Medicament for hypothermia treatment

Details Medicament for hypothermia treatment Medicament for hypothermia treatment

1999-04-16

2001-04-03

Azpuru, Carlos A. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

Reexamination Certificate

active

06210697

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a supportive use of a medicament for carrying out a hypothermia treatment safely, and a pharmaceutical composition to be used in the treatment. More specifically, it relates to a medicament which is used supportively to inhibit the suppression of immune functions or the onset of infectious complications in a mild hypothermia treatment aimed at the prevention of the cerebral perfusion disorder of a patient with serious cerebral injury.
BACKGROUND TECHNOLOGY
The hypothermia treatment is a therapeutic method carried out to prevent an irreversible cranial nerve injury in the cases of accident or angiopathy, which is characterized in that a subject in anesthetized condition is cooled with a blanket having circulating cold water so that the temperature of the spinal cord and central nervous system is kept slightly low (cerebral temperature=ca., 33° C.) for a certain period of time. Clinical application of the treatment was started from about 1994, after the effectiveness was confirmed in the field of animal experimental pharmacology around the latter half of 1980's. Since then, remarkable successes have been reported in cases of severe head injury and subarachnoid hemorrhage (Hayashi, N et al.: J. Cereb. Blood Frow Metab. 15 (Suppl.1): S724, 1995, Maekawa, T et al.: Minerva-Anesthesiol. 60(10): 537-540, 1994).
The hypothermia treatment herein referred to is entirely different from a primitive one that had been employed in the field of thoracic surgery, in which the brain temperature was simply lowered to below 30° C. By contrast, the hypothermia treatment herein described came to afford satisfactory results only after the detailed procedures for controlling the cerebral temperature, blood pressure, respiration, intracranial pressure or the like; preventing stress diseases or infectious diseases; and matters to be regarded while rewarming were established (Hayashi, N., Hirayama, A: Medical Postgraduates 31:59-71,1993).
In the hypothermia treatment, one must pay the greatest attention to a peculiar damage of immune protection system of a living body when the cerebral temperature lowered, and the immunosuppression due to tissue injury or the like while the temperature is kept low and at the time of rewarming (Hayashi, N., “Cerebral Hypothermia” Sogo-Igaku, & Co., May 29, 1995 pp.53). The suppression of immune function could result in the onset of infectious diseases such as pneumonia.
There are certain measures currently taken to maintain the immune function during the hypothermia treatment, for example, the administration of L-glutamine (Glumine™ Kyowa Hakko Kogyou Co., Ltd.) which serves as an energy source for T- or B-cells (DeBiasse MA and Milmore DW: New Horizons 2(2): 122-130, 1994); the administration of y-globulin or opsonin; or the induction of in vivo synthesis of glutamic acid through the electric stimulation of skeletal muscle (Souba WW et al., J. Parenteral and Enteral Nutrition 9(5): 608-617, 1985), but they are not perfectly effective. Accordingly, there are still some cases involved in refractory pneumonia in the absence of sufficient preventive methods.
The extent of damages of tissue functions at the time of lowering/elevating the cerebral temperature, which possibly causes immunosuppression, is suggested to vary depending on the blood hemoglobin level or renal excretion function of patients. Accordingly, the hypothermia treatment is hardly applied to some patients showing suppression of these functions, for example, a patient of renal disease or of old age, because of the above-mentioned risks.
There have not been known any medicines capable of preventing damages of immune protection system specific to hypothermia treatment, or enhancing the damaged immune function effectively. The hypothermia treatment failed to show satisfactory lifesaving effects because of infectious diseases related to immunosuppression and could not be applied widely, notwithstanding that it is expected to show remarkable effect in the lifesaving and/or the amelioration of recovery of patients with serious cerebral injury.
On the other hand, human growth hormone (hereinafter, referred to as hGH) has not only been used in the treatment of pituitary dwarfism, but also known to be effective in the healing promotion of fracture and burn wound and also in the treatment of patients in nutrient malabsorption condition (Nikkei Bio Almanac 94/95). Further, there has been reported that hGH has an immune function potentiation effect or protection effect on tissue injury caused by free radical in vivo (U.S. Pat. No. 5,317,012, Japanese Patent Publication (Kohyo) 6-503320). However, it has never been known or even suggested that hGH has an ability to prevent or reduce the damages of immune protection system of a living body especially the immunosuppression due to peculiar tissue damages in a hypothermic treatment, in particular, when rewarming.
One of purposes of the present invention is to provide a pharmaceutical composition capable of preventing the suppression of immune function, and inhibiting or relieving an infectious disease in connection with a hypothermia treatment, whereby ensuring the safety of the treatment and allowing said treatment to exhibit the excellent preventive effect on the cerebral perfusion disturbance of a patient with serious cerebral injury to the full.
DISCLOSURE OF INVENTION
The present inventors have intensively studied to solve the problems above and found that the blood hGH level decreased as the cerebral temperature lowered and that it became about zero at 32° C. The inventors further found that CD4 and CD8 (leukocyte differentiation antigens), which are indices of cellular immunity function, were recovered by the administration of hGH. Based on these findings, the present inventors then confirmed that the administration of hGH to a patient with serious cerebral injury undergoing hypothermia treatment resulted in the recovery of the immune function and a great improvement of resuscitation limit of the patient.
Thus, the present invention provides a medicament to be used supportively in a hypothermia treatment which contains human growth hormone (hGH) as an active ingredient.
The present invention for the first time discloses that the use of human growth hormone (hGH) is clinically effective for the prevention of damages associated with hypothermia treatment.
The term “medicament used supportively” as used herein refers to a medicine which is used supportively for the purpose of carrying out the hypothermia treatment safely and effectively, while avoiding the suppression of immune function or induction of infectious diseases which could occur in relation to the treatment.
The medicament of the present invention is applicable to any kinds of hypothermia treatment, but can be preferably used in a treatment for preventing the cerebral perfusion of a patient with serious cerebral injury.
The medicament of the present invention can be used more preferably in a mild hypothermia treatment conducted while controlling the cerebral temperature between 32 and 36° C.
The medicament of the present invention is especially preferred in a mild hypothermia treatment conducted while controlling the cerebral temperature between 32 and 33° C.
The medicament of the present invention exhibits immune function potentiation effect and/or microorganism infection inhibitory effect. Typical examples of microorganism infections include pneumonia and septicemia. The medicament of the present invention is especially suited to prevent pneumonia.


REFERENCES:
patent: 5426096 (1995-06-01), Sonksen et al.
J. Vet. Med. B., vol. 42, No. 1 (1995), p. 12-18.
Journal of Interferon Research, vol. 8, No. 3 (1988), p. 393-402.

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