WO2000056261A1 - Methods of treating fibrinogen-related disorders - Google Patents

Abstract

Methods for using intermittent compression devices to enhance organ and/or tissue perfusion (i.e., blood flow or circulation into organs and/or tissues) by breaking down or treating the adverse effects of fibrinogen production throughout the body, especially excess amounts of fibrinogen. Also, methods for inducing or enhancing fibrinolysis using intermittent compression devices.

Description

METHODS OF TREATING FIBRINO GEN-RELATED DISORDERS

This application claims priority to U.S. Application No. 09/272,854, filed March 19, 1999, the entirety of which is incorporated by reference herein.

FIELD OF THE INVENTION The invention relates to methods of enhancing organ and/or tissue perfusion with blood, and treating the adverse effects of fibrinogen production throughout the body through the use of an intermittent compression device.

BACKGROUND OF THE INVENTION Various patents and scientific publications are referred to throughout the specification to describe the state of the art to which the invention pertains. Each of these patents or publications is incorporated by reference herein, in its entirety.

Circulating blood maintains the needs of cells that comprise the basic structure of all tissues and organs. Cells require the delivery of oxygen, nutrients, hormones, defense cells and chemicals which are exchanged for carbon dioxide, endogenous metabolic by-products and exogenous toxic substances for degradation and excretion through mechanisms in the lungs, kidneys, liver, intestine and skin, in order to preserve normal organ and tissue function. The entire burden of this exchange resides on a microcirculatory system of capillaries and sinusoids which sense the specific needs of each organ or region of the body when adequate cardiac function and unobstructed arteries and veins are present.

Diminished organ and/or tissue perfusion with circulating blood can cause many diseases, disorders and conditions such as angina, asthma, atherosclerosis, Acquired immune Deficiency Syndrome (ALDS), cancer metastases, chronic fatigue, hypertension, etc. Many of these diseases, disorders and conditions have been linked to fibrinogen. Fibrinogen plays a major role in circulating blood because of its effects on blood viscosity. Fibrinogen is a globulin of blood plasma that is converted into an elastic filamentous protein called fibrin by the action of ionized calcium to produce coagulation of blood which is beneficial in controlling bleeding. Unfortunately, fibrinogen car adversely affect the body when excess amounts are produced therein. This condition is known as hyperfibrinogenemia. Hyperfibrinogenemia often leads to another condition called hyperviscosity, which is an abnormality of the blood involving thickening and/or reversible aggregation (clumping) of blood cells. Hyperviscosity can impede the flow of blood through the capillaries resulting in diminished organ and/or tissue perfusion with circulating blood which eventually causes organ and/or tissue dysfunction. Factors that cause hyperfibrinogenemia include among others, inactivity, the bedridden state, increasing age, diabetes mellitus, genetic influences, dyslipidemias, hypertension, low socio- economic strata, menopause, obesity, oral contraceptives, smoking, and stress. Fibrinolysis is a process where fibrinogen and its derivatives are broken down into molecules in hyperviscosity that obviate the harmful effects of fibrinogen. Endogenous fibrinolysis is a process in which some individuals are protected from the adverse excessive amounts of circulating fibrinogen by the presence of natural fibrinolytic chemicals such as plasminogen and its activators that are homoeostatically released into the circulation. Exogenous induced fibrinolysis is a process induced by artificial means (such as pharmacological) as opposed to natural (created in the body) means. This is achieved by reducing hyperfibrinogenemia and therefore leading to reductions in hyperviscosity. This, in turn, results in enhanced organ or tissue perfusion. Present methods for reducing hyperfibrinogenemia involve invasive pharmacologic fibrinolytic therapy. Regrettably, costly treatment, adverse drug effects, non-compliant patients, lifelong therapies and co-morbidities among other factors, attest to the need for safer non-invasive, non-pharmacologic fibrinolytic therapies.

The cause of increased systemic vascular resistance (SVR), and thus, primary hypertension (PH) is unknown. Consequently, treatments to reduce pressure, not target the underlying cause, can be ineffective. Paradoxically, lethalities of PH are ischemic (i.e., resulting from diminished organ perfusion), not hemodynamic, and thus these lethalities account for poor therapeutic outcomes. "Ischemic" concerns diminished microcirculatory blood flow, while "hemodynamic" indicates macrocirculatory hypertension. Most emphasis is directed at the vessel wall as the factor that controls systemic vascular resistance (SVR), but intraluminal vascular occlusion by changes in circulating blood has not been adequately entertained. This is because viscosity, the fluid property that controls blood flow in the capillaries and sinusoids, is seldom or never assessed. This assumes importance because changes in viscosity due to excessive fibrinogen are significantly amplified in patients with hypertension compared with normotensive patients.

A non-invasive, non-pharmacologic method is currently being used for treating blood clots in the legs. Hills et al, Br. Med. J., 131-135 (1972); Salzman et al, Ann. Surg., 636-641 (1987). This method employs an intermittent pneumatic compression device (ICD) having a pair of pneumatic sleeves that slip over the calves of a patient's leg. See U.S. Patent No.5,025, 781 to Ferrari. The pneumatic sleeves intermittently compress and decompress the patient's calves resulting in complete venous clearance by both physical and chemical mechanisms. Examples of ICDs are described in U.S. Patent Nos. 3,391,692; 3,865,103 to Fulman; 3,880,149 to Kawaguchi et al; 3,901,221 to Nicholson et al; 4,091,804 to Hasty et al; 4,156,425 to Arkans et al; 4,370,975 to Wright; 4,374,518 to Villanueva; 4,375,217 to Arkans et al; 5,014,681 to Neeman et al; 5,025,781 to Ferrari; and 5,989,204 to Lina. The content of these, and other references cited herein, are incorporated herein by reference.

Up until now, ICDs have not been prescribed by licensed physicians for the treatment of disorders, diseases and conditions which result from diminished or inadequate organ and/or tissue perfusion with blood.

It is thus desirable to provide a non-invasive, non-pharmacologic method for inhibiting or couriering the activity or effects of excessive amounts of fibrinogen circulating throughout the body, and thus cause conditions which lead to diminished organ and/or tissue perfusion. SUMMARY OF THE INVENTION

The invention involves the new use of an existing device. It has been found that intermittent compression devices (ICDs) can be used to enhance organ and/or tissue perfusion (i.e., blood flow or circulation into organs and/or tissues) by breaking down or treating the adverse effects of fibrinogen production throughout the body, especially excess amounts of fibrinogen. Also, methods for inducing or enhancing fibrinolysis using ICDs have been documented in clinical studies in several individuals. Many of these have used them for eighteen months and over.

Excess fibrinogen has been implicated in a variety of diseases. The invention thus relates to the use of ICDs in treating the adverse effects of fibrinogen circulating throughout the entire body from its site of production which is mostly in the liver, and leading to poor blood transport to critical areas. This includes but is not limited to cardiovascular diseases, cancer and AIDS. Specifically, these diseases and disorders include angina, asthma, atrial fibrillation, atherosicerotic plaques, atherosclerosis, AIDS, Human Immunodeficiency Virus (HIV, and other viral infections), cancer metastases, intermittent claudication, depressioi eclampsia, chronic fatigue, fibremia (excessive fibrinogen in the blood), hypertension, insomnia, mood disorders, menopausal syndrome, multisystem failure, osteoporosis, ischemic strokes, and correction of abnormal blood lipids, diabetes (Types I and 2), shock (endotoxic, cardiogenic, hypovolemic, neurogenic) traumatic states, hyperthemia, and hypothermia.

The advantages, nature, and various additional features of the invention will appear more fully upon consideration of the illustrative embodiments now to be described in detail in connection with the accompanying drawings.

BRIEF' DESCRIPTION OF THE DRAWINGS

FIGURE 1 is a perspective view depicting the use of an ICD in treating a patient with diminished organ and/or tissue perfusion.

FIGURE 2 is a graph showing the vasotension (both systolic and diastolic) measurements (both before and after treatment with the ICD) for the participants in the clinical trial described in Example 14. It is to be understood that this drawing is for purposes of illustrating the concepts of the invention and, except for graphical illustrations, are not to scale.

DETAILED DESCRIPTION OF THE INVENTION It has now been found that ICDs are effective in treating disorders: diseases and conditions which result from diminished or inadequate organ and/or tissue perfusion. For example, ICDs are effective in treating cardiovascular diseases, cancer and AIDS.

More specifically, the diseases, disorders, and conditions which can be treated or prevented by the invention include but are not limited to angina, as among, atrial fibrillation, atherosclerotic plaques, atherosclerosis, AIDS, other viral infections, cancer metastases, intermittent claudication, depression, eclampsia, chronic fatigue, fitrentia (excessive fibrinogen in the blood), hypertension, insomnia, mood disorders, menopausal syndrome, multisystem failure, osteoporosis, ischemic strokes, correction of abnormal blood lipids, endometriosis, and different stages of shock.

Of special note is the invention's use in treating cancer metastases and AIDS. In treating cancer metastases, it is known that cancer cells use fibrinogen to metastasize. It is believed that excess fibrinogen in the body can accelerate this process. Because the invention induces fibrinolysis, reductions in fibrinogen can be realized. This reduction in fibrinogen aids in slowing or preventing cancer metastases.

Regarding the treatment of AIDS, it has been found that the severity of this disease is connected with significant microcirculatory disturbances attributable to excessive circulating fibrinogen. Consequently, treatment should be directed toward improving microcirculatory perfusion [Xiu et al. , Microvascular Research, 42, 151- 159 (1991)]. The invention is therefore useful in the treatment of AIDS as it enhances microcirculatory perfusion by dissolution of fibrinogen.

Many commercially available ICDs can be used in accordance with the invention. A preferred ICD is VENODYNE® produced by Microtek Medical, Inc., Columbus, MS. FIGURE 1 shows an ICD 10 similar to the VENODYNE® applied to the limbs of a patient. The ICD 10 comprises two sleeves 12 and 14 (indicating length in inches). Each contains a compartment (not visible) for insufflation and exsuffiation of air. The sleeves 12 and 14 slide easily over the patient's legs and automatically conform to the leg size. The sizes of the sleeves 12 and 14 can be dimensionally adapted for limbs of all lengths and diameters including infants, children and adults. An electrical air pump 16 is coupled to each of the sleeves 12 and 14 by a y-shaped pressure tubing 18, and alternately inflates and then deflates each sleeve. The electrical air pump 16 may optionally contain a pressure gauge for monitoring pressure. Each cycle of inflation and deflation (intermittent compression cycle) typically has a duration of about 60 seconds. During this cycle, the sleeve is inflated via the pump for about 12 seconds with calf pressure typically regulated to between about 35 and 45 mm Hg. This pressure is evenly distributed by the sleeve which circumferentially compresses the entire calf. The maximum pressure reached is clearly below the normal range of diastolic pressure above when arterial blood supply to the limb can be jeopardized. The sleeve is then deflated by the pump for about 48 seconds of the cycle. The ICD is typically and conveniently used for one hour a day, at any desired time. When used for longer periods of time (even while asleep) the ICD imparts no adverse side effects.

The exogenously induced muscular compression provided by the ICD requires no expenditure of oxygen or exertional activity on the part of the patient. Methods to compress the muscle during exertion, such as in exercising, can lead to anaerobic

(poor oxygen) breakdown of glucose (glycolysis) and accumulation of toxic products that can be fatal. Similar adverse results can occur when the compression vest encompasses the chest to restrict breathing. Moreover, because the ICD is non- invasive, the inherent risks associated with pharmacologic methods such as bleeding, errors in administration and drug interactions, are eliminated. Moreover, unlike pharmacologic methods, the present invention does not require follow-up laboratory work nor recurrent drug administration, so patient costs are measurably reduced. Although it is preferred that the ICD be applied to the patient's calves as described above, it is also possible to apply the ICD to the patient's thighs or arms. Moreover, although it is preferred that both sleeves of the ICD be used for intermittently compressing two of the patient's limbs, treatment can also be effectively made by applying just one sleeve of the ICD to one limb of a patient. Such a case may arise in the treatment of an amputee.

The invention is believed to be effective in treating the above disorders, diseases and conditions because it generates a fibrinolytic related mechanism. As discussed earlier, when aggregates of blood cells obstruct the microcirculatory blood flow, systemic vascular resistance (SVR) increases, thus causing the condition of hyperviscosity. Cleavage of fibrin by the venous compression induced by the ICD breaks up the cellular aggregates, restores capillary patency, corrects impeded blood flow, and negates SVR. All these changes are consequent to normalizing the viscosity of the blood.

The following examples will serve to further typify the nature of the invention but should not be construed as a limitation on the scope thereof, which is defined solely by the appended claims.

The outcomes following use of the ICD are best evaluated by one or more of the following criteria: (1) Improvements(s) in symptoms (e.g., angina, insomnia), (2) Normalization of findings on clinical examination (e.g., hypertension), (3) Correction of abnormal blood tests (e.g., dyslipidemia), (4) Dissolution of radiologically detected abnormalities (e.g., atherosclerotic plaques). In some of the examples, in order to clarify the severity of the problem rectified by the ICD, the rationale connecting benefits of the ICD with the specific pathophysiological process is briefly described.

In all of the examples below, the treatment was administered at least once daily for 60 minutes over a 12 to 18 month period.

Example 1 Hypertension

The pathogenesis of hypertension is unknown. Use of the ICD normalized blood pressure in all 38 patients with hypertension within one week. The ICD did not decrease the blood pressure in 47 normotensive individuals, thus avoiding a deleterious hypotensive (shock-like state). This finding established the cause of hypertension to be due to excessive fibrinogen Example 2

Angina

Angina involves chest pain and other acute coronary syndromes (ACS) that are casually related to hypoxemia of the heart are of great concern because there are other conditions with less threat to life and that may require other forms of diagnosis and therapy. Relief of chest pain and other forms of ACS shortly after use of the ICD in 8 patients with angina substantiate the role of excessive fibrinogen as a causal factor in these conditions.

Example 3 Insomnia

Insomnia is a worldwide problem frequently accompanied with comorbidities

(other diseases or adverse conditions). Concerns of inefficient work ability, productivity, absenteeism and medical and other expenses, it costs the national economy millions of dollars. Thirteen individuals using the ICD demonstrated greatly enhanced ability to sleep using the ICD.

Example 4

Fatigue

Fatigue is a frequent complaint of patients seeking medical attention in the primary care setting. It becomes chronic in one of four patients in this patient population. Also, it is a nonspecific symptom of many identifiable diseases such as diabetes (Types 1 and 2), hypertension, cancer, hepatitis, psychiatric and other miscellaneous disorders. In clinical trials, all 9 patients with a history of fatigue reported decreased fatigue by ICD usage.

Example 5 Intermittent Claudication

Intermittent claudication is disabling calf pain on walking relatively short distances. Mostly due to atherosclerosis, it is frequently associated with risk of myocardial infarction and strokes and is strongly related to smoking. All 15 patients with this problem recovered following ICD use. Example 6

Depression

Chronic depression often seen in patients with other medical entities, such as angina, has been difficult to treat. In clinical trials, all fifteen patients with depression reported relief of this complaint by using the ICD device and is thereby suggestive to be causally related to diminishing brain and organ perfusion.

Example7

Triglvceridemia

Triglyceridemia is an established cause of myocardial infarction and is believed to be related to increased lipid levels in the blood. The biochemical test, following use of the ICD to verify beneficial changes in blood fats, served as an example of laboratory testing as a criterion of assessing the utility of the ICD. All seven patients with this normality were benefited by ICD therapy.

Example 8 Menopausal Syndrome

Menopausal syndrome symptoms, consisting of hot flashes and other manifestations present in six patients during the change of life, were immediately relieved by the ICD. This group does not represent the common inconvenience felt by most individuals entering this phase in life but is comprised of the women in whom the severity of the symptoms is of sufficient gravity to seek pharmacologic treatment such as estrogens that can have serious side effects.

Example 9

Alopecia

Baldness (alopecia) was alleviated in all 4 patients suffering from this common disorder. The hair follicles of the scalp are particularly vulnerable to diminished blood perfusion because of the thickness of the skin of the scalp.

Example 10

Constipation

Constipation is a common inconvenience affecting society today. All four patients with this complaint relieved of this symptom were hypertensives who were receiving medications known to have this inconvenient side effect. Example 11

Chronic atrial fibrinogen (irregular heartbeats) of 20 years duration was converted to normal in a 76 year old male following use of the ICD. Example 12 Bipolar mood disorder (depression alternating with manic episodes of a suicidal nature) were improved in a 29 year old woman using the ICD. Example 13

A 56 year old male with an atherosclerotic plaque in the subclavian artery that supplies the upper limb had restoration of an absent pulse and blood. Pressure in that extremity after radiological imaging studies were confirmatory. Example 14

Since ICD causes fibrinolysis, hyperfibrinogenemia may be, in whole or part, the cause of both PH and its co-morbidities. Fibrinolytically reversible obstruction of the arteriolar-capillary junctions by microthrombi 1) increases SVR, adaptively causing compensatory PH proximal to the obstruction, and 2) compromises organ perfusion with resultant organ dysfunction distal to the obstruction. The clue that led to the clinical trial of this Example, and to the establishment of fibrinogen as the potential cause of increased SVR (and thus PH), was the chance observation that revealed normalization of PH (from 180/100 to 135/75) and relief of angina (an ischemic condition) immediately following use of intermittent pneumatic calf compression (ICD) in a 59 year old male. Our objective, therefore, was to verify this unexpected finding in prospective clinical trials. These trial results identified excessive fibrinogen effect as the potential cause of PH.

The methods were designed as a randomized trial, divided between population groups of 1) normotensives and hypertensives, and 2) homogenous, homogeneous Haitians and mixed ethnicities. To standardize ICD pressure and compression times within safe and effective ranges, the same federally approved ICD device was used. This also prevented excessive pressure and compression times that may cause peroneal nerve injury and lethal rhabdomyolysis of limb muscle and ischemic gangrene of the lower extremities. These may be likely to occur when sequentially combined calf and thigh compression devices are employed. Before and after ICD use, blood pressures were recorded serially. ICD applications were recommended for an hour every other day, continued 3 - 7 times weekly, ad infmitum. Just before tabulation of data, responses to a questionnaire pertaining to improvements in morbidities (if present) were obtained. To authenticate the long-term effects of ICD on blood pressure, the results (see

Figure 2) include subjects studied for up to 30 months, between May 1997 through November 1999. All except five hypertensives normalized their pressures. Four of these five took 25 - 50 mg niacin PO OD prescribed to relieve vasoconstriction and subsequently normalized their pressures. Comorbidities (angina, etc.) were alleviated in both hypertensives and normotensives. Remarkably, blood pressures in normotensives were not affected by ICD use. Normalization of blood pressures in hypertensives and alleviation of comorbidities such as angina, insomnia, claudication, etc. was realized within 24 hours to 1 week of initiation of ICD use in most subjects. The antihypertensive and organ perfusion capabilities of the ICD are evident from this trial. While the benefit of an ICD for deep vein thrombosis prophylaxis is believed to be the propulsive effect on venous blood flow, most physicians may not appreciate that calf compression results in fibrinolysis as well (Jacobs DE, Piotroski JJ, Hoppensteadt DA, et al. Hemodynamic and Fibrinolytic Consequences of Intermittent Pneumatic Compression: Preliminary Results. J. Trauma, 1996; 40:710- 717.). This finding affirms the presence of hyperfibrinogenemia pre-ICD use. This consequentially causes hyperviscosity. When aggregates of blood cells obstruct microcirculatory blood flow, SVR increases. Though partly hemodynamic, the role of the kidney in mediating this response must be entertained. Cleavage of fibrin by the fibrinolytic effects of venous compression induced by ICD breaks up the cellular aggregates, restores microvascular patency and blood flow, decreases SVR and normalizes blood pressure. This condition of the microcirculatory obstruction by circulating blood is called hyperviscosity, a property implying excessive resistance to flow largely by fibrinogen.

Hyperviscosity is a pathologic state that impedes blood flow in the microcirculation (as opposed to the macrocirculation) at the anatomic sites of capillaries and sinusoids. At these sites, life-sustaining oxygen, nutrients and defense mechanisms are delivered to cells in exchange for carbon dioxide, metabolic wastes, and toxins. SVR, the major factor causing PH, is believed to take place in the pre- capillary arterioles. Our investigation uniquely indicated obstruction of the capillaries with two different consequences. Immediately proximal to the block, SVR increases and blood pressure rises, indicating an adaptive (perhaps compensatory) response that opens "resting" microcirculatory vessels to reroute blood flow and obviate organ dysfunction. Distal to the block, capillary blood flow is impaired and organ perfusion compromised, the decrease in perfusion ultimately leads to organ dysfunction. These widely disparate consequences account for the priority of current paradoxical diagnostic and therapeutic approaches to the management of PH. However, as proven above, these disparate consequences can be addressed by the current invention.

The foregoing detailed description is given for clearness of understanding only, and that no unnecessary limitations should be understood therefrom. Hence, numerous modifications and changes can be made by those skilled in the art without departing from the spirit and scope of the invention as described in the attached claims.

Claims

What is claimed:

1. A method of enhancing organ perfusion in a patient, the method comprising the steps of applying an intermittent compression device to at least one limb of the patient; and operating the device for an effective period of time.

2. The method according to claim 1, wherein the device includes at least one sleeve for attachment to the limb of the patient and a pump for intermittently inflating and deflating the sleeve for the effective period of time, the sleeve being operative for circumferentially compressing the limb with an even distribution of pressure when inflated by the pump.

3. The method according to claim 1, or in the device intermittently compresses the limb of the patient for a predetermined number of seconds during the effective period of time and releases the compression for a predetermined number of seconds during the effective period of time.

4. A method of treating at least disease or disorder in a patient caused by diminished tissue or organ perfusion with blood, the method comprising the steps of applying an intermittent pneumatic compression device to at least one limb of the patient and operating the device for an effective period of time.

5. The method according to claim 4, wherein the diminished tissue or organ perfusion is cause by undesirable amounts of fibrinogen in the patient.

6. The method according to claim for, wherein the disease or disorder comprises cardiovascular diseases or cancer.

7. The method according to claim for wherein the disease or disorder caused by diminished tissue or organ perfusion with circulating blood is selected from the group consisting of angina, asthma, atrial fibrillation, atherosicerotic plaques, atherosclerosis, ADS, Human Immunodeficiency Virus, (HIV, and other viral infections), cancer metastases, intermittent claudication, depression, eclampsia, chronic fatigue, fibremia (excessive firbrinogen in the blood), hypertension, insomnia, mood disorders, menopausal syndrome, multisystem failure, osteoporosis, ischemic strokes, and correction of abnormal blood lipids, diabetes, shock (endotoxic, cardiogenic hypovolemic, neurogenic) traumatic states hyperthemia, and hypothermia.

8. The method according to claim 4, wherein the device includes at least one sleeve for attachment to the limb of the patient and a pump for inflating and deflating the sleeve, the sleeve being operative for circumferentially compressing the limb with an even distribution of pressure when inflated by the pump.

9. The method according to claim 4, wherein the device intermittently compresses the limb of the patient for a predetermined number of seconds during the effective period of time and releases the compression for a predetermined number of seconds during the effective period of time.

10. A non-pharmacological, non-invasive method of inducing or enhancing fibrinolysis in a patient, the method comprising the steps of applying an intermittent compression device to at least one limb of the patient; and operating the device for an effective period of time.

11. The method according to claim 10, wherein the device includes at least one sleeve for attachment to the limb of the patient and a pump for inflating and deflating the sleeve, the sleeve being operative for circumferentially compressing the limb with an even distribution of pressure when inflated by the pump.

12. The method according to claim 10, wherein the device intermittently compresses the limb of the patient for predetermined number of seconds during the effective period of time and releases the limb of the patient for a predetermined number of seconds during the effective period of time.

13. A method of normalizing pulmonary hypertension in a patient, the method comprising the steps of applying an intermittent compression device to at least one limb of the patient; and operating the device for an effective period of time.

14. The method according to claim 13, wherein the device includes at least one sleeve for attachment to the limb of the patient and a pump for inflating and deflating the sleeve, the sleeve being operative for circumferentially compressing the limb with an even distribution of pressure when inflated by the pump.

15. The method according to claim 13, wherein the device intermittently compresses the limb of the patient for a predetermined number of seconds during the effective period of time and releases the limb of the patient for a predetermined number of seconds during the effective period of time.