ischemia is a major challenge of health care system. In the recent past, medical structures, specialist training and new therapies have been developed to improve outcome. Brain ischemia is characterized by 3 different zones 5 Baron JC.
- LBPP may improve both systolic and diastolic velocities on ophthalmic arteries which has an interest in treating ocular disorders.
Abstract
A method for the treatment of an individual having a cerebral vascular deficiency is disclosed. Said method comprises applying to the individual a lower body positive pressure efficient to increase the upper part of the body, brain or ocular perfusion, notably by applying a lower body positive pressure ranging between 10 and 40 mm Hg. The cerebral vascular deficiency is selected from acute stroke and sub acute stroke, chronic vascular dementia and Alzheimer disease. The ocular disorder is selected from anterior ischemic optic neuropathy, retinal artery occlusion or age related macular degeneration.
Description
Method for the treatment of an individual having a vascular deficiency in the upper part of the body especially a cerebral vascular deficiency or an ocular vascular disorder.
The present invention relates to a method for the treatment of an individual having a vascular deficiency in the upper part of the body, such as a cerebral vascular deficiency or an ocular disorder . It also relates to a combination product as well as to the use of means useful in such treatment.
INTRODUCTION:
Cerebral ischemia is the second etiology for death in western countries. It is also the first cause of acquired handicap in adult and the second cause of dementia after Alzheimer disease (WHO report 1999). As a consequence, cerebral ischemia is a major challenge of health care system. In the recent past, medical structures, specialist training and new therapies have been developed to improve outcome. Brain ischemia is characterized by 3 different zones 5 Baron JC.
Perfusion thresholds in human cerebral ischemia: historical perspective and therapeutic implications. Cerebrovasc Dis. 2001; 11 suppl 1:2-8) : the one which is not perfused leading to tissue necrosis. The surrounding area of this necrosis, called the at "risk area". This area is still perfused but not enough to allow the brain tissue to work normally. Around this "at risk" zone, the normal parenchyma might be dysfunctioning because of the release of local substances: reactive oxygen species, neuromediators, neurotoxic substances, etc...
The first approach focused on drugs able to reperfuse the obstructed vessels such as thrombolytic drugs iv administered (rTPA). Such a drug can only be used within the 3 hours after the stroke onset, leading to treat only few cases (5%) (The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue Plasminogen Activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-1588). In addition, this therapy may have adverse effects such as bleeding transforming ischemia in an intra-cerebral hematoma. The second approach consisted in the development of neuroprotective strategy for the at "risk zone". The clinical trials performed until now had negative results for all of them fWahlαren NG, Ahmed N. Neuroprotection in cerebral ischaemia: facts and fancies--the need for new approaches. Cerebrovasc Dis. 2004; 17 Suppl 1:153-66). Such a failure may come from the remaining hypoperfusion in this area, impairing the drug delivery to the tissue.
Since the 1950's, in a non medical purpose or for mechanical ventilation, such as a sudden increase or decrease in gravitation during supersonic flight (WB Albery, TL Chelette. Effect of G suit type on cognitive performance. Aviat Space Environ Med. 1998 ; 69 (5) :474-479) mechanical ventilation in intensive care unit (DM Payen, CJL Brin-Buisson, PA Carli et al. Hemodynamic gas exchange, and hormonal consequences of LBPP during PEEP ventilation . J Appl Physiol 1987 2(1): 61-70), it has been developed the concept of lower body positive pressure (LBPP) to ensure an adequate partition of volume within supra and infra- aortic territories especially for micro-gravitation flight. It has been documented that LBPP is able to shift blood from the lower to the upper part of the body, increasing the central cardiopulmonary blood volume (S. Bondurant,
JB Hickam, JK Isley. Pulmonary and circulation effect of acute pulmonary vascular engorgement in normal subjects. J Clin Invest 1957; 5:670-675).
The present inventors have unexpectedly discovered that LBPP can also increase the blood volume in the brain, recruiting vessels both at the venous and arterial sides. As a consequence, the brain perfusion, in particular in the "at risk area" could be improved by this vessel recruitment. This was particularly unobvious for a skilled Physician since such a blood pressure increase in the brain may induce further vasoconstriction to protect the brain from hypertension, the so called autoregulation.
The present inventors has also discovered that LBPP may improve both systolic and diastolic velocities on ophthalmic arteries which has an interest in treating ocular disorders.
PURPOSES OFTHE INVENTION
The present invention has for main purpose to provide a new method and means for treatment of an individual having a vascular deficiency on the upper part of the body. In the sense of the invention the upper part of the body designates the head and especially the brain on the one hand and the eyes on the other hand.
The present invention has also for main purpose to provide a new method and means for treatment of an individual having a cerebral vascular deficiency.
Another purpose is to provide a new method and means for treatment of an individual having ocular disorder.
According to the invention, this new treatment should be simple, efficient and with minimal costs.
In addition, the invention should be performed according to a simple step, which can be implemented by hospital personnel without long lasting training.
All these purposes have been reached for the time by the invention in a way, which is safe and reliable and usable not only in the hospitals but also outside in any place without substantial adaptation costs.
SUMMARY OF THE INVENTION
The invention relates to a method for the treatment of an individual having a vascular deficiency on the upper part of the body, comprising applying to this individual a lower body positive pressure efficient to increase the perfusion of the upper part of the body.
The invention relates also to a method for the treatment of an individual having a cerebral vascular deficiency, comprising applying to this individual a lower body positive pressure efficient to increase brain perfusion. The invention relates also to a method for the treatment of an individual having an ocular disorder, comprising applying to this individual a lower body positive pressure efficient to increase ocular vascular recruitment. The method may improve both systolic and diastolic velocities on ophthalmic arteries.
The present invention also relates to the use of a therapeutic agent for the preparation of a composition intended to be administered to an individual having a vascular deficiency in the upper part of the body, especially a cerebral vascular deficiency or ocular disorder, wherein the delivery of the therapeutic agent to the upper part of the body, especially the brain or the eye is helped or increased by application of pressure to the lower part of the body.
The present invention also relates to a therapeutic agent and a device generating positive pressure, as a product of combination to be applied to an individual having a vascular deficiency on the upper part of the body, especially a cerebral vascular deficiency or ocular disorder, wherein the delivery of the therapeutic agent to the upper part of the body, especially the brain or the eye, is helped or increased by application of pressure to the lower part of the body. The present invention also relates to the use of a positive pressure to produce a pressurized fluid intended to produce a lower body positive pressure to an individual having a vascular deficiency on the upper part of the body to increase the perfusion of the upper part of the body in this individual
DETAILED DESCRIPTION OF THE INVENTION:
According to a first aspect, the invention relates to a method for the treatment of an individual having a vascular deficiency on the upper part of the body comprising applying to this individual a lower body positive pressure efficient to increase upper part of the body perfusion.
According to a second aspect, the invention relates to a method for the treatment of an individual having a cerebral vascular deficiency, comprising applying to this individual a lower body positive pressure efficient to increase brain perfusion.
According to a third aspect, the invention relates to a method for the treatment of an individual having an ocular disorder, comprising applying to this individual a lower body positive pressure efficient to increase ocular vascular recruitment. According to a particular feature of the invention, the lower body positive pressure comprises a positive pressure, which is higher in limbs as compared to the positive pressure applied to abdomen to increase upper part of the body perfusion, especially brain perfusion or ocular vascular recruitment, as a result of improving intra-thoracic blood volume. According to another specific embodiment of the invention, the lower body positive pressure is ranging between 10 and 40 mm Hg with a preference of between 10 and less than 20 mm Hg on abdomen compartment and a preference of between 20 and 40 mm Hg in the lower limbs. According to another specific embodiment of the invention method, the lower body positive pressure has to be applied for a period of time ranging between 10 minutes and 2 hours, at least once a day and preferably twice a day, without maximum number of applications.
The lower body positive pressure can be applied day to day until clinical improvement usually within a week of treatment.
According to a specific embodiment, the cerebral vascular deficiency is selected from the group consisting of acute stroke and subacute stroke.
According to another specific embodiment of the invention, the cerebral vascular deficiency comprises chronic vascular dementia.
According to another specific embodiment of the invention, the cerebral vascular deficiency comprises Alzheimer disease.
According to another specific embodiment of the invention, the ocular disorder comprises anterior ischemic optic neuropathy or retinal artery occlusion.
According to another specific embodiment of the invention, the ocular disorder comprises age related macular degeneration.
According to another specific embodiment, the cerebral vascular deficiency is a cerebral vascular deficiency without symptoms and in such a case, the lower body positive pressure treatment can be performed as a proactive treatment to recruit vascular vessel. According to another specific embodiment, ocular disorder is an ocular disorder without symptoms and in such a case, the lower body positive pressure treatment can be performed as a proactive treatment to recruit ocular vascular vessel.
According to another specific embodiment of the invention, the lower body positive pressure is externally applied by a fluid, which may be a gas or a liquid, compression or by a mechanical compression.
When a fluid compression is applied, it is preferred to use a liquid compression.
In such a case, the liquid generates pressure by having said liquid contained in a confined or free recipient, thereby having the individual lower body part immersed or compressed still the diaphragm.
According to another embodiment, the mechanical compression can be generated by a specific mechanical device applied to the lower body part under the diaphragm to the feet, such a mechanical device including support stockings, or anti-gravitational trousers.
According to a another embodiment, the present invention further relates to the use of a positive pressure for the manufacture of an apparatus for the treatment of an individual having a vascular deficiency
in the upper part of the body, especially a cerebral vascular deficiency or ocular disorder.
According to a specific embodiment, the lower body positive pressure is generated by a device adapted to deliver this positive pressure. Such a device may comprise a water bath, a calibrated swimming-pool, support stockings, and anti-gravitational trousers.
According to another aspect, the present invention furthers relates to the use of a therapeutic agent for the preparation of a composition intended to be administered to an individual having a vascular deficiency, on the upper part of the body, wherein the delivery of the therapeutic agent to the upper part of the body is helped or increase by application of pressure to the lower part of the body.
By delivery of a theraupeutic agent it is to be understood that the therapeutic agent is administered by conventional means and routes, including parenteral, oral, nasal routes, especially infusion or injection (preferably intravenous and intraarterial), and its delivery (bioavailability to the target organ) to the upper part of the body, such as the brain and the eyes, is facilitated by the pressure applied according to the invention.
According to another aspect, the present invention furthers relates to the use of a therapeutic agent for the preparation of a composition intended to be administered to an individual having a cerebral vascular deficiency, wherein the delivery of the therapeutic agent to the brain is helped or increased by application of pressure to the lower part of the body.
According to an other aspect, the present invention further relates to the use of a therapeutic agent for the preparation of a composition intended to be administered to an individual having ocular disorder
wherein the delivery of the therapeutic agent to the eye is helped or increased by application of pressure to the lower part of the body.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from a group comprising anticoagulant agents, fibrinolytics, antioxidants, free radical-trapping agents, NMDA receptor antagonists, calcium channel blocker, NO donors, gap junction channel blockers, anti-inflammatory agents such as corticoids, anti adhesion molecules, cytokines antagonists such as anti-
TNFα, compounds that prevent the activation of pro-inflammatory transcription factors such as C/EBPβ, IRF-I and NF-κB, agonists of PPARα and PPARγ, growth factors such as NGF, BDNF, EGF, VEGF, anti-apoptotic factors, anticholinesterasic drugs and glutamate facilitator
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from anticoagulant agents.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from heparine and argatroban.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from fibrinolytics,
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from rtPA, alfimarase, microplasmine and ancrod. According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from antioxidants.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from gluthation, N- acetylcysteine, vitamin E or C.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from desferoxamine and allopurinol.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from NMDA receptor antagonists.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from ketamine.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from free radical- trapping agents.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from calcium channel blocker. According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from nimodipine, amlodipine.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from NO donors.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from molsidomine.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from gap-junction channel blockers.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from anti-inflammatory agents.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from corticosteroids and statins.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from anti-adhesion molecules.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from cytokines antagonists. According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from anti-TNFα and infliximad
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from compounds that prevent the activation of pro-inflammatory transcription factors such as C/EBPβ, IRF-I and NF-κB.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from agonists of PPARα and PPARγ.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from growth factors such as NGF, BDNF, EGF, VEGF.
According to another specific embodiment the therapeutic agent related to cerebral vascular deficiency is selected from anti-apoptotic factors such as bcl2.
According to another specific embodiment the therapeutic agent related to dementia (Alzheimer disease) is selected from anticholinesterasic drugs.
According to another specific embodiment the therapeutic agent related to dementia (Alzheimer disease) is selected from donezepil, galanthamine, rivastigmine.
According to another specific embodiment the therapeutic agent related to dementia (Alzheimer disease AD) is selected from glutamate facilitator.
According to another specific embodiment the therapeutic agent related to dementia (Alzheimer disease ) is selected from memantine.
According to another specific embodiment the therapeutic agent related to ocular disorder (age related macular degeneration, AMD) is selected from a group consisting of antioxidants, anti-inflammatory agent, trophic factors, apoptosis inhibitors and statins.
According to another specific embodiment the therapeutic agent related to ocular disorder (AMD) is selected from antioxidants. According to another specific embodiment the therapeutic agent related to ocular disorder (AMD) is selected from vitamin A, E, β-carotene, zinc.
According to another specific embodiment the therapeutic agent related to ocular disorder (AMD) is selected from free radical scavengers.
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from selenium, vitamin A, C, E, Ginkgo Biloba, green tea, grape seed extracts, lycopene and melatonin.
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from catalytic mimetics
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from EUK-134 (a low molecular weight salen manganese complex)
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from metal chelator.
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from desferoxamine. According to another specific embodiment the therapeutic agent related to ocular disorder is selected from anti-inflammatory agent- According to another specific embodiment the therapeutic agent related to ocular disorder is selected from pexelizumab and TPlO.
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from trophic factors.
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from CNTF (ciliary neurotrophic factor), PEDF (pigment epithelium-derived factor).
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from apoptosis inhibitors.
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from capsases inhibitors.
According to another specific embodiment the therapeutic agent related to ocular disorder is selected from statins. According to another embodiment the invention relates to the use as described above wherein the pressure is intended to increase the perfusion of the upper part of the body, especially to increase brain perfusion in this individual or to increase ocular vascular recruitment in this individual. According to another embodiment the invention relates to the use as described above wherein the therapeutic agent is intended to treat cerebral disorder or ocular disorder.
According to another embodiment the invention relates to the use as described above wherein the positive pressure in the lower part of the body is ranging between 10 and 40 mm Hg.
According to another embodiment the invention relates to the use as described above wherein the positive pressure in the lower part of the body is ranging between 20 and 40 mm Hg.
According to another embodiment the invention relates to the use as describe above wherein the positive pressure in the lower part of the body is applied for one length of time ranging between 10 minutes than two hours per day.
According to another embodiment the invention relates to the use as described above wherein the positive pressure in the lower part of the body is applied in the lower limbs and/or the abdomen.
According to another embodiment the invention relates to the use as described above wherein the lower body positive pressure is ranging between 20 and 40 mm Hg on lower limbs and between 10 and less than 20 mm Hg on abdomen compartment.
According to another embodiment the invention relates to the use as describe above wherein said cerebral vascular deficiency is selected from the group consisting of acute stroke, sub acute stroke and cerebral vascular deficiency without symptoms.
According to another embodiment the invention relates to the use as describe above wherein said cerebral vascular deficiency is Alzheimer disease. According to another embodiment the invention relates to the use as describe above wherein said cerebral vascular deficiency is chronic vascular dementia.
According to another embodiment the invention relates to the use as describe above wherein ocular disorder is selected from the group consisting of anterior ischemic optic neuropathy, retinal artery occlusion.
According to another embodiment the invention relates to the use as describe above wherein ocular disorder is selected from age related macular degeneration.
According to another embodiment the invention relates to a therapeutic agent and a device generating positive pressure, as a product of combination to be applied to an individual having a vascular deficiency in the upper part of the body, wherein the delivery of the therapeutic agent to the upper part of the body is helped or increase by application of pressure to the lower part of the body.
According to another embodiment the invention relates to a therapeutic agent and a device generating positive pressure, as a product of combination to be applied to an individual having a cerebral vascular deficiency, wherein the delivery of the therapeutic agent to the brain is helped or increase by application of pressure to the lower part of the body.
According to another embodiment the invention relates to a therapeutic agent and a device generating positive pressure, as a product of combination to be applied to an individual having ocular disorder, wherein the delivery of the therapeutic agent to the eye is helped or increase by application of pressure to the lower part of the body.
According to another specific embodiment the invention relates to a product of combination as described above wherein the therapeutic agent related to cerebral vascular deficiency is selected from a group comprising anticoagulant agents, fibrinolytics, antioxidants, NMDA receptor antagonists, free radical-trapping agents, calcium channel blocker, NO donors, gap junction channel blockers, anti-inflammatory agents such as
corticoids, anti adhesion molecules, cytokines antagonists such as anti TNFα, compounds that prevent the activation of pro-inflammatory transcription factors such as C/EBPβ, IRF-I and NF-κB, agonists of PPARα and PPARγ, growth factors such as NGF, BDNF7 EGF, VEGF, an anti apoptotic factors, anticholinesterasic drugs and glutamate facilitator. According to another specific embodiments of the invention:
- the therapeutic agent related to cerebral vascular deficiency is selected from anticoagulant agents
- the therapeutic agent related to cerebral vascular deficiency is selected from heparine and argatroban
- the therapeutic agent related to cerebral vascular deficiency is selected from fibrinolytics
- the therapeutic agent related to cerebral vascular deficiency is selected from rtPA, alfimarase, microplasmine and ancrod - the therapeutic agent related to cerebral vascular deficiency is selected from antioxidants
- the therapeutic agent related to cerebral vascular deficiency is selected from gluthation, N-acetylcysteine, vitamin E or C.
- the therapeutic agent related to cerebral vascular deficiency is selected from desferoxamine and allopurinol
- the therapeutic agent related to cerebral vascular deficiency is selected from NMDA receptor antagonists
- the therapeutic agent related to cerebral vascular deficiency is selected from ketamine - the therapeutic agent related to cerebral vascular deficiency is selected from free radical-trapping agents
- the therapeutic agent related to cerebral vascular deficiency is selected from calcium channel blocker
- the therapeutic agent related to cerebral vascular deficiency is selected from nimodipine, amlodipine
- the therapeutic agent related to cerebral vascular deficiency is selected from NO donors. - the therapeutic agent related to cerebral vascular deficiency is selected from molsidomine
- the therapeutic agent related to cerebral vascular deficiency is selected from gap-junction channel blockers
- the therapeutic agent related to cerebral vascular deficiency is selected from anti-inflammatory agents
- the therapeutic agent related to cerebral vascular deficiency is selected from corticosteroids and statins
- the therapeutic agent related to cerebral vascular deficiency is selected from anti-adhesion molecules. - the therapeutic agent related to cerebral vascular deficiency is selected from cytokines antagonists
- the therapeutic agent related to cerebral vascular deficiency is selected from anti TNFα and infliximad
- the therapeutic agent related to cerebral vascular deficiency is selected from compounds that prevent the activation of pro-inflammatory transcription factors such as C/EBPβ, IRF-I and NF-κB
- the therapeutic agent related to cerebral vascular deficiency is selected from agonists of PPARα and PPARγ
- the therapeutic agent related to cerebral vascular deficiency is selected from growth factors such as NGF, BDNF, EGF, VEGF
- the therapeutic agent related to cerebral vascular deficiency is selected from anti-apoptotic factors such as bcl2.
- the therapeutic agent related to dementia (AD) is selected from anticholinesterasic drugs
- the therapeutic agent related to dementia (AD) is selected from donezepil, galanthamine, rivastigmine
- the therapeutic agent related to dementia (AD) is selected from glutamate facilitator - the therapeutic agent related to dementia (AD) is selected from memantine.
According to another specific embodiments of the invention:
- the therapeutic agent related to ocular disorder (AMD) is selected from a group consisting of antioxidant, anti-inflammatory agent, trophic factors, apoptosis inhibitors and statins
- the therapeutic agent related to ocular disorder (AMD) is selected from antioxidant
- the therapeutic agent related to ocular disorder (AMD) is selected from vitamin A, E, β-carotene, zinc - the therapeutic agent related to ocular disorder (AMD) is selected from free radical scavengers
- the therapeutic agent related to ocular disorder (AMD) is selected from selenium, vitamin A, C, E, Ginkgo Biloba, green tea, grape seed extracts, lycopene and melatonin - the therapeutic agent related to ocular disorder (AMD) is selected from catalytic mimetics
- the therapeutic agent related to ocular disorder (AMD) is EUK-134 (low molecular weight salen manganese complex)
- the therapeutic agent related to ocular disorder (AMD) is selected from metal chelator
- the therapeutic agent related to ocular disorder (AMD) is selected from desferoxamine
- the therapeutic agent related to ocular disorder (AMD) is selected from anti-inflammatory agents
- the therapeutic agent related to ocular disorder (AMD) is selected from pexelizumab and TPlO
- where the therapeutic agent related to ocular disorder (AMD) is selected from trophic factors - the therapeutic agent related to ocular disorder (AMD) is selected from CNTF (ciliary neurotrophic factor), PEDF (pigment epithelium-derived factor)
- the therapeutic agent related to ocular disorder (AMD) is selected from apoptosis inhibitors - the therapeutic agent related to ocular disorder (AMD) is selected from capsases inhibitors.
- the therapeutic agent related to ocular disorder (AMD) is selected from statins
According to another embodiment the invention relates to a product of combination as describe above wherein the said device deliver a positive pressure ranging between 10 and 40 mmHg.
According to another embodiment the invention relates to a product of combination as describe above wherein the said device deliver a positive pressure ranging between 20 and 40 mmHg. According to another embodiment the invention relates to a product of combination as describe above wherein the said device deliver a positive pressure is ranging between 20 and 40 mm Hg on lower limbs and between 10 and less than 20 mm Hg on abdomen compartment.
According to another embodiment the invention relates to a product of combination as describe above wherein the said device deliver a positive pressure is ranging between 20 and 40 mm Hg on lower limbs and between 10 and less than 20 mm Hg on abdomen compartment.
According to another embodiment the invention relates to a product of combination as describe above wherein said cerebral vascular deficiency
is selected from the group consisting of acute stroke, sub acute stroke and cerebral vascular deficiency without symptoms.
According to another embodiment the invention relates to a product of combination as describe above wherein cerebral vascular deficiency comprises chronic vascular dementia.
According to another embodiment the invention relates to a product of combination as describe above wherein said cerebral vascular deficiency is Alzheimer disease.
According to another embodiment the invention relates to a product of combination as describe above wherein ocular disorder is selected from the group consisting of anterior ischemic optic neuropathy, retinal artery occlusion.
According to another embodiment the invention relates to a product of combination as describe above wherein ocular disorder is selected from age related macular degeneration.
According to an other embodiment the invention relates to the use of a positive pressure to produce a pressurized fluid intended to produce a lower body positive pressure to an individual having a vascular deficiency on the upper part of the body to increase the perfusion of the upper part of the body in this individual. This increased perfusion improves the status of the individual, say it improves the treatment of the disorder owing the increase of blood volume due to increased perfusion. The increased perfusion may be helpful per se or may be used or combined to facilitate delivery of drugs. It may concern the brain or the eyes as explained herein.
According to an embodiment the invention relates to the use of a positive pressure to produce a pressurized fluid intended to produce a lower body positive pressure to an individual having a cerebral vascular
deficiency to increase brain perfusion in this individual and improve the status thereof.
According to an other embodiment the invention relates to the use of a positive pressure to produce a pressurized fluid intended to produce a lower body positive pressure to an individual having ocular disorder to increase ocular vascular recruitment in this individual and improve the status thereof.
Other purposes, advantages and aspects of this invention will appear from the following description in relationship with the accompanying drawings and based on the treatment of several patients , given by way of examples.
IN THE DRAWINGS:
- figure 1 shows a first embodiment of the invention comprising a confined recipient containing a liquid, for instance water, said recipient being of a depth sufficient to enable immersing of an individual until substantially the diaphragm, to apply said Lower Body Positive Pressure (LBPP);
- figure 2 is a second embodiment of the invention wherein the positive pressure can be applied with a mechanical device comprising support stockings;
- figure 3 shows a third embodiment of the positive pressure applied by an apparatus comprising anti-gravitational trousers;
- figure 4 shows the results obtained with lower body positive pressure in a healthy volunteer, showing that LBPP application did not change any velocities measured in cerebral medial artery; and
- figure 5 shows the positive results obtained by lower body positive pressure in the middle cerebral artery of the brain.
- figures 6, 7, 8 and fig 9 show the positive results obtained by lower body positive pressure on ocular recruitment (ophthalmic arteries). In figures 6,7,8 and 9 it is agreed that for x-coordinate (PAG)
1- refers to Baseline 2- refers to After fluid loading
3- refers to 10 minutes after LBPP application
4- refers to 90 minutes after LBPP application
5- refers to 10 minutes after LBPP deflation.
EXAMPLE 1 of the invention
In figure 1, it is shown a very simple apparatus for the treatment of an individual having cerebral vascular deficiency and which comprises a confined recipient 10 filled with a liquid 12 such as water at a depth D, which is of about 1 m to 1.20 m and which, as well known to those skilled in the art, will provide a positive pressure at the lower body 14 of an individual or patient P, which is the highest around the feet and lower i at the level close to the surface S of the liquid, which should correspond essentially with diaphragm. The water is a very simple way to provide a pressure ranging between 10 and less than 20 mm mercury on the abdomen compartment and between 20 and 40 mm mercury on the lower limbs.
With such an apparatus comprising such a confined recipient 10 or equivalents with a free recipient, which can be an appropriate part of a swimming pool, it is very easy to perform the invention method as follows: The invention method for the treatment of an individual having a cerebral vascular deficiency, as herein previously described, comprises applying to the individual a lower body positive pressure efficient to increase brain perfusion here provided by the water pressure.
The patient P or individual having such a cerebral vascular deficiency can be immersed until the diaphragm to have the lower body part immersed till the diaphragm and this will usually be done twice a day minimally for a period of time ranging between 10 minutes and 2 hours. Another or further number of applications can be done in the same day without any side effect. The treatment, which such lower body positive pressure, can be performed day-to-day until clinical improvement, which is usually about one week of treatment.
With the invention, as previously said, all cerebral vascular deficiencies can be treated and efficiently improved. As above said, this comprises acute stroke and sub acute stroke; chronic vascular dementia and Alzheimer disease. It can also relate to a cerebral vascular deficiency without symptoms and in such a case, lower body positive pressure can be used as a proactive treatment to recruit vascular vessels.
EXAMPLE 2 of the invention
Invention apparatus with support stockings
As shown in figure 2, the invention positive pressure on the lower body can be provided by support stockings 110, born by the patient P. The support stockings 110 are those which can provide a lower body positive pressure ranging between 20 and 40 mm mercury at the level of the feet or lower limbs and in the range of 10 to less than 20 mm mercury on abdomen compartment. Such support stockings are available on the market. The treatment will be performed as set forth in example 1 in relationship with figure 1.
EXAMPLE 3 of the invention
Provision of lower body positive pressure with antiqravitational trousers
With this third embodiment, the positive pressure in the lower body is provided by using an apparatus comprising anti-gravitational trousers or garment 210, also named anti-G suit, like those available on the market manufactured by LIFE SUPPORT PRODUCTS INC, Saint Louis, Missouri,
USA, named trauma air pants shown in figure 3.
In this particular embodiment, the anti-gravitational trousers 210 comprise three independent bladders 212, 214, 216 connected to three pneumatic extremities 222, 224, 226 with manometers 232, 234, 236 providing instantaneous pressure values, inflated through inflating lines
242, 244, 246 by an inflating pump 240.
For performing the invention treatment of individual having a cerebral vascular deficiency, the anti-gravitational garment is applied from ankle to costal margin and the bladder pressures were set at 20 mm mercury Hg on lower limbs and 10 mm Hg on abdominal area to keep a positive pressure gradient.
The patients were lying on supine position. Before lower body positive pressure application, 500 ml of colloid was infused in 50 minutes to avoid any risk of hypovolemia in patients fasting and restricted in fluid intake.
Lower body positive pressure was applied for a period of time of 90-minute at each session. Four patients with symptomatic carotid occlusion have been tested with LBPP as provided by the anti-gravitational trousers device of this example. The impact of LBPP on cerebral perfusion has been assessed:
1) with continuous Doppler (4 MHz probe Multidopp T DWL, Germany) to measure and record systolic and diastolic velocities on common,
internal and external carotid arteries. A resistance Index (Systolic Velocity-Diastolic velocity/Systolic velocity) on common carotid arteries was computed by the machine.
2) with pulsed Doppler (2MHz probe Multidopp T DWL Germany) to measure and record systolic and diastolic velocities on middle cerebral arteries (at a constant depth of 53 mm)
3) with Perfusion-Weighted Imaging (PWI) using bolus tracking method: 3 or 4 regions of interest (ROI) have been mapped out in white matter of both hemisphere to measure relative cerebral blood volume (rCBV). The impact of LBPP on systemic circulation has been assessed by monitoring of arterial blood pressure (non-invasively) and heart rate.
All hemodynamic parameters have been collected at baseline, after fluid loading, 15 min after LBPP application, at the end of LBPP session (90 min) and finally 15 min after LBPP deflation. PWI has been performed in 2 out of said 4 patients before and within 3 hours after LBPP procedure.
Results obtained with LBPP application Controls:
In order to better interpret the effects observed in patients, we applied LBPP in a healthy volunteer. The important result was that LBPP application did not change any velocities measured in middle cerebral artery, (figure 4). The inventors concluded therefrom that modifications induced in patients resulted from the LBPP technical effect on the cerebral deficiency, here due to a stroke. 1. Treatment of 4 Patients:
Case n°l: a 28 year-old woman was hospitalized in our stroke unit 2hrs30 after a right facial and upper limb paralysis with aphasia related to a left fronto-parietal ischemic stroke. Initial NIH Stroke Scale (NIHSS) score was at 17, which a severe level. Intravenous recombinant tissue
plasminogen activator infusion (5.1 mg bolus and 17.1 mg over 20 minutes) was administrated 2h40 after the stroke onset. The magnetic resonance imaging (MRI) performed 24 hours after stroke onset showed a single infarct restricted to the sub cortical region of the left middle cerebral artery. The MRAngiograpy showed bilateral dissection of internal carotid artery with a severe intracranial hemodynamic impairment. The Doppler confirmed bilateral high resistance to flow on common carotid arteries and bilateral low flow on middle cerebral arteries (MCA). The LBPP procedure was performed 2 days after stroke onset, while NIHSS score was stable at 17. LBPP application was done only once during 120 minutes. During the procedure there was marked modifications of systolic and diastolic velocities of the left middle artery with a dramatic increase reaching more than 50% (figure 5). This improvement in the left MCA velocity was maintained during and after the LBPP session (until 48 hours), while blood pressure and heart rate remained stable.
The clinical evolution was characterized by an early clinical improvement: after 7 days she has completely recovered the right arm mobility and facial palsy while aphasia improved more slowly. On MRI performed 5 days after stroke onset, the volume of ischemic territory as well as the intensity of signal were reduced on diffusion weighted images (DWI) and flair T-2 weighted images. The MRA showed a reopened right internal carotid artery while the left one remained occluded and intracranial perfusion improved in both MCA territories.
After three weeks the patient left home with a NIHSS score at 2. The clinical evolution was considered as unexpected taking in account the severity of the initial ischemic lesion.
Case n°2: a 61 year-old man was hospitalized in our stroke unit after two reversible episodes of left monocular blindness associated with a right
distal upper limb weakness. The clinical examination showed a total paralysis of right hand . The DWI showed a distal field infarction between anterior and middle cerebral territories. The MRA showed an occlusion of left internal carotid and a poor collateral supply by anterior communicating artery and a apparent non functional posterior communicating artery.
Duplex scanning confirmed the occlusion at the origin of left carotid artery related to atherosclerosis responsible for an impaired blood flow in the left middle cerebral artery assessed by transcranial Doppler.
The LBPP was applied once during 90 minutes 2 days after stroke onset. During the LBPP procedure we observed an immediate improvement of the right hand mobility, which was sustained until discharge. The patient left hospital after one week with a complete recovery.
Case n°3: a 43 year-old woman was admitted in our stroke unit to explore a transient left hemiplegia lasting for 30 minutes. At the admission clinical examination was normal. The MPJ diffusion weighted images (DWI) showed a punctiform hypersignal in the right corona radiata. The MRAngiography showed an occlusion of the right internal carotid artery related to dissection.
The LBPP procedure has been performed once, one day after the transient ischemic attack (TIA) during 90 minutes. On the cerebral perfusion weighted images (PWI) performed after LBPP application, there was an average increase of rCBV in the right hemisphere reaching 44% compared to 22% in the left one.
Case n°4: a 46 years-old woman was hospitalized after the onset of a severe left hemiplegia and hypoesthesia related to right fronto-parietal ischemic stroke due to a right internal carotid artery dissection. The
worsening of the neurological status led to practice a decompressive craniectomy 48 hours after the stroke onset. After surgery the patient survived but remained completely hemiplegic with a minor hemisphere syndrome (NIHSS score 20). Immediately after the first LBPP procedure, she was able to move slightly the proximal part of the left lower limb. The PWIs performed before and after the first LBPP session showed a mean increase of 49% of blood volume in the right hemisphere compared to 21% in the left normal one. Therefore we decided to perform two additional LBPP procedures within one week. After the three sessions, she was able to maintain the left lower limb against gravity (NIHSS score 16).
2. Discussion
Thus, 4 individuals having symptomatic carotid occlusion were treated with the invention LBPP applied within 24 hours to 5 weeks after stroke onset.
The application of LBPP induces a significant increasing effect on brain perfusion by mobilization towards the upper part of the body of blood stocked in lower limb through venous and slight arterial compression. LBPP application results in:
1. a new repartition of blood volume that may recruit extra and intracranial collateral arteries leading to improvement of intracranial velocities as it was observed in case 1 namely a dramatic improvement of left MCA velocities during the procedure; 2. an increase in cerebral blood volume as illustrated by case 3 and 4 in which the relative cerebral blood volume, rCBV, recorded in both hemisphere reached 44% and 49% in the ischaemic one and 21% to 25% in the contralateral one. This increased rCBV was recorded immediately after the LBPP procedure in both cases. The increase of rCBV appears to
be related to vasodilatation or recruitment of non circulating vessels in the oligemic territories by a higher blood flow. In an other hand, the increase of cerebral blood volume may also result from a slight cerebral venous congestion. The increase in arterial blood input associated with a decreased venous drainage under LBPP is therefore to overwhelm the vascular resistances and result in small cerebral vessel opening and dilatation. This vessel recruitment may persist after anti-G suit removal. Once the vessels are opened, the vascular resistances lowered the perfusion is easily maintained.
EXAMPLE 4 of the invention
Application of lower body positive pressure on ocular circulation. Four patients have been submitted to lower body positive pressure according to the invention and as shown in figure 6, measures on ocular circulation have been recorded on ophthalmic arteries by continuous Doppler (4 Mz probe MultidoppT DWL,Germany)
After LBPP application , an increase of both systolic and diastolic velocities recorded on ophthalmic arteries is observed as shown in fig.6 for all patients
We conclude that LBPP is a non-pharmacological, and non-invasive method to increase CBV and provides to be a promising way to improve clinical outcome in cerebral vascular deficiencies such as acute cerebral ischemia and also ocular diseases such as anterior ischemic optic neuropathy, retinal artery occlusion or age related macular degeneration.
In view of the above, the application of the lower body positive pressure (LBPPP) comprises the following treatments, without limitation:
Improvement of cerebral vascular recruitment in different clinical situations
1-Acute phase of cerebral ischemia due to impairment of cerebral perfusion whatever the mechanism(s): -Ischemic stroke
-Vasospasm
2-Sub acute phase of cerebral ischemia due to a persistent impairment of cerebral perfusion to improve functional recovery
-Ischemic stroke 3-Chronic cerebral ischemia due to a chronic impairment of cerebral perfusion
-In Alzheimer disease: where the hypothesis of a primary vascular deficiency is still debated
-In vascular dementia 4- Improvement of ocular vascular recruitment in different clinical situations
-Acute phase of ischemia -anterior ischemic optic neuropathy (AION) -retinal artery occlusion -Chronic impairment of choroidal perfusion
-Age related macular degeneration (AMD).
5-Use of LBPP to help or increase the delivery of a therapeutic agent for cerebral vascular deficiency selected from a group comprising anticoagulant agents, fibrinolytics, antioxidants, NMDA receptor antagonists, free radical-trapping agents, calcium channel blocker, NO donors, gap junction channel blockers, anti-inflammatory agents such as corticoids, anti adhesion molecules, cytokines antagonists such as anti TNFα, compounds that prevent the activation of pro-
inflammatory transcription factors such as C/EBPβ, IRF-I and NF-κB, agonists of PPARα and PPARγ, growth factors such as NGF, BDNF, EGF, VEGF, an anti apoptotic factors, anticholinesterasic drugs and glutamate facilitator in hypoperf used body zones.
6- Use of LBPP help or increase the delivery of a therapeutic agent for ocular disorders selected from a group comprising antioxidants, anti-inflammatory agents, trophic factors, apoptosis inhibitors and statins in hypoperfused body zones.
Claims
1. A method for the treatment of an individual having a vascular deficiency in the upper part of the body comprising applying to the individual a lower body positive pressure efficient to increase upper part of the body perfusion.
2. The method of claim 1, comprising applying to this individual a lower body positive pressure efficient to increase brain perfusion.
3. The method of claim 1, comprising applying to this individual a lower body positive pressure efficient to increase ocular vascular recruitment.
4. The method of claims 1, 2 or 3, wherein the lower body positive pressure is ranging between 10 and 40 mm Hg.
5. The method of claim 4 , wherein the lower body positive pressure is ranging between 20 and 40 mm Hg on lower limbs and between 10 and less than 20 mm Hg on abdomen compartment.
6. The method of claims 1, 2 or 3, wherein the lower body positive pressure is applied for 10 minutes to 2 hours a day.
7. The method of claim 2, wherein the cerebral vascular deficiency is selected from the group consisting of acute stroke, sub acute stroke and cerebral vascular deficiency without symptoms.
8. The method of claim 2, wherein the cerebral vascular deficiency comprises chronic vascular dementia.
9. The method of claim 2, wherein the cerebral vascular deficiency comprises Alzheimer disease.
10. The method of claim 3 wherein ocular disorder is selected from the group consisting of anterior ischemic optic neuropathy, retinal artery occlusion.
11. The method of claim 3 wherein ocular disorder is selected from age related macular degeneration.
12. The method of claims 1,2 or 3, wherein the lower body positive pressure is externally applied by a fluid compression.
13. The method of claims 1,2 or 3, wherein the lower body positive pressure is externally applied by a mechanical compression.
14.The method of claim 13, wherein the lower body positive pressure is externally applied by liquid compression, with a confined or free recipient filed with said liquid and wherein the lower body part of the individual is immersed till substantially the diaphragm.
15. The method of claim 14, wherein the mechanical compression is generated by a specific mechanical device applied to the lower body part under the diaphragm to the feet.
16. The method of claim 17, wherein said specific mechanical device comprises support stockings.
17. The method of claim 17, wherein said mechanical device comprises anti-gravitational trousers.
18. Use of a therapeutic agent for the preparation of a composition intended to be administered to an individual having a vascular deficiency in the upper part of the body, wherein the delivery of the therapeutic agent to the upper part of the body is helped or increased by application of pressure to the lower part of the body.
19. The use of claim 18, wherein the composition is intended to be administered to an individual having a cerebral vascular deficiency, and the delivery of the therapeutic agent to the brain is helped or increased by application of pressure to the lower part of the body.
20. The use of acclaim 18, wherein the composition is intended to be administered to an individual having ocular disorder wherein the delivery of the therapeutic agent to the eye is helped or increased by application of pressure to the lower part of the body.
21. The use according to claim 19, wherein the therapeutic agent is selected from a group comprising anticoagulant agents, fibrinolytics, antioxidants, NMDA receptor antagonists, free radical- trapping agents, calcium channel blocker, NO donors, gap junction channel blockers, anti-inflammatory agents such as corticoids, anti adhesion molecules, cytokines antagonists such as anti TNFα, compounds that prevent the activation of proinflammatory transcription factors such as C/EBPβ, IRF-I and NF- KB, agonists of PPARα and PPARγ, growth factors such as NGF, BDNF, EGF, VEGF, an anti apoptotic factors, anticholinesterasic drugs and glutamate facilitator.
22. The use according to claim 20 wherein the therapeutic agent is selected from a group consisting of antioxidants, anti- inflammatory agents, trophic factors, apoptosis inhibitors and statins.
23.A therapeutic agent and a device generating positive pressure, as a product of combination to be applied to an individual having a vascular deficiency in the upper part of the body, wherein the delivery of the therapeutic agent to the upper part of the body is helped or increased by application of pressure to the lower part of the body.
24.The product of combination of claim 23, to be applied to an individual having a cerebral vascular deficiency, wherein the delivery of the therapeutic agent to the brain is helped or increased by application of pressure to the lower part of the body.
25. The product of combination of claim 24, to be applied to an individual having ocular disorder, wherein the delivery of the therapeutic agent to the eye is helped or increased by application of pressure to the lower part of the body.
26. The product of combination according to claim 24, wherein the therapeutic agent is selected from a group comprising anticoagulant agents, fibrinolytics, antioxidants, NMDA receptor antagonists, free radical-trapping agents, calcium channel blocker, NO donors, gap junction channel blockers, antiinflammatory agents such as corticoids, anti adhesion molecules, cytokines antagonists such as anti TNFα, compounds that prevent the activation of pro-inflammatory transcription factors such as C/EBPβ, IRF-I and NF-κB, agonists of PPARα and PPARγ, growth factors such as NGF, BDNF, EGF, VEGF, an anti apoptotic factors , anticholinesterasic drugs and glutamate facilitator.
27. The product of combination according to claim 25, wherein the therapeutic agent is selected from a group consisting of antioxidants, anti-inflammatory agents, trophic factors, apoptosis inhibitors and statins.
28. Use of a positive pressure to produce a pressurized fluid intended to produce a lower body positive pressure to an individual having a vascular deficiency on the upper part of the body to increase the perfusion of the upper part of the body in this individual .
29. The use of claim 28, wherein the individual has a cerebral vascular deficiency and the lower positive pressure is used to increase brain perfusion in this individual.
30. The use of claim 28, wherein the individual has ocular disorder and the lower positive pressure is used to increase ocular vascular recruitment in this individual .
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| US90352307P | 2007-02-27 | 2007-02-27 | |
| US60/903,523 | 2007-02-27 |
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| US12/954,564 Continuation US20110191417A1 (en) | 2008-07-04 | 2010-11-24 | Methods and systems for brands social networks (bsn) platform |
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| WO2008104861A1 true WO2008104861A1 (en) | 2008-09-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2008/000425 WO2008104861A1 (en) | 2007-02-27 | 2008-02-27 | Method for the treatment of an individual having a vascular deficiency in the upper part of the body especially a cerebral vascular deficiency or an ocular vascular disorder |
Country Status (1)
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| WO (1) | WO2008104861A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2311428A1 (en) * | 2009-10-13 | 2011-04-20 | Mego Afek Ac Ltd. | Compression bag |
| CN103908023A (en) * | 2014-04-03 | 2014-07-09 | 宁波江北怡和工业设计有限公司 | Cycling trousers with massage function |
| US10208049B2 (en) | 2009-12-08 | 2019-02-19 | Case Western Reserve University | Compounds and methods of treating ocular disorders |
| WO2019229160A1 (en) | 2018-05-31 | 2019-12-05 | Neuraltide | Pressure application garment |
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| WO2004112796A1 (en) * | 2003-06-20 | 2004-12-29 | Alcon, Inc. | Treatment of amd with combination of ingredients |
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| DE4022010A1 (en) * | 1989-07-15 | 1991-01-17 | Boehringer Ingelheim Int | Anticoagulant compsn. for treatment and prophylaxis of thrombosis - contains vascular anti-coagulant protein (annexine) and divalent salt of calcium, cadmium, zinc, manganese or cobalt |
| WO2004112796A1 (en) * | 2003-06-20 | 2004-12-29 | Alcon, Inc. | Treatment of amd with combination of ingredients |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2311428A1 (en) * | 2009-10-13 | 2011-04-20 | Mego Afek Ac Ltd. | Compression bag |
| US8622943B2 (en) | 2009-10-13 | 2014-01-07 | Mego Afek Ac Ltd. | Compression bag |
| US10208049B2 (en) | 2009-12-08 | 2019-02-19 | Case Western Reserve University | Compounds and methods of treating ocular disorders |
| CN103908023A (en) * | 2014-04-03 | 2014-07-09 | 宁波江北怡和工业设计有限公司 | Cycling trousers with massage function |
| CN103908023B (en) * | 2014-04-03 | 2015-04-08 | 宁波江北怡和工业设计有限公司 | Cycling trousers with massage function |
| WO2019229160A1 (en) | 2018-05-31 | 2019-12-05 | Neuraltide | Pressure application garment |
| CN112533572A (en) * | 2018-05-31 | 2021-03-19 | 诺伊拉尔泰德公司 | Pressure garment |
| JP2021533947A (en) * | 2018-05-31 | 2021-12-09 | ニューラルタイド | Compression clothing |
| JP7462617B2 (en) | 2018-05-31 | 2024-04-05 | ニューラルタイド | Compression garments |
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