WO2004026097A2 - Traitement de steatose par hyperthermie - Google Patents

Traitement de steatose par hyperthermie Download PDF

Info

Publication number
WO2004026097A2
WO2004026097A2 PCT/US2003/028730 US0328730W WO2004026097A2 WO 2004026097 A2 WO2004026097 A2 WO 2004026097A2 US 0328730 W US0328730 W US 0328730W WO 2004026097 A2 WO2004026097 A2 WO 2004026097A2
Authority
WO
WIPO (PCT)
Prior art keywords
patient
raised
steatosis
core temperature
returned
Prior art date
Application number
PCT/US2003/028730
Other languages
English (en)
Other versions
WO2004026097A3 (fr
Inventor
Jan Van Hattum
Charles Mccartney
Marguerite Schipper
Original Assignee
First Circle Medical, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by First Circle Medical, Inc. filed Critical First Circle Medical, Inc.
Priority to AU2003270615A priority Critical patent/AU2003270615A1/en
Publication of WO2004026097A2 publication Critical patent/WO2004026097A2/fr
Publication of WO2004026097A3 publication Critical patent/WO2004026097A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/02—Compresses or poultices for effecting heating or cooling
    • A61F2007/0295—Compresses or poultices for effecting heating or cooling for heating or cooling or use at more than one temperature
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • A61F2007/126—Devices for heating or cooling internal body cavities for invasive application, e.g. for introducing into blood vessels

Definitions

  • This invention relates to hyperthermic treatment of steatosis.
  • Steatosis is an abnormal accumulation of fat in the liver.
  • Microvesicular and macrovesicular forms relate to the vesicle size of fat in the liver.
  • Steatosis can be prominent in alcoholic liver disease (alcoholic steatohepatitis), non- alcoholic steatohepatitis (NASH syndrome), hepatitis B or C infections, obesity, diabetes mellitus, malabsorption, use of steroids, and use of certain other drugs.
  • alcoholic liver disease alcoholic steatohepatitis
  • NASH syndrome non- alcoholic steatohepatitis
  • hepatitis B or C infections obesity, diabetes mellitus, malabsorption, use of steroids, and use of certain other drugs.
  • steatohepatitis When the accumulation of fat goes along with inflammation the condition is known as steatohepatitis. Overtime this condition can lead to liver fibrosis and/or cirrhosis.
  • Steatosis will cause elevations in liver enzymes and is diagnosed through imaging techniques like ultrasound, CT, MRI, and/or liver biopsy.
  • imaging techniques like ultrasound, CT, MRI, and/or liver biopsy.
  • the invention provides a method for treating a patient having a level of steatosis comprising raising the core temperature of the patient and then returning the core temperature of the patient to normal at least one time.
  • the core temperature is raised to a temperature range and a duration sufficient to eliminate or reduce the patient's level of steatosis by 30 percent or more six months after the core temperature has been raised and returned to normal at least one time, and the patient's level of steatosis is determined at least once before the core temperature has been raised said at least one time.
  • the invention provides a method for treating a patient having a level of steatosis comprising raising the core temperature of the patient and then returning the core temperature of the patient to normal at least one time.
  • the core temperature is raised to a temperature range and a duration sufficient to reduce the patient's level of steatosis by 30 percent or more six months after the core temperature has been raised and returned to normal at least one time, and the patient's level of steatosis is determined at least once before the core temperature has been raised said at least one time.
  • “Returning the core temperature of the patient to normal” includes allowing the patient to cool through ambient heat loss and actively cooling the patient.
  • the patient is cooled by ambient heat loss and active cooling to a temperature of 39°C.
  • the patient is released from the treatment center and the patient's temperature gradually returns to normal (37°C) over a period of a few days.
  • the core temperature of the patient is raised and returned to normal one time.
  • the core temperature of the patient is raised and returned to normal two or more times.
  • the core temperature is raised by circulating the patient's blood from the patient, through an extracorporeal blood flow circuit, and back to the patient, wherein the blood returned to the patient has been heated within the blood flow circuit to an elevated temperature range.
  • the patient's blood can be circulated from the patient through a blood vessel and returned to the patient through a blood vessel.
  • the patient's blood is circulated from the patient through a vein and returned to the patient through a vein.
  • the patient's blood is circulated from the patient through an artery and returned to the patient through a vein.
  • the core temperature is raised by inserting a heating element into the patient and the heating element heats the patient's blood. The heating element can be inserted into a blood vessel of the patient.
  • the heating element can be inserted into a central vessel, i.e., aorta or vena cava, where it can heat the blood passing by and eventually heating the blood to such a degree that the net temperature gain exceeds the losses due to the normal (physiologic) cooling mechanisms. Over time the body temperature can be raised to a predetermined point and maintained for a predetermined time.
  • the heating element can be housed within a sheath or catheter at one or multiple positions along its length.
  • the sheath or catheter can contain wires, conduits, fiberoptic, or other materials to supply power to the heating element. External to the body there could be a plug to connect the sheath or catheter to the control system.
  • the sheath or catheter can be treated to give it antithrombogenic properties.
  • This treatment can be chemical or a high energy corona or plasma discharge in the presence of a monomeric gas.
  • the method of insertion can be through a cut-down or percutaneously (Seldinger Technique).
  • the heating element's method of heating can be by an electrical heating, radiofrequency, or laser.
  • the heating element should not exceed 50°C at the surface that contacts blood.
  • Such a heating element can be used for core heating and can also be used for local or regional heating.
  • a percutaneous insertion into an artery with a hollow sheath or catheter can be made to accommodate a steering guidewire so the device can be placed into the hepatic artery.
  • a second hollow catheter with a thermistor tip can be placed, via a venous percutaneous stick, into the hepatic vein for liver temperature.
  • Methods which heat the blood to raise the core temperature are preferred.
  • methods in which the core temperature is raised by other methods such as by infrared radiation, convection, or surface contact such as a heating blanket can also be used in the method of the invention.
  • the core temperature can be raised to a temperature range of from 38 to 43°C, more preferably 41 to 42°C.
  • the core temperature can be raised for a period of from 2 minutes to sixteen hours, a period of from one-half to three hours, a period of from one to two hours, or a period of from 100 to 140 minutes, or for 120 minutes.
  • the core temperature can be taken rectally.
  • the "core temperature” means rectal temperature. Temperatures other than the rectal temperature can be taken in the practice of the invention, e.g., esphogeal, bladder, tympanic, or cardiac line temperatures. The relationship between such other temperatures and the rectal temperature is well known in the art and such measurement by other methods will allow determination of the core temperature as defined herein.
  • the patient's level of steatosis can be determined at least once before the core temperature has been raised at least one time; at least once after the core temperature has been raised and returned to normal at least one time; at least two different times after the core temperature has been raised and returned to normal at least one time, or combinations thereof.
  • the patient's level of steatosis is reduced by 30 percent or more six months after the core temperature has been raised and returned to normal at least one time, more preferably, by 50 percent or more, more preferably, by 75 percent or more, by 90 percent or more, or by 95 percent or more. In a preferred embodiment, the patient's level of steatosis is eliminated six months after the core temperature has been raised and returned to normal at least one time.
  • Steatosis is determined by liver biopsy to see if steatosis is present in the liver.
  • the patient has macrovesicular steatosis, microvesicular steatosis, or both macrovesicular and microvesicular steatosis.
  • the existence of macrovesicular steatosis can be established by a liver biopsy showing large fatty vesicles.
  • Microvesicular steatosis can be established by a liver biopsy showing small fatty vesicles.
  • the patient has macrovesicular steatosis and the macrovesicular steatosis is eliminated six months after the core temperature has been raised and returned to normal said at least one time.
  • the patient has microvesicular steatosis and the microvesicular steatosis is eliminated six months after the core temperature has been raised and returned to normal said at least one time.
  • the patient is infected with hepatitis C virus; the patient is not infected with hepatitis C virus; the patient is infected with hepatitis B virus; and the patient is not infected with hepatitis B or C virus.
  • the patient has steatohepatitis; the patient has non-alcoholic and non-viral steatohepatitis; the patient has viral steatohepatitis; and the patient has alcoholic steatohepatitis.
  • the patient is obese, the patient has diabetes mellitus, the patient has malabsorption, the patient has been exposed to steroids and/or the patient has been exposed to certain other drugs.
  • the patient's level of steatosis is reduced by 30 percent or more three months after the core temperature has been raised and returned to normal at least one time, more preferably, by 50 percent or more, by 75 percent or more, by 90 percent or more, or by 95 percent or more.
  • the patient's level of steatosis is eliminated six months after the core temperature has been raised and returned to normal at least one time.
  • the method of the invention can further comprise treating the patient with a pharmaceutical indicated for hepatitis C.
  • the efficacy of a pharmaceutical effective for treatment of HCV in some patients can be increased when combined with hyperthermia.
  • the method of the invention can also comprise treating the patient with a pharmaceutical indicated for HCV where such pharmaceutical was not efficacious for stand alone treatment for HCV and when combined with hyperthermic treatment results in the pharmaceutical being efficacious in some patients.
  • the patient can be treated with a single pharmaceutical effective against hepatitis C or with two or more pharmaceuticals effective against hepatitis C.
  • the drug can be administered to the same patient at several points: before raising the core temperature of the patient at least one time, while the core temperature of the patient is raised, and after the core temperature of the patient has been raised and returned to normal at least one time, or combinations thereof.
  • the pharmaceutical can be selected from interferons, protease inhibitors, cytokines, or any combination of antiviral drugs.
  • the pharmaceutical can be selected from ribavirin, lamivudine, interferon alfacon-1, interferon alfa-2a, interferon alfa-2b, interferon- alfa-nl, thymosin alpha- 1, interleukin-2, interferon alpha-n3, ketoprofen, interferon beta-la, interferon gamma- lb, interleukin-12, histamine dihydrochloride, thymalfasin, zidovudine, didanosine, zalcitabine, stavudine, abacavar, nevirapine, delaviridine, efavirenz, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, or combinations thereof.
  • the pharmaceutical can be selected from an interferon, ribavirin, or lamivudine. In another preferred embodiment, the pharmaceutical is an alpha interferon.
  • the pharmaceutical can also include antioxidants, non-steroidal anti- inflammatory drugs, cholic acids like ursodeoxycholic acid and/or reactive oxygen free radical scavengers.
  • interferons include LNFERGEN (interferon alfacon-1, manufactured by Amgen Inc., Thousand Oaks, California), ROFERON-A, (interferon alfa-2a, manufactured by Roche Pharmaceuticals, Nutley, New Jersey), INTRON A (interferon alfa-2b, manufactured by Schering Corporation, Kenilworth, New Jersey), and WELLFERON (interferon alfa-nl, manufactured by Glaxo Wellcome Inc., Research Triangle Park, North Carolina).
  • Ribavirin (1- ⁇ -D- ribofuranosyl-lH-l,2,4-triazole-3-carboximide) in combination with INTRON-A is sold as REBETRON by Schering Corporation.
  • a patient infected with HCV might have an acute HCV infection or a chronic HCV infection.
  • the patient might be co-infected with a pathogen.
  • the pathogen might be a virus, a spirochete, or a bacterium.
  • the virus might be a heat labile virus.
  • the heat labile virus might be selected from herpesviruses, hepadnaviruses, togaviruses, flaviviruses, coronaviruses, rhabdoviruses, filoviruses, paramyxoviruses, othomyxoviruses, bunyaviruses, arenaviruses, or retroviruses.
  • the heat labile virus might be HIV, hepatitis B virus, Ebstein-Barr virus, cytomegalo virus, or varicella-zoster virus.
  • the heat labile virus is HIV.
  • the spirochete might be from the genus treponema, borrelia, or leptospira.
  • the spirochete might be Treponema pallidum,
  • the method of the invention can further comprise treating the patient with a pharmaceutical indicated for steatohepatitis.
  • the efficacy of a pharmaceutical effective for treatment of steatohepatitis in some patients can be increased when combined with hyperthermia.
  • the method of the invention can also comprise treating the patient with a pharmaceutical indicated for steatohepatitis where such pharmaceutical was not efficacious for stand alone treatment for steatohepatitis and when combined with hyperthermic treatment results in the pharmaceutical being efficacious in some patients.
  • the patient can be treated with a single pharmaceutical effective against steatohepatitis or with two or more pharmaceuticals effective against steatohepatitis.
  • the drug can be administered to the same patient at several points: before raising the core temperature of the patient at least one time, while the core temperature of the patient is raised, and after the core temperature of the patient has been raised and returned to normal at least one time, or combinations thereof.
  • the pharmaceutical can be selected from cholic acids such as ursodeoxycholic acid, vitamin E, metformin, and betaine.
  • the invention also provides a method for treating a patient having a level of steatosis comprising raising the temperature of the patient's liver and then returning the temperature of the patient's liver to normal at least one time.
  • the temperature of the patient's liver is raised to a temperature range and a duration sufficient to eliminate or reduce the patient's level of steatosis by 30 percent or more six months after the temperature of the patient's liver has been raised and returned to normal at least one time, and the patient's level of steatosis is determined at least once before the temperature of the patient's liver has been raised said at least one time.
  • the temperature of the liver is raised by local, regional, or intraperitoneal hyperthermia.
  • the liver can be heated by the methods for raising the core temperature that are described herein.
  • Conventional hyperthermia equipment can be used in the methods of the invention.
  • Treatment consisted of one single session of EWBH with the core temperature raised to 41.8° ⁇ 0.15°C for 120 minutes.
  • the device used is based on a small volume extracorporeal veno-venous circulation through a heater- cooler system (TemetTM, First Circle Medical, Minneapolis, MN, USA).
  • Pre-treatment biopsies revealed steatosis in 50% (6/12) of the patients.
  • the results of the biopsies are shown in Table 2 below.
  • Steatosis was macrovesicular only in one, microvesicular only in one, and mixed macrovesicular and microvesicular in four.
  • the steatosis was classified as macrovesicular or microvesicular based on histological appearance. A liver biopsy is taken, the tissue is fixed in formalin and cut to slices which are stained and subsequently read under a microscope. If steatosis (fat) is present, it is characterized as macrovesicular and/or microvesicular steatosis.
  • Each type is quantified by counting the steatotic cells as a percentage of the total number of liver cells in the same area.
  • the scoring code used was: score 0: no steatosis; score 1: mild steatosis, ⁇ 5%; score 2: moderate steatosis, 5-30%; score 3: severe steatosis: > 30%.
  • a 30 percent reduction in steatosis would occur, for example, if the total number of steatotic cells (macrovesicular and microvesicular) declined by 30 percent (e.g., 30 percent down to 21 percent).
  • EWBH Extracorporeal Whole Body Hyperthermia
  • Patients with HCV infections can be safely treated with EWBH ⁇ Patients treated with EWBH have lower Hepatitis C viral load values at various individual time intervals, during the first 24 weeks after EWBH than during the last 24 weeks before EWBH.
  • the purpose of this investigation is to assess the safety and early effect on viral load of EWBH treatment over 24 weeks in individuals with chronic HCV infection, Genotypes 1.
  • the study is an open label pilot study in a single centre.
  • Chronic hepatitis C Fifteen patients with chronic hepatitis C, genotype la or lb, will be enrolled in this study. Enlisted will be patients non-responding to or relapsers from previous interferon alpha monotherapy or combination therapy (with ribavirin and/or amantadine), patients who were intolerant of interferon alpha therapy and those who refused drug treatment.
  • Chronic hepatitis C is defined as: positive antibodies to HCV, positive serum HCV RNA and elevated transaminases at least once in the previous 6 months. Patients will be identified, screened and enrolled under supervision of Dr. J. van Hattum, Chief of the Department of Hepatology of the UMC (Utrecht, the Netherlands).
  • the patients will undergo a single session of EWBH treatment, with their core temperature raised to 41.80°C ⁇ 0.20°C for 120 minutes.
  • Serum creatinine ⁇ 150 ⁇ mol/L • Abnormal ASAT and/or ALAT at least once in the previous 6 months.
  • FEV1 Forced Expiratory Volume
  • VC vital capacity
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Depression as defined by (1) a major depression episode requiring medication, hospitalization or electroconvulsive treatment; (2) any history of suicidal ideation; (3) history of severe psychiatric disorders or other psychiatric disorder which in the opinion of the investigator might be exacerbated by the use of EWBH.
  • the patients After obtaining the informed consent the patients will undergo a complete medical history, physical examination and laboratory check according to the flowchart (appendix 8). Preferably all patients will have a liver biopsy before starting the EWBH.
  • the investigator Once a patient has fulfilled all screening criteria, the investigator will document the eligibility on the study data forms. The investigator shall then document on the study data forms the patient ID and the patient will be treated according to protocol.
  • NPO non-per os
  • OR or treatment room that is used for the procedure does not have to be modified for this procedure.
  • Operating table shall be equipped with a foam rubber mattress and/or pads for flexor point protection. Arms will be placed at 70° sideway position.
  • V ⁇ ECG equipment (lead V5)
  • Vffl EEG equipment (2 channel)
  • Temperature probes (rectal, esophageal and tympanic) must be certified to have been calibrated within 0. l°Cto a NIST traceable device.
  • Each patient will be continuously monitored for temperature during the procedure. Temperatures will be recorded in the CRF every 10 minutes throughout the procedure. The perfusionist will record all perfusion data in the CRF. Other patient's parameters will be recorded on standard O.R. (operating room) flow sheets.
  • the perfusionist should prime the circuit with a balanced electrolyte, isotonic solution, and circulate until totally de-aired.
  • the femoral veins will be cannulated using open or percutaneous methods for connection with the extracorporeal circuit.
  • a predetermined dose of heparin required for extracorporeal circulatory bypass will be calculated at 2 mg/kg in 1 dose with an ACT (Active Clotting Time) determination before and after the dose.
  • An ACT of more than 350 will be maintained during EWBH. Further doses of heparin, if needed, will be administered according to ACT measurement.
  • EWBH shall be initiated at a blood flow rate of approximately 500 mL/min.
  • the water circulating through the heat exchanger shall not exceed 49°C. II.
  • T E or T R reaches 41.60°C the plateau phase will begin.
  • the time to reach a core temperature of 41.60°C is generally not less than 60 minutes.
  • Cooling will be initiated by resetting the thermostat of the TEMET to 35°C. II. WhenT E reaches 39°C, bypass will be discontinued.
  • IJJ De-cannulate and reverse heparin with protamine sulfate.
  • No medical or surgical resident will write any medication orders of patients treated with EWBH without prior authorization from members of the hyperthermia team.
  • At least one physician member of the hyperthermia team will evaluate the patient at every two-hour interval, or more frequently if indicated, for the initial four hours in the ICU.
  • Patients may be discharged from the hospital not within 12 hours after treatment neither before 24 hours after admission to the hospital.
  • a CXR will be obtained to rule out the presence of pulmonary problems such as pneumothorax, atelectasis, or edema.
  • patients will be educated regarding precautions for administration of hepatically metabolized medications. After discharge from the hospital, it will again be emphasized that all discretionary medications are to be reviewed and authorized by the a physician member of the hyperthermia team prior to prescribing and administering to any patient treated with EWBH, including medications ordered by patient' s private physician.
  • Liver function tests e.g. including, but not limited to, AST, ALT, alkaline phosphatase, total and direct and indirect bilirubin, must be drawn and analyzed immediately prior to prescribing and administering the medication. Whenever possible, avoid prescribing and administering any benzodiazepine or acetominophen-containing medication if any LFT is considered Grade 3 or 4 toxicity (appendix 7).
  • Liver function tests e.g. including, but not limited to, AST, ALT, alkaline phosphatase, total and direct and indirect bilirubin must be drawn and analyzed within 72 hours and once weekly after prescribing and administering the medication. If any LFT rises to a Grade 3 or Grade 4 toxicity following administration of any medication in the 4-week period following EWBH, immediate discontinuation of the suspect medication is indicated with liver function tests repeated 24 hours later and followed to resolution (appendix 7). X.
  • Blood samples for immunological determinations will be stored anonymously in a central laboratory. Only members of the hyperthermia team are allowed to use them. Blood will be tested for cytokines and cellular immunity if an effect of the EWBH treatment on viral load has been proven.
  • Thrombopenia may occur during the EWBH. Rarely there are side effects involving the circulatory system including heart failure, myocardial infarction, TLA and stroke. If the patient is prone to Herpes Simplex, the heat treatment may cause an outbreak.
  • Patients may voluntarily withdraw from the study at any time. Patients may be withdrawn from the study by their physician at any time. The reason for withdrawal has to be recorded in the Case Report Form provided for documentation of patient withdrawal. If the patient elects to pursue non-protocol therapy, every effort (e.g. phone calls, registered letters, etc.) will be made to obtain a final assessment of disease status, laboratory assessments and toxicity grading prior to the patient's departure from the study. If patients are lost-to- follow-up, all efforts will be made to locate the individual and follow the patient for safety and disease status during the remaining protocol follow-up period. In the case of a patient voluntarily withdrawing or being lost-to-follow-up within the first 8 weeks of the post-EWBH period, another patient as per protocol will be recruited. Ancillary Protocol, Immunology
  • a pilot study on the safety and therapeutic effect of whole body hyperthermia in 10-15 patients with hepatitis C infection will be performed in the University Medical Center in Utrecht.
  • the study will be an open, single center study on chronic hepatitis C patients who have either not responded to previous therapy with Interferon- ⁇ (IFN- ⁇ ), with or without ribavirin, or for whom treatment was not feasible. Only patients with genotype 1 (a or b) will be included.
  • hyperthermia is a relatively safe procedure which has an effect on immunologic processes as well as tumour growth. Furthermore, the hemodynamic and cardiac effects of hyperthermia are being extensively studied in animals as well as in humans. In humans, whole body hyperthermia is already being used to treat cancer (1).
  • the therapeutic effect of hyperthermia is mainly thought to be due to the release of cytokines, especially TNF- ⁇ , Interleukin-1 (IL-1) and IL-6, after the hyperthermia treatment (2,3).
  • HCV hepatitis C
  • the antiviral mechanism of whole body hyperthermia is not known. Two possible mechanisms may cause the antiviral effect:
  • Hyperthermia causes the release of a scala of chemokines from leukocytes and other cells, including antiviral interferons, interleukins and complement factors.
  • the outburst cytokines at febrile temperatures might trigger the early activation of the host's defences.
  • These chemokines may act anti-virally in several ways; by lysis of infected cells (TNF-V, interferon-V and -(, LL-6, IL- 10, which might explain the increase in the viral load in serum or plasma) and indirectly by stimulating the specific immune response to the hepatitis C virus (IL-1V and 3, IL-2, interferon-().
  • Hyperthermia induces an increased expression of viral antigens and a release of virus from the hepatocytes and other cells that are infected (eg. Leukocytes). This increase of viral antigens, present on the cell surface and free in the serum, induces an increase in the immune reactions to the virus.
  • Aim 3 and 4 only apply if there seems to be an anti- viral effect documented with quantitative HCV PCR (aim 1), i.e. at least a 10-fold decrease in HCV PCR during the 6 months follow-up.
  • Levels of cytokines, aim 2, however, will be measured anyway to document the influence of hyperthermia on their release.
  • T 2 weeks
  • T 3 weeks
  • T 12 weeks
  • T 24 weeks.
  • HCV quantitative PCR will be performed 15 times per patient, HCV genotyping will be performed pre-study.
  • serum IL-13 immunoreactive cytokine
  • IL-2 immunoreactive cytokine
  • IL-6 Th2 type cellular immune response
  • IL-10 Thl type cellular immune response, polymorphism (9)
  • TNF-V anti-viral cytokine
  • IFN-( antiviral and immune stimulatory).
  • Test can/may be: 1. Measurement of CD8 (+) HCV-specific IFN-( producing cells, as these show a correlation with HCV clearance in acute HCV infection (4, 5) with spot-ELISA and/or tetramers conjugated with HCV antigens and/or intracellular cytokine detection for CD4 and CD 8 cells. 2. Measurement of T-cell proliferation to HCV-structural (Core, El, E2) and non-structural (NS3/4, NS5) proteins (6, 7, 8). These methods will be tried out in the laboratory first and the optimal method (in terms of test result, feasibility) will be chosen.
  • the immune parameter testing will be analysed and based on the results, a decision will be made whether or not to continue with the testing.
  • the patient will undergo a liver biopsy.
  • the sample of liver tissue obtained will be investigated for histology (Pathology department) as well as by PCR with HCV-specific primers and by DNA-hybridisation with HCV-specific probes. 6 months after the treatment another biopsy will be taken (providing informed consent has been obtained) to investigate the same parameters.
  • the device used in the Clinical Protocol is the TEMETTM System.
  • the TEMETTM System is composed of three (3) main components: TEMETTM System 1000 Console, TEMETTM System heater-cooler, and TEMETTM System 1000 TransPakTM Blood Circuit. All of these components are available from First Circle Medical, Minneapolis, Minnesota.
  • the TEMETTM System 1000 incorporates a console, a heater-cooler, a blood circuit and temperature probes used for the induction and monitoring of the hyperthermia procedure.
  • the console contains the drive motor, motor controller and electronics for monitoring system parameters (temperature, pressure and flow).
  • the TEMETTM System 1000 heater-cooler is used to supply heated or cooled water to the heat exchanger located in the TEMETTM System 1000 TransPakTM Blood Circuit. If heated water is circulated through the heat exchanger, the desired effect is to elevate the patient's blood temperature. If cool water is circulated through the heat exchanger, the desired effect is to reduce the patient's blood temperature.
  • the sterile disposable blood contact circuit (TEMETTM System 1000 TransPakTM Blood Circuit) is comprised of components for inducing and monitoring hyperthermia.
  • vascular access is required. Blood leaves the patient via a venous cannula and PVC tubing, which directs blood to a centrifugal pump. From the pump, the blood is propelled through the heat exchanger where thermal exchange occurs, with the assistance of the heater-cooler. After the blood is heated it passes through a blood filter before returning to the patient via a second venous cannula.
  • a calibrated thermistor probe placed within the outlet of the heat exchanger monitors circuit temperature. This position will represent the highest blood temperature reading in the circuit.
  • the patient temperatures and the temperatures recorded from the blood circuit and the heater-cooler water bath will be the basis of the circuit operator management.
  • Circuit flow is measured by an electrically isolated electromagnetic flow meter built into the console, and a flow insert that is located in the blood circuit. Once a venovenous circuit is established, flow is initiated through the circuit. Flow should not exceed 5% of patient's assessed resting cardiac output until integrity of circuit is established. Once circuit integrity is established flow is increased so as not to exceed 20% of assessed resting cardiac output (average cardiac output is between 5 to 6.5 L per minute). Blood flow rate adjustment can be used with water bath temperature adjustment to fine tune the process and maintain the core body temperature within a narrow range for the appropriate time.
  • Circuit pressure monitoring is accomplished by the pressure electronics built into the console and a transducer, which is located at the input side of the heat exchanger. This position, within the circuit, allows the operator to monitor resistance to flow downstream of the pump. Changes in the pressure reading can be used as a diagnostic tool to determine circuit integrity.
  • the TEMETTM System 1000 Console and the TEMETTM System heater- cooler have been tested and have passed all applicable international safety standards and are qualified for CE Mark.
  • the TEMETTM System 1000 heater- cooler selection is based on ability to meet required specification, safety and durability standards.
  • the TEMETTM System 1000 TransPakTM Blood Circuit is designed to circulate the patient's blood by means of a centrifugal pump to a heat exchanger that heats the patient's blood to the desired parameters through a blood filter and a flow sensor then returns the heated blood to the patient.
  • the circuit is connected to the patient via 2 cannulae each placed in the patient's greater femoral venous system at the groin region.
  • the use of a centrifugal pump provides the necessary pressure (between 250 and 300 mmHg) to efficiently pump the blood while using less pressure than a peristaltic pump (3000 to 5000 mmHg), which could potentially damage blood cells.
  • the TEMET System TransPak Blood Circuit and its components have been tested for biocompatibility and will be provided "Sterile" to the end user.
  • the TransPakTM Blood Circuit will be labeled "For Single Use Only” as to prevent the possible cross contamination between patients or to health care workers coming in contact with the device.
  • Computerized controls can be added to all of the equipment described above.

Landscapes

  • Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Thermal Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Thermotherapy And Cooling Therapy Devices (AREA)

Abstract

L'invention concerne un procédé de traitement d'un patient atteint de stéatose consistant à élever, au moins une fois, la température corporelle interne du patient puis à revenir à sa température corporelle interne normale, la température corporelle interne étant élevée dans une plage de températures et pendant une durée suffisantes pour réduire le niveau de stéatose du patient de 30 pour-cent ou plus six mois après avoir une fois élevé et redescendu sa température à la normale.
PCT/US2003/028730 2002-09-19 2003-09-12 Traitement de steatose par hyperthermie WO2004026097A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003270615A AU2003270615A1 (en) 2002-09-19 2003-09-12 Treatment of steatosis using hyperthermia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41208002P 2002-09-19 2002-09-19
US60/412,080 2002-09-19

Publications (2)

Publication Number Publication Date
WO2004026097A2 true WO2004026097A2 (fr) 2004-04-01
WO2004026097A3 WO2004026097A3 (fr) 2004-11-11

Family

ID=32030799

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/028730 WO2004026097A2 (fr) 2002-09-19 2003-09-12 Traitement de steatose par hyperthermie

Country Status (2)

Country Link
AU (1) AU2003270615A1 (fr)
WO (1) WO2004026097A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501275A (en) * 1981-07-06 1985-02-26 Maahs Jerry D Mammalian subject heating unit using radiant heat
US5211631A (en) * 1991-07-24 1993-05-18 Sheaff Charles M Patient warming apparatus
US5476444A (en) * 1992-09-04 1995-12-19 Idt, Inc. Specialized perfusion protocol for whole-body hyperthermia
US6436131B1 (en) * 1993-02-10 2002-08-20 Radiant Medical, Inc. Heat exchange catheter having heat exchange surface formed of metal foil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501275A (en) * 1981-07-06 1985-02-26 Maahs Jerry D Mammalian subject heating unit using radiant heat
US5211631A (en) * 1991-07-24 1993-05-18 Sheaff Charles M Patient warming apparatus
US5476444A (en) * 1992-09-04 1995-12-19 Idt, Inc. Specialized perfusion protocol for whole-body hyperthermia
US6436131B1 (en) * 1993-02-10 2002-08-20 Radiant Medical, Inc. Heat exchange catheter having heat exchange surface formed of metal foil

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US10925885B2 (en) 2005-05-26 2021-02-23 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound

Also Published As

Publication number Publication date
AU2003270615A1 (en) 2004-04-08
WO2004026097A3 (fr) 2004-11-11
AU2003270615A8 (en) 2004-04-08

Similar Documents

Publication Publication Date Title
US6347633B1 (en) Treatment of hepatitis C using hyperthermia
US6415797B1 (en) Treatment of human herpesviruses using hyperthermia
Meng et al. Essential role for IL-6 in postresuscitation inflammation in hemorrhagic shock
Sugimoto et al. Irreversible electroporation versus radiofrequency ablation: comparison of systemic immune responses in patients with hepatocellular carcinoma
Creighton et al. Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis
WO2002003879A1 (fr) Traitement du vih par hyperthermie
Tutunchi et al. Expression of NF‐κB, IL‐6, and IL‐10 genes, body composition, and hepatic fibrosis in obese patients with NAFLD—Combined effects of oleoylethanolamide supplementation and calorie restriction: A triple‐blind randomized controlled clinical trial
Matthay Treatment of acute lung injury: clinical and experimental studies
Siddiqui et al. A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas
Sherwood et al. β2 microglobulin knockout mice are resistant to lethal intraabdominal sepsis
Mendoza-Sagaon et al. Comparison of the stress response after laparoscopic and open cholecystectomy
WO2004026097A2 (fr) Traitement de steatose par hyperthermie
Vertrees et al. Smoke/burn injury-induced respiratory failure elicits apoptosis in ovine lungs and cultured lung cells, ameliorated with arteriovenous CO2 removal
Hogle Malignant hemangiopericytoma: a clinical overview and case study.
Katogiannis et al. Leukostasis-related fatal cardiopulmonary arrest as initial chronic myeloid leukemia presentation
RU2444998C1 (ru) Способ прогноза интерферон-рибавирининдуцированной нейтропении у больных хроническим гепатитом с, получающих комбинированную противовирусную терапию
RU2287825C1 (ru) СПОСОБ ПРОГНОЗИРОВАНИЯ РЕЗУЛЬТАТОВ ЛЕЧЕНИЯ БОЛЬНЫХ ХРОНИЧЕСКИМ ВИРУСНЫМ ГЕПАТИТОМ С ПРЕПАРАТАМИ ИНТЕРФЕРОНА-α
US20040073259A1 (en) Treatment of patients infected by disease causing organisms or biological warfare agents using hyperthermia
El-Amin et al. ESTIMATION OF SERUM INTERLEUKIN-18 IN HEPATITIS C PATIENTS IN ZAGAZIG UNIVERSITY HOSPITALS
Kim Heart and circulatory system
Ellul-Micallef et al. The hypereosinophilic syndrome—a diagnostic enigma
Gauvreau et al. Pauca sed Matura: Few, but Ripe
Karaaslan et al. HEDEFE YÖNELİK SICAKLIK YÖNETİMİYLE İYİLEŞTİRİLMİŞ SONUÇLAR (HSY): POST-KARDİYAK ARREST HASTALARDA KLİNİK ÖNEMİ
Elsayed et al. Evaluation of Metabolic Changes in HCV Diabetic Patients Treated With Direct Acting Antiviral Agents
Kemp et al. Effect of Warm in Travenous Fluid Administration on Management of Hypothermia on CABG Patients

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP