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Title:  Method for treating mammals with modified mammalian blood
United States Patent: 
6,986,888
Issued: 
January 17, 2006
Inventors: 
Bolton; Anthony E. (Ontario, CA)
Assignee:
 Vasogen Ireland Limited (IE)
Appl. No.: 
564583
Filed: 
May 5, 2000


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

An improved method for treating or preventing a pathological condition in a mammalian subject in which modified mammalian blood is administered to the subject. The method comprises administering to the subject from two to four aliquots of modified mammalian blood, with the administration of any pair of consecutive treatments either being on consecutive days or being separated by a rest period of l to 21 days. The treatment is useful for treating or preventing a wide range of pathological conditions in which modified mammalian blood is effective, including preconditioning a mammalian subject to better withstand the adverse effects of ischemic stress, atherosclerosis and rheumatoid arthritis.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

According to a preferred process of the present invention, an aliquot of blood is extracted from a mammalian subject, preferably a human, and the aliquot of blood is treated ex vivo with certain stressors, described in more detail below. The teens "aliquot", "aliquot of blood" or similar terms used herein include whole blood, separated cellular fractions of the blood including platelets, separated non-cellular fractions of the blood including plasma, plasma components, and combinations thereof. The effect of the stressors is to modify the blood, and/or the cellular or non-cellular fractions thereof, contained in the aliquot. The modified aliquot is then re-introduced into the subject's body by any suitable method, most preferably intramuscular injection, but also including subcutaneous injection, intraperitoneal injection, intra-arterial injection, intravenous injection and oral, nasal or rectal administration.

The stressors to which the aliquot of blood is subjected ex vivo according to the method of the present invention are selected from temperature stress (blood temperature above or below body temperature), an oxidative environment and an electromagnetic emission, individually or in any combination, simultaneously or sequentially. Suitably, in human patients, the aliquot has a sufficient volume that, when re-introduced into the patient's body, has the desired effect.

Preferably, the volume of the aliquot is up to about 400 ml, preferably from about 0.1 to above 100 ml, more preferably from about 5 to about 15 ml, even more preferably from about 3 to about 12 ml, and most preferably about 10 ml.

It is preferred, according to the invention, to apply all three of the aforementioned stressors simultaneously to the aliquot under treatment, in order to ensure the appropriate modification to the blood. It may also be preferred in some embodiments of the invention to apply any two of the above stressors, for example to apply temperature stress and oxidative stress, temperature stress and an electromagnetic emission, or an electromagnetic emission and oxidative stress. Care must betaken to utilize an appropriate level of the stressors to thereby effectively modify the blood to achieve the desired effect.

The temperature stressor warms the aliquot being treated to a temperature above normal body temperature or cools the aliquot below normal body temperature. The temperature is selected so that the temperature stressor does not cause excessive hemolysis in the blood contained in the aliquot and so that, when the treated aliquot is injected into a subject, the desired effect will be achieved. Preferably, the temperature stressor is applied so that the temperature of all or a part of the aliquot is up to about 55 C., and more preferably in the range of from about -5 C. to about 55 C.

In some preferred embodiments of the invention, the temperature of the aliquot is raised above normal body temperature, such that the mean temperature of the aliquot does not exceed a temperature of about 55 C., more preferably from about 40 C. to about 50 C., even more preferably from about 40 C. to about WC, and most preferably about 42.5 C.

In other preferred embodiments, the aliquot is cooled below normal body temperature such that the mean temperature of the aliquot is within the range of front about -5 C. to about 36.5 C., even more preferably from about 10 C. to about 30 C., and even more preferably from about 15 C. to about 25 C.

The oxidative environment stressor can be the application to the aliquot of solid, liquid or gaseous oxidizing agents. Preferably, it involves exposing the aliquot to a mixture of medical grade oxygen and ozone gas, most preferably by bubbling through the aliquot, at the aforementioned temperature range, a stream of medical grade oxygen gas having ozone as a minor component therein. The ozone content of the gas stream and the flow rate of the gas stream are preferably selected such that the amount of ozone introduced to the blood aliquot, either on its own or in combination with other stressors, does not give rise to excessive levels of cell damage such that the treatment is rendered ineffective Suitably, the gas stream has an ozone content of up to about 300 μg/ml, preferably up to about 100 μg/ml, more preferably about 30 μg/ml even more preferably up to about 20 μg/ml, particularly preferably from about 10 μg/ml to about 20 μg/ml, and most preferably about 14.51.0 μg/ml. The gas stream is suitably supplied to the aliquot at a rate of up to about 2.0 liters/min, preferably up to about 0.5 liters/min, more preferably up to about 0.4 liters/min, even more preferably up to about 0.33 liters/min, and most preferably about 0.240.024 liters/min. The lower limit of the flow rate of the gas stream is preferably not tower than 0.01 liters/min more preferably not lower than 0.1 liters/min, and even more preferably not lower than 0.2 liters/min.

The electromagnetic emission stressor is suitably applied by irradiating the aliquot under treatment from a source of an electromagnetic emission while the aliquot is maintained at the aforementioned temperature and/or while the oxygen/ozone gaseous mixture is being bubbled through the aliquot. Preferred electromagnetic emissions are selected from photonic radiation, more preferably ultraviolet (UV), , visible and infrared light, and even more preferably UV light. The most preferred sources of U V light are UV lamps emitting primarily UV-C band wavelengths, i.e. wavelengths shorter than about 280 nm. Such lamps may also emit amounts of visible and infrared light. Sources of W light corresponding to standard UV-A (wavelengths from about 315 to about 400 nm) and U V-B (wavelengths from about 280 to about 315) can also be used. For example, an appropriate dosage of such UV light, applied simultaneously with one or both of the aforementioned temperature and oxidative environment stressors, can be obtained from up to eight lamps arranged to surround the sample container holding the aliquot, operated at an intensity to deliver a total UV light energy at the surface of the blood of from about 0.025to about 10 joules/cm2, preferably from about 0.1to about 3.0 joules/cm2. Preferably, four such lamps are used.

The time for which the aliquot is subjected to the stressors is normally within the time range of up to about 60 minutes. The time depends to some extent upon the chosen intensity of the electromagnetic emission, the temperature, the concentration of the oxidizing agent and the rate at which it is supplied to the aliquot. Some experimentation to establish optimum times may be necessary on the part of the operator, once the other stressor levels have been set. Under most stressor conditions, preferred times will he in the approximate range of from about 2 to about 5 minutes, more preferably about 3 minutes. The starting blood temperature, and the rate at which it can be warmed or cooled to a predetermined temperature, tends to vary .from subject to subject. Such a treatment provides a modified blood aliquot which is ready for injection into the subject.

In one preferred embodiment of the present invention, the aliquot of blood is stressed by being simultaneously subjected to all three of the above stressors using an apparatus of the type described in aforementioned U.S. Pat. No. 4,969,483, issued on Nov. 6, 1990 to Mueller. The aliquot is placed in a suitable, sterile, UV light-transmissive container, which is fitted into the machine. The UV lamps are switched on for a fixed period before the gas flow is applied to the aliquot providing the, oxidative stress, to allow the output of the UV lamps to stabilize. The UV lamps are typically on while the temperature of the aliquot is adjusted to the predetermined value, e.g. 42.51 C. Then the oxygen ozone gas mixture, of known composition and controlled flow rate, is applied to the aliquot, for the predetermined duration of up to about 60 minutes, preferably to 5minutes and most preferably about 3 minutes as discussed above, so that the aliquot experiences all three stressors simultaneously. In this way, blood is appropriately modified according to the present invention to achieve the desired effects.

In the preferred method of the invention, each course of treatment comprises the administration to a mammalian subject of from two to four aliquots of mammalian blood which has been modified as discussed above.

For optimum effectiveness of the treatment, it is preferred that no more than one aliquot of modified blood be administered to the subject per day. In some preferred embodiments of the invention, at least one rest period is provided during the course of treatment. As used herein, the term "rest period" is defined as the number of days between consecutive aliquots on which no aliquots of modified blood are administered to the subject. The maximum rest period between any two consecutive aliquots during the course of treatment is preferably no greater than about 21 days, and is more preferably from about 3 to about 15 days. .

In some preferred embodiments, aliquots of modified blood are administered to the subject on consecutive days, i.e. without an intervening rest period. Some preferred embodiments of the invention (comprising administration of 3 or 4 aliquots) include administration of a pair of aliquots on consecutive days and also provide for a rest period between a pair of consecutive aliquots.

More preferably, a course of treatment comprises administration of two or three aliquots to the subject, the course of treatment optionally including at least one rest period, with the longer (in the case of three aliquots) or the only (in the case of two aliquots) rest period between consecutively administered aliquots being from about 5 to 15 days.

Where the course of treatment comprises the administration of two aliquots to the subject, it is most preferred that the aliquots be administered on consecutive days without an intervening rest period.

Where the course of treatment comprises the administration of three aliquots to the subject, it may be preferred to provide two rest periods, including a longer rest period having a length of 9 to 13 days, more preferably about 10 to 12 days, and most preferably about 11 days; and a shorter rest period of 1 to 3 days.

However, where the course of treatment comprises three injections, it is most preferred to administer two of the three aliquots on consecutive days, and also to provide a rest period between two aliquots having a length of 9 to 13 days, more preferably about 10 to 12 days, and most preferably about 11 days. 1n a particularly preferred example, the first and second aliquots are administered on consecutive days without an intervening rest period, and the second and third aliquots are separated by a rest period of 11 days.

Although it may be sufficient to administer only one course of treatment as described above to the subject, it may be preferred in some circumstances to administer two or more courses of treatment, or to follow the above-described course of treatment by periodic "booster" treatments, if necessary, to maintain the desired effects of the present invention. In particular, it may be preferred to administer booster treatments or to administer a second course of treatments to the subject following a time period of several weeks or months. For example, it may be preferred to provide a tune period of from about 1 to about 4 months between consecutive courses of treatment, with 6 weeks being particularly preferred in some embodiments of the invention.

In one preferred embodiment, it is preferred to administer a fast course of therapy comprising three injections, with the first and second aliquots being administered on consecutive. days without an intervening rest period, and the second and third aliquots are separated by a rest period of 11 days. Following a period of six weeks from the end of the first course of therapy, an identical second course of therapy is administered to the subject.

 

Claim 1 of 6 Claims

1. A method for inhibiting injury arising from atherosclerosis or ischemia in a mammalian subject which method comprises:

identifying a mammalian subject at risk of injury from atherosclerosis or ischemia;

administering to said subject three aliquots of modified mammalian blood according to the following regimen:

a) two aliquots of modified mammalian blood in a volume of about 0.1 ml to 100 ml on consecutive days; and

b) a third aliquot of modified mammalian blood in a volume of 0.1 ml to 100 ml, after a rest period of 11 days after administration of the second aliquot,

wherein said blood is modified extracorporeally by exposure for a period of from about 2 to 5 minutes to a combination of stressors selected from the group consisting of a concentration of ozone from about 10 to 20 μg/ml, UV light at a dosage of from about 0.1 to about 3 Joules/cm2; and a temperature from about 0 to about 50 C.
 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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