Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-05-12
2003-05-20
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S401000
Reexamination Certificate
active
06565887
ABSTRACT:
The present invention relates to a method for treating a patient using targeted hysteresis therapy. In particular, it relates to a method of treating patients using site directed hysteresis heat loss.
Diseases of the human body such as malignant tumours are generally treated by excision, chemotherapy, radiotherapy or a combination of these approaches. Each of these is subject to limitations which effects clinical utility. Excision may not be appropriate where the disease presents as a diffuse mass or is in a surgically inoperable locality. Chemotherapeutic agents are generally non-specific, thus resulting in the death of normal and diseased cells. As chemotherapy, radiotherapy is also nonspecific and results in the death of normal tissues exposed to ionising radiation. Furthermore, some diseases such as tumours may be relatively resistant to ionizing radiation. This is a particular problem with the core of a tumour mass.
Hyperthermia has been proposed as a cancer treatment. There is a great deal of published evidence to confirm that hyperthermia is effective in treating diseases like cancerous growths. The therapeutic benefit of hyperthermia therapy is mediated through two principal mechanisms: (1) a directly tumouricidal effect on tissue by raising temperatures to greater than 42° C. resulting in irreversible damage to cancer cells; and (2) hyperthermia is known to sensitise cancer cells to the effects of radiation therapy and to certain chemotherapeutic drugs. The lack of any cumulative toxicity associated with hyperthermia therapy, in contrast to radiotherapy or chemotherapy, is further justification for seeking to develop improved systems for hyperthermia therapy.
Mammalian cells sustain hyperthermic damage in a time/temperature and cell-cycle dependant manner. This cellular response to heat is in turn modified by a variety of intra- and extra-cellular environmental factors. The intra-cellular factors that influence hyperthermic cell damage include intrinsic variation between different species, organs and even cell lines. The extra-cellular factors include the oxygen and nutritional status of cells, the pH of the extra-cellular mileiu, the absolute temperature rise and the hyperthermic duration.
Although there is some evidence that neoplastic cells are more sensitive than their normal tissue counterparts to the effects of hyperthermia, this is not a universal finding and several recent studies have demonstrated that tissue susceptibility to hyperthermic damage is not strongly linked to a cell's neoplastic-normal status.
A number of studies have confirmed that hyperthermia and radiotherapy are synergistic. Even small fractions of a degree of temperature variation can significantly alter the prospects of cells surviving a radiation insult.
Factors affecting the synergistic action of hyperthermia and radiotherapy include the degree of duration of hyperthermia, the sequence of hyperthermia and radiotherapy, the fractionated and total dose of radiation, the pH of the extra-cellular milieu, the oxic state and nutrient status of cells and the histological type and malignant status of the cells.
Cells in the central avascular compartment of tumours are invariably acidotic hypoxic and in a state of nutritional deprivation. All these factors appear to potentiate independently the effect of hyperthermia. By the same token, severely hypoxic cells are approximately, three times more resistant to ionising radiation than oxic cells. Of major importance is the fact that although these hypoxic cells might survive the effects of radiation, hyperthermia can partly overcome this radioresistance and can potentiate radiotherapeutic killing of acidotic and hypoxic cells.
There are many problems associated with the currently available methods for inducing clinical hyperthermia in patients. Normal body tissues and organs are heat sensitive and at temperatures of greater than 42° C. many tissues will undergo irreversible damage. The current available methods of delivering clinical hyperthermia are non-specific and will heat normal tissues as well as tumour cells. Almost all heating techniques create heat generation over a broad target area with little specificity for diseased tissue, although focussing devices for both ultrasound and electromagnetic heat generation are now being developed to improve the concentration of heat generation in more defined target areas.
Several techniques are currently available for inducing clinical hyperthermia either regionally, in selected local regions of specific organs or over the whole body. Some of these techniques are discussed below.
Whole body hyperthermia may be induced by endogenous or exogenous heat sources, but is generally not tolerated above 42° C. without anaesthesia. Regional hyperthermic techniques include organ perfusion, various forms of electromagnetic radiation, or ultrasound.
Plain wave electromagnetic or ultrasound heating is limited by poor tissue penetration and a rapid decline of energy with increasing depth.
Ultrasound at frequencies of from 0.3 to 3 MHz is limited by the perturbations induced by tissue interfaces such as air, bone etc. However, improved focussing devices are being developed that may make this a more acceptable form of heating for deep tissues.
Microwave heating at frequencies between 434 and 2450 MHz has been used, although there is generally poor tissue penetration. Phase array devices are able to focus microwave energy in deep tissues, but variation in the heating effect remains a problem.
Radiofrequency waves at frequencies up to 434 MHz have been used with some success. These heating techniques include both dielectric and inductive modalities and can result in relatively even tissue heating. However, focussing for deep organ heating using inductive current remains a problem.
There are two basic requirements for such therapies to be effective. First, there is a need to localise the treatment to the target site. Second, there is a need to maximise heating within the diseased tissue while maintaining hyperthermia therapy within safe operating limits for the patient.
While considerable success has been observed in treating superficial tumours using hyperthermia therapy, there remains a need for a method of selectively targeting and treating diseased tissue in a patient. Major limitations due to insufficient penetration depth and poor focussing capabilities of externally applied microwave or ultrasound beams have grossly restricted a physicians ability to deliver an adequate heat load to deep seeded diseased without any unacceptable level of coincident damage to surrounding healthy tissue. The present invention seeks to ameliorate at least the problems associated with penetration depth and inadequate localisation of heat when using hyperthermia therapy.
SUMMARY OF THE INVENTION
The present invention provides an improved method for site specific treatment of diseased tissue in a patient, which comprises the steps of:
(i) selecting at least a magnetic material which has a magnetic heating efficiency of at least about 4.5×10
−8
J.m./A.g, when magnetic field conditions are equal to or less than about 7.5×10
7
A/s;
(ii) delivering the magnetic material to diseased tissue in a patient; and
(iii) exposing the magnetic material in the patient to a linear alternating magnetic field with a frequency of greater than about 10 kHz and a field strength such that the product of field strength, frequency and the radius of the exposed region is less than about 7.5×10
7
A/s to generate hysteresis heat in the diseased tissue.
Preferably, steps (i) to (iii) in the method are repeated until the diseased tissue has been destroyed or treated sufficiently to ameliorate the disease.
The magnetic material employed in the method of the invention must have a magnetic heating efficiency (MHE) of greater than about 4.5×10
−8
J.m./A.g, when magnetic field conditions are equal to or less than about 7.5×10
7
A/s. Preferably, a magnetic material is selected which has a MHE of greater than about 7×1
Gray Bruce Nathaniel
Jones Stephen Keith
Dees Jose′ G.
George Konata M.
Merchant & Gould P.C.
Sirtex Medical Limited
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