“Cancer” has been the leading cause of death in Japanese people since 1981, and is steadily increasing year by year with the coming of an aging society. The incidence of pain in cancer patients, which inflicts unbearable agony on the patients, increases with the worsening of their condition, and 80% of patients with end-stage cancer suffer from persistent severe pain and fall into extreme anxiety in fear of death.
Since most of anxiety-ridden feeling comes from pain, WHO has proposed that analgesic used for treatment of pain associated with cancer be divided into 3 groups according to the stages of pain. The analgesic used for final-stage pain are morphine and the like. The analgesic used for alleviating relatively mild first-stage pain are non-narcotic analgesic, such as acetaminophen, aspirin and ibuprofen, and drugs for controlling special pain or other symptoms, such as antidepressant, antiepileptic, antiemetic and antianxiety drug, are also used as adjuvant drugs. To control moderate second-stage pain, weak narcotic analgesic are concurrently used with other analgesic. Typical examples of weak narcotic analgesic are codein and oxycodone-combined drug. In order to set patients free from unbearable final-stage pain associated with cancer, various morphine formulations have been developed. In the meantime, to get rid of anxiety of patients, glucocorticoid formulations (commonly known as steroid), as an anti-stress hormone, have been frequently used.
The reasons why appropriate treatment for pain is absolutely necessary are not only that setting patients free from pain improves patients' quality of life (QOL), but that pain causes patients to lose the energy to fight against diseases. Imperfect treatment for pain causes patients to be in anxiety, and hence to lose the energy to fight against cancer and receive treatment for cancer. If treatment for cancer cannot alleviate patients' pain sufficiently, the foundation of the treatment can be very questionable. A very important point is that pain is unnecessary, which simply worsens the condition of patients. Treatment for pain should be considered to be a problem of great urgency and not be deferred for future discussion. In other words, treatment for severe pain is as important as treatment for cancer itself. Pain largely affects the condition of patients, and therefore treatment for pain should not be distinguished from treatment for cancer. The two cannot be separated from each other.
A sensation of pain is highly apt to be influenced by a state of mind, and patients with cancer feel less pain when they spend their time with their family at home while feeling the rhythm of the day and that of the week. Treatment for pain is more effective at home, if possible, than in hospital. However, the question about treatment for cancer at home is that the usage of morphine and steroid has not been commonly known to the lowest levels of medical institutions. There are many cases where a patient is treated by an expert in a specialized medical institute and recovers his or her appetite by administration of steroid, but once the patient is discharged from the institute and sees a non-specialist in a local hospital, the non-specialist regards taking steroid as dangerous and stops the patient from taking steroid. Since morphine and steroid are drugs that needs care upon use, discontinuation of their administration cannot be rejected in a wholesale manner as a wrong measure.
The reason that morphine and steroid can be used without restriction in treatment of cancer is that they are used as part of the terminal care that sets patients free from pain and anxiety and allows them to die with dignity as human beings.
However, the abuse of morphine makes patients lapse into drug dependence and it is significantly difficult for the patients to recover from their drug dependence. Further, morphine inhibits the intestinal peristalsis, and therefore morphine-treated patients come to have abdominal distention and severe constipation. Patients with cancer have smaller food ingestion due to a poor appetite compared with healthy individuals and treatment with morphine causes them to have severe constipation, and thus it is no rare matter that they have only one bowel movement for 7 to 10 days. Long retention of old stools in the body inevitably affects the normal metabolic and immunological functions. A laxative is mainly prescribed for the constipation caused by morphine, but its efficacy is limited. No morphine formulations which do not cause constipation have come into existence yet. Morphine is also known to cause vomiting. It is reported that the incidence of vomiting by morphine does not differ depending on the route of morphine administration, it is one third in morphine-treated patients, and that only one third of morphine-treated patients need not co-administration of an antiemetic with morphine. Such a high incidence of vomiting gives rise to even an opinion that all the morphine-treated patients should be co-administered an antiemetic with morphine when the morphine administration is started. In many morphine-treated patients, the time when they need an antiemetic is about 2 weeks after the start of morphine administration, since the resistance to emetic action appears relatively early; however, the escalation of health care cost due to the concomitant treatment is problematic. In addition, there is a side effect, drowsiness, in about 20% of morphine-treated patients. Other side effects are also observed associated with morphine, such as respiration depression, confusion, hallucination, lightheaded feeling, pressure reduction, perspiration and pruritus. Mouth dryness found in about half of morphine-treated patients is a side effect that seriously lowers the QOL. These side effects not only cause patients to have an unwell feeling, but also act as a pressure to escalate health care cost.
Steroid used as an anti-stress hormone also has various side effects. The side effect on which most careful watch should be kept is an immunosuppressive effect. The main cause of death in patients with cancer is said to be multiple organ failure which is caused by the invasion of opportunistic pathogen due to the decrease in immunopotency of the patients. Accordingly, the possibility cannot be denied that steroid, which decreases the immunopotency of patients, shortens the patients' lives. In addition, due to its strong catabolism, steroid probably accelerates the debility of patients and therefore shortens their lives. Other side effects of steroid include: for example, anasarca and urinary retention due to the suppression of sodium excretion in urine; and fracture due to the acceleration of calcium elution from bone.
Even when the pain and anxiety in patients with cancer are excellently controlled, it is no rare thing that their condition takes a sudden turn for the worse in a very short period of time. This is called cancerous symptoms of urgency. Cancerous symptoms of urgency include: for example, dyspnea, increase in pain, disturbance of consciousness/derangement, urinary retention, fracture, hemorrhage, paralysis/weakness of upper extremities, and paralysis of one side of the body. These symptoms are probably related to the overdosage of morphine and steroid.
Control of pain caused by cancer and of patients' anxiety accompanying the pain is medical care in an extreme situation, and there are a large number of diseases other than cancer that require control of pain and anxiety. In other words, getting rid of pain and anxiety accompanying the pain occupies an important position in medical care. Thus, a social need is very strong for means which can improve pain and get rid of anxiety at low cost, while avoiding such side effects that morphine and steroid have.
In the mean time, pain or low back pain which accompanies arthritis is also a serious problem. Typical examples of arthritis are rheumatoid arthritis, osteoarthritis, frozen shoulder, and arthritis caused by sports injuries. Low back pain is pain in junctions of bones.
Rheumatoid arthritis is a chronic inflammatory disease that causes polyarthritis, the disease is more than 3 times as common in females as in males, and it is said that the incidence is high in their 30s to 50s. Of the factors contributing to the onset of the disease, the following three factors: inborn pre-disposition, immunological factors and circumstance are regarded as important. It is said, with respect to the immunological factors, that rheumatoid factor synthesized in the joints binds to immunoglobulin G to cause arthritis, which leads to the progression of joint destruction. The circumstance includes, for example, chill, humidity, stress and infection with virus. Early symptoms consist mainly of stiff joints when waking up in the morning, joint pain and joint swelling. Frequently affected joints are those of the finger and toe, wrist, ankle, elbow, knee and shoulder and when the disease has progressed, they can sometimes be deformed. The disease may cause systemic symptoms such as feeling of weakness, lassitude and low-grade fever, besides symptoms in joints. Once affected with rheumatoid arthritis, patients are hard to be perfectly cured and have to live with the disease throughout their lives. To prevent the worsening of the disease, patients need to try to rest both mind and body, do moderate exercise, take in nutrients such as vitamins, minerals and proteins, and defend themselves against the cold and humidity.
Osteoarthritis is a non-inflammatory disease which causes little by little the deformation of the diarthrosis, in particular, joints to which loads are applied, and hence pain and limited range of motion in such joints. The disease is characterized pathologically by the destruction of articular cartilage and the osteogenesis of subchondral bone. The disease is classified into two: a primary osteoarthritis which is developed with aging; and a secondary osteoarthritis which is developed with underlying diseases such as injuries and rheumatoid arthritis. The pathogeny and the mechanism of osteoarthritis are thought to be as follows. Primary osteoarthritis is a symptom of senility in articular cartilage which is developed by mechanical impact probably under the influence of aging, metabolic disorder, circulatory disorder, obesity and sex hormone. Underlying diseases which may cause secondary osteoarthritis include, for example, injuries, rheumatoid arthritis, alkaptonuria, hemochromatosis, gout and Charcot joint. More than half of the adults are said to have secondary osteoarthritis and the incidence of the disease increases with aging in a geometric series manner. Those in 60s or more without the disease, including a mild case, are unusual. The disease is almost as common in males as in females.
Frozen shoulder, tennis elbow, baseball shoulder and various types of low back pain are also characterized by the pain occurring in the junctions of bones, and thus classified as diseases of joint. The pain caused by these diseases might not threaten the patient lives, but is generally intractable and takes a chronic course.
At present, drugs usually prescribed to alleviate the pain caused in the joints by rheumatoid arthritis, osteoarthritis, etc. or the pain caused in the junctions of bones such as low back pain include, for example, several tens of synthetic compounds referred to as non-steroidal analgesic or antiphologistics, such as aspirin, indomethacin, ibuprofen and diclofenac and synthetic glucocorticoid hormone etc. referred to as steroid.
Pain is mediated by prostaglandin, and if the biosynthesis of prostaglandin is decreased/stopped by inhibiting cyclooxygenase with a non-steroidal antiinflammatory drug, pain is alleviated. However, since prostaglandin influences hemodynamics in stomach, if its synthesis in stomach is inhibited, peptic ulcer is caused frequently in the stomach whose blood flow is decreased. Conventional non-steroidal antiinflammatory drugs are double-edged swards which inhibit both cyclooxygenase-1 and cyclooxygenase-2 as rate-limiting enzymes in the synthesis of prostaglandin. A current topic in the field of non-steroidal antiinflammatory drugs is the advent of cox-2 inhibitor that inhibits specifically the cyclooxygenase-2 (cox-2) developing in the inflammatory regions. The cox-2 inhibitor is expected to make it possible to decrease peptic ulcer, which has been an inevitable result of the use of non-steroidal antiinflammatory drugs.
Glucocorticoid (what is called steroid) as an adrenal cortical hormone is also frequently used for treatment of arthritis. Although steroid provides a dramatic improving effect on arthritis, its use is significantly limited due to the incidence of various side effects. Treatment with steroid causes serious side effects in patients; for example, it decreases the immunopotency of the patients and causes the patients to be susceptible to infectious diseases, frequently causes peptic ulcer, and induces diabetes in the patients. In addition, discontinuation of its administration causes rebound phenomenon that the symptoms are worsened before administration.
Gold preparation, penicillamine, immunosuppressive drug and antiinterleukin-6 antibody are also used for treatment of arthritis, but their prescription is restricted within narrow limits.
Pain in joints, even pain accompanying frozen shoulder, low back pain or sport injuries which have good chances of being cured, is characterized by its taking a chronic course. And in rheumatoid arthritis and osteoarthritis, it is very difficult for patients to make a complete recover from the diseases and once affected with the diseases, the patients are to live with the diseases throughout their lives. To allow pain in joints to subside, patients can be given physical therapy such as balneotherapy, but the mainstream is medicinal treatment with non-steroidal antiinflammatory drugs and steroid. As aforementioned, these drugs induce peptic ulcer with a high frequency following long-term administration. Thus, a method has long been sought of improving pain in joints in high safety while avoiding the induction of peptic ulcer.
Lactofferin is an iron-binding protein existing in milk of various kinds of mammals. It was first discovered in bovine's milk in 1939 and found later to exist in milk of many kinds of mammals other than bovine. In 1960 it was first isolated from milk of bovine and human beings, and its structure was determined by Baker et al. using X-ray diffraction method (Baker et al. Proc. Natl. Acad. Sci. USA 84: 1769-1773, 1987). In human beings, lactofferin is isolated not only from milk, but also exocrine fluids such as tears, nasal discharge, saliva, bronchial and uterine mucus, seminal fluid, bile and pancreatic fluid; body fluids such as blood plasma, urine and amniotic fluid; and secondary granules of neutrophil, and about 5 g per day of lactofferin is probably biosynthesized, taking into consideration the biological half-life of neutrophil.
Since lactofferin has a wide distribution and is synthesized in large amounts in living bodies, its applications have been examined in various industries. There have been reported a preventive effect on microorganism infection at each individual animal level (Miyazaki et al. Chemotherapy 39: 829-835 (1991)), and besides, cancer-related effects, for example, an anticancer effect (Bezault et al. Cancer Res. 54: 2310-2312 (1994)), a carcinogenesis preventive effect (Sekine et al. Jpn. J. Cancer Res. 88: 523-526 (1997)), a metastasis preventive effect (Kuhara, Rinsho Meneki (Clinical Immunology) 34: 376-381 (2000)), and a metastasis inhibitive effect by inhibiting neovascularization (Shimamura et al., proceedings of the 60th annual meeting of the Japan Cancer Association (October, 2001)). Lactofferin is supposed to have various functions since it has a wide distribution and is synthesized in large amounts in living bodies. And because it exists in the eyes, the mucous membrane of the oral cavity and the gastrointestinal tract, the nasal cavity, and the mucus covering the bronchiole, through which living bodies are directly in contact with the outside world, there has been an emphasis particularly on its function as a first defensive wall for defending living bodies against infections of pathogenic microorganisms and viruses. And in recent years, lactofferin has been used in clinical applications, for example, in the field of treatment for hepatitis C, secondary prevention of carcinoma of the colon and rectum, and Trichophyton infection of skin. However, there has been no report on effective use of lactofferin for improving pain and getting rid of anxiety of patients suffering from pain. There has been known no example of trying treatment for rheumatoid arthritis, osteoarthritis, frozen shoulder, chronic low back pain, tennis elbow and baseball shoulder by orally administering lactofferin to patients.