The present invention relates to use of a staphylococcus vaccine for the manufacture of a pharmaceutical preparation. It also related to methods for treatment and/or prevention of fibromyalgia.
Fibromyalgia and chronic fatigue are relatively new entities in the nosology of medical disorders. They encompass conditions with symptoms such as pain, fatigue and a wide range of other symptoms which seem to have many clinical and demographic characteristics (see e.g. Buchwald D., et al., Comparison of patients with chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivities, Arch. Intern. Med. 154:2049-2053, 1994). Both diseases are diagnosed on the basis of clinical criteria.
Fibromyalgia
The term fibromyalgia was first delineated in 1981 by Yunus M. B., et al., in Primary fibromyalgia (fibrositis): A clinical study of 50 patients with matched normal controls, Semin. Arthritis Rheum., 11:151-171, 1981. However, the condition has been described in the literature of medicine since the middle of the 19th century (see e.g. Simons D. G., Muscle pain syndromesxe2x80x94part 1, Am. J. Phys. Med., 54:289-311, 1975). Fibromyalgia is often considered as a form of non articular rheumatism, which may be connected with the formulation in the classification set forth by the American College of Rheumatology (ACR 90) (see Wolfe F., et al., The American College of Rheumatology 1990 criteria for the classification of fibromyalgia; report of the multicentre criteria committee, Arthritis Rheum., 33:160-172, 1993). The most important criteria according to The American College of Rheumatology are widespread pain and the presence of at least 11 of 18 possible tender points, so called trigger points. In the consensus report from the 2nd World Congress of Myofascial Pain and Fibromyalgia in Copenhagen, Denmark, in 1992 the disease is described as follows: a painful, nonarticular condition predominantly involving musclesxe2x80x94the most usual cause for widespread musculoskeletal pain. The condition normally leads to persistent fatigue, non-refreshing sleep, as well as stiffness in the whole body. Fibromyalgia is a syndrome which encompasses headaches, irritable bowels, irritable bladder, dysmenorrhoea, cold sensitivity, Raynaud""s phenomenon, restless legs, atypical patterns of numbness and tingling, intolerance to physical exertion, complaints of weakness etc. A varying percentage (20-25%) of patients suffering from fibromyalgia experience significant depression or anxiety.
It is common that the symptoms vary during the day and the year. The prevalence is high. Fibromyalgia is estimated to affect 2-6% of the population (see Wolfe F., et al. The prevalence and characteristics of fibromyalgia in the general population, Arthritis Rheum., 36((9S):57, 1993, and Buskila, D., et al., Assessment of nonarticular tenderness and prevalence of fibromyalgia in children, J. Rheumatol. 20:368-370, 1993). Fibromyalgia is more common in women than in menxe2x80x94less than 10% of the patients with fibromyalgia are men.
The aetiology of fibromyalgia is not known, but many factors are considered to have pathological importance. Though the pain is primarily located to the muscles, research findings do not support any explanation of the syndrome that is based on only peripheral changes. The type of painxe2x80x94persistent pain even when the patient is restingxe2x80x94and the widely spread pain and soreness points at disorders in the central nociceptive system. The idea that there may be a central sensibilisation has been put forward by Bengtsson, A, et al., in Primary fibromyalgia. A clinical and laboratory study of 55 patients, Scand. J. Rheumatol. 15:340-347, 1986. Neuroendocrinological findings, such as disturbances in the metabolism of serotonine and insufficient release of growth hormone have been discussed as possible cause of some of the manifestations of fibromyalgia (see e.g. Bennett, R. M., et al., Low levels of somatomedin C in patients with fibromyalgia syndrome, Arthritis Rheum., 32:454-460, 1992, and Russel, I. J., Biochemical abnormalities in fibromyalgia syndrome, J. Musculoskeletal Fain, 2:101-115, 1994). Immunological factors have also been suggested as possible cause (see Klein, R., et al., Clinical relevance of antibodies against serotonin and gangliosides in patients with primary fibromyalgia syndrome, Psychoneuroendocrinology, 17:593:598, l992).
No curative therapy for fibromyalgia is clinically available at present; only symptomatic treatment are offered to the fibromyalgic patients. Anaigetics, i.e. anti-inflammatory drugs and paracetamol, do not seem to redice the symptoms (see Lorenzen, I., Fibromyalgiaxe2x80x94which is the best treatment? A personalized comprehensive, ambulatory, patient-involved management programme, Balliere""s Clin. Rheum., 4:333-370, 1994). Treatment with antidepressant drugs has some effects (see Jacobsen, S., Chronic widespread muscoskeletal painxe2x80x94the fibromyalgia syndrome, doctoral thesis, Copenhagen: Laegeforeningens forlag, 1994). Fibromyalgic patients can often improve their physical condition by physical training.
Chronic Fatigue Syndrome
This concept was introduced in 1988 by Centers for Disease Control (see Holmes G. P., et al., Chronic fatigue syndrome: a working case definition, Ann. Intern. Med., 108:387-389, 1988 greater than . The syndrome was thoroughly defined and the diagnostic criteria was formulated. The obligate symptom was a fatigue of an incapacitating and chronic nature that should have lasted for at least six months. Eleven minor criteria were also defined and included: mild fever or chills, sore throat, painful lymph nodes, unexplained general muscle weakness, myalgia, prolonged general fatigue after exercise, headaches, migratory arthraigia, neurophysiologic complaints and sleep disturbances. There may also be physiological signs, such low fever, non-exudative pharyngitis, and palpable or tender cervical or axillary lymph nodes. In order to diagnose a patient with chronic fatigue syndrome, the patient must fulfill eight of the eleven criteria besides the chronic fatigue, or six of the eleven criteria and two of the physiological signs.
Many physicians were critical against these criteria an variations was used both in Australia and England. This led to a new definition, which was published in December 1994, (see Fukuda, K., et al., The chronic fatigue syndrome: a comprehensive approach to its definition and study, Ann. Intern. Med., 121:953-959, 1994). The new criteria are as follows: 1a) a clinical assessed, unexplained persistent chronic fatigue, that i) the patient has not experienced earlier, ii) is not the result of ongoing exercise, iii) does not improve with rest, iv) considerably reduces the potential for the patient to carry out previous activities at work or during leisure time; 1b) the patient should also have at least four of the following six symptoms, and they should have been manifested for at least six consecutive months, but not before the onset of the fatigue, i) a self-reported impairment of the short-term memory and the concentration ability, ii) a sore throat, iii) tender cervical or axillary lymph nodes, iv) muscular aches, v) headaches of a new type and severity, vi) fatigue upon awakening, vii) a feeling of being xe2x80x9cillxe2x80x9d for more than 24 hours after physical exertions
A possible connection between fatigue and infectious diseases, in particular viral diseases, has been proposed. Chronic fatigue syndrome is often considered to be the result of an acute infectious disease. Some infectious diseases that have been suggested as being of importance for chronic fatigue syndrome are infections caused by Epstein-Barr virus (EBV), human herpes virus type 6 (HBV-6), enterovirus and retrovirus, but no signs of a higher frequency of such diseases have been reported for patients suffering from chronic fatigue syndrome. There are reports on immunologic abnormalities, such as a decrease of subgroups of IgG, an increase of circulating antigen-antibody complexes, a lower activity of natural killer cells, a decrease of subgroups of the T-cells CD-4 and CD-8 and a decreased delayed hypersensitivity reaction on skin test antigens (see the review by Wilson, A., et al, Longitudinal study of outcome of chronic fatigue syndrome, Br. Med. J., 308:756-759, 1994). There are reports of a reduced amount of markers for cell mediated immunity compared to normal controls and patients with non melancholic depression. Studies in order to estimate the prevalence of chronic fatigue syndrome have been made at many research centres all over the world. A prevalence of 51-131 per 100,000 inhabitants has been reported for England, while preliminary statistic estimates from Centers for Disease Control indicate a prevalence of 2-7 per 100,000 inhabitants in four American states. An Australian study has reported a prevalence of 37 per 100,000 inhabitants.
The two syndromes, fibromyalgia and chronic fatigue syndrome, xe2x80x9coverlapxe2x80x9d and it has been suggested that it is in fact only one disease manifested in different ways.
The present invention relates to use of staphylococcus bacteria or a product thereof for the manufacture of a pharmaceutical preparation for treatment and/or prevention of fibromyalgia and chronic fatigue syndrome. It also relates to use of the manufactured pharmaceutical preparation.
Furthermore it relates to a method for treatment of and/or prevention of chronic fatigue syndrome or fibromyalgia, characterised in that a staphylococcal vaccine is administered in a therapeutically effective amount.
The characterising features or the invention will be evident from the following description and the appended claims.
According to the present invention it is thus possible to manufacture a pharmaceutical preparation which can be used for treatment and prophylaxis of fibromyalgia and chronic fatigue syndrome. The main ingredient in the preparation is a substance functioning as a staphylococcal vaccine; it may be any kind of antigen products from Staphylococcus, or any kind of synthetically produced compound mimicking such a product.
The pharmaceutical preparation is preferably formulated for injection.
The preparation may advantageously further comprise vitamin B12 and/or folacin. It has been found that a subgroup of patients suffering from fibromyalgia or chronic fatigue syndrome, also have levels of vitamin B12 in their cerebrospinal fluid that are lower than normal, and levels of homocysteine that are higher than normal. The high levels of homocysteine is indication a lack of vitamin B12 and folacin. It has been shown that this sub-groups of patients have a specific set of genes.
The preparation according to the intention may also comprise, such as pharmaceutically acceptable additives, e.g. solvents, adjuvants, carriers and/or preservatives.
The invention also relates to a method for treatment of and/or prevention of chronic fatigue syndrome or fibromyalgia, characterised in that a staphylococcal preparation is administered in a therapeutically effective amount.
The treatment is preferably conducted as a series of administrations with increasing doses during a specific period. Preferably the vaccine is administered in 8-10 increasing doses during 4-12 weeks, preferably 8-10 weeks. The reason for the increasing doses is that during the first week or weeks the patient will probably suffer from side effects, and it is therefore advantageously to start with a low dose. The side effects will diminish after some time.
In order to obtain the desired effect for a prolonged period of time the staphylococcal preparation should be administered at several occasions. It is not enough to administer the preparation just a few times since the patient then will not be cured at all, or the disease will reoccur within short. The first series of administrations is therefore followed by repeated administrations given approximately once a week for 5-15 weeks, preferably for 10 weeks.
To prevent recurrence the repeated administrations are then followed by a maintenance treatment with administrations approximately once a month, which preferably area continued for several years, such as 1-10 years, preferably approximately 5 years.
The doses in the repeated administrations the maintenance treatment are preferably constant and relatively high, for example the dose used in the last administration in the first series.
These repeated administrations result in an unspecific activation of the immune system over a long period of time.
The administrations can be made in any way known in the art, but they are preferably made as injections.
Vitamin B12 and/or folacin is preferably administered simultaneously or parallelly with the staphylococcal preparation.
If the known staphylococcal vaccine Staphypan Berna from the Serum- and Vaccine Institute Bern, Switzerland is used, a typical treatment schedule may be as follows: 8-10 administrations are made during a period of 4-12 weeks, preferably 8-10 weeks, wherein the dose of the staphylococcal preparation is gradually increased from 0.1 ml to 1 ml of the pure vaccine The increase depends on the response from the patient. It may e.g. be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1.0 ml, respectively. If the patient shows a strong local reaction it is possible to repeated a dose, before increasing it. The dose of the staphylococcal preparation in the repeated administrations and in maintenance treatment is 1 ml.