As can be seen from the literature, persons with CRS received a complex therapy. A special emphasis was laid on the general-sustaining therapy and recovery of hematopoiesis which demonstrated a good effect in case of termination of exposure or a significant reduction in doses received by patients. The treatment was strictly individualized (Kurshakov 1956; Guskova and Baysogolov 1971). It should be noted that a variety of symptoms, particularly in mild cases of the syndrome, frequently complicated the choice of a drug and dosage.

In order to speed up the removal of radionuclides, complexing agents (aminophylline, sodium citrate, atofan, soda), substances that help remove radioactive strontium from the body (espatite, diuretin, pectin), and agents influencing metabolism (magnesium-rich diet, 4-chamber baths) were used. Aminophylline was administered intravenously every third day (3 % – 10 ml, two times a day with an interval of 6 h, 3–6 injections per course) and intramuscularly (12 % – 2 ml, daily for 10–14 days). Yatren was applied in a 5 % solution, 10 ml intravenously, once a day at intervals of 2–3 days, 3 injections per course, in all. A 10 % solution of calcium salt of EDTA was administered intravenously, 10 ml daily, 5–6 injections per course. Sodium citrate and strontium nitrate solutions were administered orally, 1 tablespoon three times a day. Patients received atofan, 0.5 g three times a day in combination with four-chamber baths. The duration of the course of treatment was 10–14 days.

In addition, salts of stable strontium, magnesium, and calcium to replace ⁹⁰Sr, as well as the agents espatite and diuretin facilitating the removal of the isotope from the body, were administered. It was assumed that espatite was capable of adsorbing radiostrontium in the lumen of the intestine, and diuretin was administered as a diuretic. Espatite 1–2 g/day and diuretin 0.5 g three times per day were administered.

The course of treatment usually continued for 2–3 weeks. The effectiveness of the treatment was evaluated by comparing the amount of ⁹⁰Sr in biosubstrates before, during, and after the administration of the drug. Typically, over 4–7 days prior to the drug administration, the content of isotope in the daily amount of urine and feces was measured daily, then the excretion of ⁹⁰Sr was measured during the whole period of drug administration and for another 3–7 days after the cessation of treatment. The content of ⁹⁰Sr in biosubstrates was measured based on the intensity of β-radiation.

The effectiveness of removal of radioactive strontium by means of the above-listed drugs was evaluated in 132 persons with CRS, mostly at the initial stages of the syndrome. Based on the analysis of the data obtained, it was inferred that the use of aminophylline (both intravenously and intramuscularly), yatren, and “magnesium” diet in the initial period of observation (1951–1955) had exerted a minor effect on excretion of radioactive strontium and exclusively in the period of radionuclide intake. When strontium was fixed in the bone tissue, the use of drugs ceased to produce any effect. The rest of the drugs proved ineffective (Alexeyeva et al. 1963; Ivanov 1971).

The understanding of CRS pathogenesis contributed to the development of more effective therapeutic approaches. In treating CRS, a special attention was paid to general health-improving measures, such as dietary regime, rest, sleep, and physical exercises, included in the complex of therapeutic procedures (Kurshakov 1956; Glazunov et al. 1959). They had a beneficial effect on the function of the nervous, cardiovascular, and digestive systems.

In the URCRM clinic, patients with CRS were on a nourishing high-calorie diet, with a high content of protein (~140 g per day) and vitamins. The ingredients of the diet varied depending on the functional state of the digestive system and the clinical course of the disease. The adequacy of the diet was assessed based on the adequacy of the content of vitamins in the food. Wild rose extract (vitamin C) and fruit were added to the usual diet.

The treatment of CRS was predominantly symptomatic by its nature, and it was administered with account taken of the stage and severity of the syndrome (Alexeyeva et al. 1963). During the period of CRS formation, the therapy was focused on the blood and nervous system disorders and the ostealgic syndrome. The therapeutic measures were aimed at restoring the function of the nervous system and its regulatory influence on the visceral organs. The task of restoring the function of hematopoiesis was no less important in terms of the treatment of CRS.

As it has been noted earlier, the clinical picture of CRS was most frequently represented by the hematopoietic disorders manifested by the development of cytopenia and changes in the BM. Therefore, symptomatic therapy was, first of all, focused on the recovery of hematopoiesis. To stimulate leukopoiesis, sodium nucleinate, pentoxyl, and Thesan¹ were used. The course of treatment with these drugs was usually prolonged, especially in cases when a positive result was achieved. In case of marked leukopenia and neutropenia, sodium nucleinate was administered at 0.3 g three times per day for 3–4 weeks; pentoxyl at 0.2–0.4 g three times per day for 2–3 weeks; 0.1 % Thesan at 1.0 ml intramuscularly was given daily for 10 days. In cases of erythropoiesis inhibition, when megaloblastoid elements emerged, vitamin B12 was administered at 50 gammas intramuscularly, 3-day courses followed by 3-day intervals, 3–4 courses in total. To stimulate erythropoiesis, liver preparations were also used: Antianemin, campolon, and iron preparations (Ivanov 1968).

According to GD Baysogolov, sodium nucleinate, pentoxyl, Thesan, and vitamin B12 did not improve significantly the status of hematopoiesis in persons with CRS. Only a part of patients manifested a short-term increase in the number of peripheral blood leukocytes after administration of sodium nucleinate, pentoxyl, and to a lesser degree, Thesan. However, later on, even while the patients were taking these preparations, decreased leukocyte counts, lower than those before the treatment, were observed. From the point of view of GD Baysogolov, inefficiency of Thesan and pentoxyl in treating CRS was determined by the fact that the stimulation of proliferation and differentiation of hematopoietic cells caused by these substances contributed to a more rapid depletion of the regenerative capacity of a hypoplastic BM. Thus, it can be suggested that these medicines can only be applied at the initial stage of CRS. The signs of hypoplasia manifested by the BM in persons with CRS can, evidently, be regarded as a contraindication to the use of these drugs (Baysogolov 1961; Ivanov 1968).

The use of therapeutic agents for treating cytopenia provided a positive effect in approximately half of the patients. A transient increase in the content of granulocytes in the BM mainly due to mature forms and an increase in the number of leukocytes due to peripheral blood neutrophils were observed (Alexeyeva et al. 1963; Ivanov 1971). A more lasting effect was achieved in cases of a concomitant use of sodium nucleinate, vitamin B12, and folic acid. In the absence of a positive effect of treatment, the medication was substituted, or a combined treatment was applied. If there was still no effect, the administration of any stimulating drugs was revoked.

In cases of BM hypoplasia, transfusions of whole blood and its components (especially packed leukocytes) were used with a considerable effect. In some cases involving severe cytopenia and BM hypoplasia, transfusions of 250 ml of blood one to two times a week for 3–4 weeks were administered (Ivanov 1968). In all cases, blood transfusions resulted in the improvement of the patients’ general health status, regression of general weakness, headaches and dizziness, and elevation of blood pressure. There was a temporary increase in the number of all blood corpuscles in the peripheral blood, including leukocytes, thrombocytes, and erythrocytes. The replacement therapy of blood transfusions produced only temporary positive effect (Baysogolov 1961).

In vegetative dysfunction and asthenic syndrome, different pharmacological agents and physiotherapeutic procedures were used: intravenous infusion of 40 % glucose solution (20 ml daily), usually in combination with 2 ml of vitamins C and B1, and 10 % solution of calcium chloride (10 ml), 10–15 infusions per course. Positive effect was observed from the use of multivitamin preparations containing phosphorus (Lipocerebrin,² calcium glycerophosphate, Phosphren,³ adenosine triphosphoric acid), pantocrine, ginseng and Chinese magnolia tinctures, insulin, valerian, bromides, and neuroplegic agents (Ivanov 1968).

Sleep disorders were treated with somniferous substances of the barbiturate group at normal doses. Good results were also achieved by physiotherapy: coniferous baths, Shcherbak galvanic collar, and reflexive galvanic therapy.

If the hypertension syndrome developed, the treatment was provided using the commonly applied methods: intravenous infusions of hypertonic solutions of glucose, calcium chloride, intramuscular administration of 25 % solution of magnesium sulfate (5 ml), counter-attraction drugs.

In cases of pains of polyneurotic origin, procaine blocks were used. The treatment of organic lesions of the central nervous system using proserine, dibazol, and large doses of vitamins B12 and B1 provided only a temporary subjective improvement. The intensity of headaches decreased; in some cases the symptoms of asthenia disappeared. The follow-up examinations after treatment confirmed the persistence of organic damage to the nervous system.

The treatment of the ostealgic syndrome was, as a rule, a long-lasting process (Ivanov 1968). The course of therapy was of a comprehensive character, and it provided for an impact on the major pathogenetic links (lesions of the CNS pathways and receptors, vasotrophic changes, etc.). To treat patients with ostealgic syndrome, the following therapeutic regimen was administered: (1) intravenous infusion of 10–20 ml of 0.5 % procaine, (2) injections of 2.0 ml of vitamin B1 in a 0.5–2 % solution and 50 mg of nicotinic acid three times a day, (3) 0.1–0.3 g per day of pachycarpine, and (4) appropriate physiotherapeutic and balneological procedures (iontophoresis to the shins with procaine and calcium, sulfurated hydrogen baths). The most favorable effect from the use of nicotinic acid was observed in patients complaining of numbness and coldness in the extremities, which was probably due to the vasodilating effect of nicotinic acid, and a leading role played by the angiospastic component in the pathogenesis. A satisfactory effect was registered after treatment with vitamin B1, apparently, due to its suppressive effect on the development of the secondary neuritic process (Oliper 1960).

Positive results, particularly at the early stages of ostealgic syndrome, were noted when the patients were receiving pachycarpine which was administered in a dose of 0.1 g two times a day for 15–20 days. An improvement was observed in 75 % of the patients. Positive effect of pachycarpine therapy, according to TV Oliper, was due to the change in the conduction of neural stimulation in the vegetative nodes which restored the influence of CNS on the muscle tone of blood vessels and reduced the severity of the vascular disorders and also blocked the conduction of pain sensation in the synapses of the vegetative nervous system (Oliper 1960). However, the effectiveness of pachycarpine and procaine was significantly lower than that of vitamin B12.

A distinct effect was observed when patients received high doses of vitamin B12 which was administered intramuscularly in doses of 300–1,000 gammas daily, and the course of treatment included 10–15 injections. After treatment with vitamin B12, the intensity of bone pains reduced or disappeared completely in patients with ostealgic syndrome. The decrease in the intensity of pains usually occurred at the end of the course of treatment. As the pains decreased, a decrease in the sensitivity of the periosteum was noted; sometimes an increase in vibration sensitivity was registered. The positive effect of the treatment usually lasted for a period of several months to several years.

Vitamin B12 not only had a local effect on persons with CRS, but it significantly improved the patients’ well-being and health status. General weakness, fatigability, and irritability decreased. Subjective improvement was accompanied by normalization of the electrical activity of the brain. The electroencephalogram taken after treatment with vitamin B12 demonstrated a decrease in the background bioelectric activity, excitability, and reactivity of the cortical cells. The attending physicians got an impression that the analgesic effect of vitamin B12 was due to its impact both on the CNS and directly on the nerve receptors of the bone tissue (Ivanov 1968). According to EEG, vitamin B12 exerted an inhibitory effect on the CNS and reduced thereby the reactivity and excitability which resulted in a suppressed perception of pains. Through its influence on the nerve receptors of the bone tissue, vitamin B12 reduced the focus of irritation and decreased the pain impulsation to the higher divisions of the nervous system. All this led to the recovery of the neurodynamics followed by disappearance of stagnant irritation foci and reduction in the symptoms of a typical asthenic state.

In most cases, a long-term, systematic, and timely initiated treatment led to a significant reduction in the severity of ostealgic syndrome or its disappearance. The best effect was achieved when a comprehensive therapy was administered, i.e., a combination of a course of pachycarpine therapy with vitamins and periodic repeated courses of hydrosulphuric baths.

In case of impaired functions of the digestive system organs, in addition to diet and depending on the symptoms, the following medicinal preparations were administered: hydrochloric acid together with pepsin, gastric juice, cholenzim, pancreatin, tincture of belladonna, and atropine (Doshchenko 1960; Ivanov 1968). Of the physiotherapeutic methods, diathermy and galvanization of solar and mesenteric plexus were administered. Gastrointestinal disorders were corrected taking into account the degree of disease severity. In mild cases, high-calorie diverse diet with a higher content of proteins of high biological value was administered. Replacement therapy in patients with sharply reduced acidity and appetite disorders included natural gastric juice, as well as vitamin B6, insulin, and nicotinic acid. In cases of moderate severity, with the same requirements to the diet, replacement therapy and medicines aimed at stimulating the secretory function of the stomach (pyridoxine, folic acid, vitamin B6) played a more important role. The patients received prolonged and repeated courses of treatment.

To improve the function of the cardiovascular system, lily-of-the-valley, pheasant’s-eye, and valerian tinctures were used.

Antihemorrhagic medicines (vitamins P and C, calcium chloride, and others) as well as antibiotics (penicillin, streptomycin, Aureomycin, or Laevomycetin) were prescribed for medical indications. They were administered without fail if bleeding or infection occurred (Ivanov 1968).

The diet rich in vitamins did not exclude administration of vitamin complexes. Ascorbic acid was widely used. Sometimes, intravenous administration of 5 % solution of ascorbic acid in 40 % glucose solution, which played the role of a nutritive, a general stimulant, and a detoxifying substance, was used. Vitamin B1 was administered at a dose of 3–20 mg per day, intramuscularly or subcutaneously, and vitamin B2 in a daily dose of 5–10 mg orally or intramuscularly to prevent the development of a cataract. Vitamin B1 was also administered for neuralgia and neuromyalgia. Vitamin PP contributed to the normal functioning of the GIT, skin, and nervous system. Vitamin A was administered for exhaustion and skin disorders.

Factors with a general health-improving effect included oral intake of calcium supplements, phytin,⁴ and Phosphren. As was noted above, in asthenic syndrome, Lipocerebrin was used (15–20 days).

Measures exerting general health-improving and rehabilitating effects included transfusions of blood and its components (plasma, erythrocytes, leukocytes) which, apart from their replacement potential, had a stimulating effect on the hematopoiesis (Ivanov 1968). Blood transfusions (usually 150–250 ml/day) were given in case of hematopoiesis inhibition with accompanying malnutrition, and in cases of hematopoiesis inhibition resistant to other types of treatment. Blood transfusions were administered repeatedly at intervals of a few days. In cases of unfavorable reactions to blood transfusions, transfusions of plasma, having a hematopoiesis-stimulating property, or serum were performed. Packed erythrocytes are preferred in anemia, while leukapack (packed white cells) are preferable in leukopenia (Kurshakov 1956). Blood transfusions were combined with infusions of glucose and solution of calcium chloride and ascorbic acid.

In mild cases physiotherapy was applied. In headaches, dizziness, associated with vegetative cardiovascular and cerebrospinal fluid flow disturbances, galvanic collar was used, while in neurasthenic syndrome, hydrotherapy: baths and shower followed by massage.

In case of effective comprehensive therapy, which usually included general health-improving and symptomatic medicines, and physiotherapeutic procedures, the patients’ general condition started to improve even in the process of treatment (Alexeyeva et al. 1963; Ivanov 1968, 1971). At rest, the patients’ headaches and dizziness were noted to decrease. Diffuse headaches became localized, and their prevalence decreased. In general, there was just a temporary regression of headaches. Psychoemotional stress and physical or mental activity provoked a renewal of headaches. It is important to note that headache was one of the most common complaints the persons with CRS presented with at the initial stages. Being, evidently, a manifestation of the functional disturbances of hemo- and liquor dynamics, headache, on the one hand, was quickly treatable by means of therapy which normalizes such processes, and, on the other hand, a slightest strain (physical, emotional, or mental) induced recurrence of these disorders.

In isolated cases normalization of dosed dermographism, histamine reaction, and skin thermotopography was observed; blood pressure normalized (increased), tachycardia subsided, heart sounds became clearer, apical systolic murmur decreased, and cardio-cerebral and postural reflexes were next to normal.

The above-mentioned changes were indicative of the improved functional activity of the cardiovascular system which was probably due to the increased sympathetic nervous system tone. Approximately one third of the patients manifested improved functional activity of organs of the digestive and urinary systems. Secretion of the pancreas and intestines increased; liver function returned to normal (Alexeyeva et al. 1963; Ivanov 1968).

After the treatment, the patients manifested increased physical performance and reduced fatigability. In some patients the findings of the assessment of higher nervous activity were indicative of normalized behavioral responses; decreased irritability and improved memory, attention, and sleep were noted in the first place; the functions of the olfactory and gustatory analyzers were restored. All the above-noted changes were regarded as a sign of balance between excitatory and inhibitory processes.

As it has been mentioned above, many CRS symptoms in terms of their genesis were due to the impaired regulatory function of the nervous system. Therefore, various general restorative agents in combination with physiotherapy contributed to the reduction of visceral manifestations of CRS, through normalization of the nervous system activity. However, the positive effect of the treatment was generally unstable. Infections, stressful situations, and traumas resulted in disadaptation of the body and aggravation of the CRS course. The treatment of organic damage to the nervous system was, as a rule, unsuccessful (Ivanov 1968).

The efficacy of the comprehensive pharmaco- and physiotherapy was the highest at the early stages of CRS, but it became significantly lower as the disease progressed. The highest efficacy was achieved in mild cases of CRS, whereas in CRS of moderate severity, the effectiveness of the therapy was relatively low, and the improvement of physical well-being and health status after the treatment was unstable. In some cases, no positive effect of the therapy could be achieved. Symptomatic therapy, according to the attending doctors, did not always give the desired results. The problem was that ⁹⁰Sr, being one of the etiological factors of CRS, was retained in the skeleton for a long time, and it continued to be a source of protracted internal exposure of the surrounding tissues, especially the BM (Ivanov 1968).

It is important to note that the cessation of exposure was the factor that had the most significant effect on the recovery from radiation-induced disorders.

If patients who had suffered CRS developed somatic diseases, the treatment of the specific pathological conditions was provided.

Medicines that are of interest as potential pathogenetic agents in the treatment of CRS can be divided into the following groups:

It is well known that antioxidants regulate the level of the ROS, nitrogen oxide, and products of lipid peroxidation. They provide a protective effect against cytotoxic and mutagenic activity of free radicals and protect the cells against the oxidative damage. The most important intracellular antioxidants are glutathione and MnSOD and CuZnSOD enzymes. Antioxidants are able to directly remove hydroxyl radicals, peroxyl radicals, peroxynitrite anions, and singlet oxygen, protecting thereby the cell membranes, cytosolic proteins, and nuclear DNA (Shirazi et al. 2007). The cyclic nitroxides manifest their activity indirectly, through complex mechanisms, such as SOD-mimetic action, inhibition of lipid peroxidation, transfer of catalase-like activity to heme-containing proteins, and inhibition of the Fenton reaction. Other antioxidants (e.g., melatonin) also increase the activity of antioxidant enzymes and reduce the activity of NO-synthase pro-oxidative enzyme (Shirazi et al. 2007). Combinations of antioxidants may be more effective than individual agents (Prasad 2005).

Antioxidants, as well as radical scavengers, cytokines, growth factors, inhibitors of p53-mediated apoptosis path, and inhibitors of caspases in the process of apoptosis, also reduce the frequency of radiation-induced apoptosis in thymocytes, lymphocytes, spermatogonia, and intestinal and BM stem cells (Brown and Attardi 2005; Meyn et al. 2009).

It has been established that the suppression of the renin–angiotensin system (RAS), caused by ACE inhibitors or AII receptor antagonists, reduces or prevents functional damage in the irradiated kidneys, lungs, and skin (Moulder et al. 1998, 2007). Thiol-containing ACE inhibitors, such as captopril, are able to eliminate free radicals and to maintain endothelial cell functions in the irradiated tissues (Ward et al. 1988, 1992). AII receptor antagonists prevent radiation-induced increase of TGF_β and slow down hereby the development of fibrosis in the irradiated tissue. Other mechanisms of these drugs are associated with suppression of aldosterone which stimulates fibrosis and inhibits fibroblast proliferation in unexposed tissues (Moulder et al. 2007).

Growth factors and cytokines exert their effects through specific receptors on the surface of target cells, inducing proliferation, self-renewal, and differentiation of cells (Kaushansky 2006). The use of endothelial cell response modifiers causes a shift of the thrombohemorrhagic balance toward the procoagulant state, increase in fibroproliferative properties and chemotaxis, as well as the activation of immunocompetent cells (Hauer-Jensen et al. 2004).

It is known that radiation exposure causes excessive production of eicosanoids (prostaglandins, prostacyclins, thromboxanes, and leukotrienes) in cells. Many cells are capable of synthesizing diffusing eicosanoids, which, along with the direct effect of radiation on endothelial cells, cause impairment of hemodynamics, permeability of blood vessels, and thrombogenesis after radiation exposure (ICRP 2012).

Glucocorticosteroids (GCS) inhibit the excessive synthesis of eicosanoids which represent endogenous mediators of inflammatory reactions, formation of micro-clots, and extravasation of leukocytes and change vascular permeability. The mechanism of their action is related mainly to the inhibition of the synthesis and activity of phospholipase A2 which leads to the inhibition of the release of arachidonic acid (precursor of prostanoids and leukotrienes) from the cell membrane. The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is due to the inhibition of cyclooxygenase which directly catalyzes the synthesis of prostanoids without affecting the synthesis of leukotrienes.