RU2181046C2 - Method to treat hemorrhagic fever at renal syndrome - Google Patents

Abstract

FIELD: medicine, therapy of infectious diseases. SUBSTANCE: patients are prescribed to apply iodantipyrine at the early terms of the disease in question, not later than the fifth day, perorally - during the first 4 d per 0.2 g (2 tablets) 3 times daily, during the next 5 d per 0.1 g (1 tablet) 3 times daily. A total course corresponds to 9 d. The suggested treatment is conducted at the background of the common therapy which includes application of isotonic solutions of glucose and sodium chloride, ascorbic acid, antihistaminic preparations, desaggregants, diuretics. EFFECT: shortened duration for periods and separate symptoms of the disease. 2 ex, 6 tbl

Description

 The invention relates to medicine, namely to infectious pathology, in particular to the treatment of hemorrhagic fever with renal syndrome (HFRS) in the early stages of the disease.

 A common method for the treatment of HFRS is pathogenetic therapy aimed at reducing intoxication, restoring circulating blood metabolism, improving rheology and microcirculation, reducing vascular permeability, normalizing the acid-base state, and relieving pain (Therapeutic Archive, 11, 1995, p. 30-33) . However, this therapy is not always effective in preventing the severity of the disease. With this method of treatment, there is no effect on the etiological factor of the disease - the virus, also the immunological reactivity of the body, and the interaction of these two factors plays a role in the pathogenesis of HFRS.

 Despite the successes of modern medicine, the treatment of HFRS remains an urgent problem. A search is underway for the treatment of HFRS with interferon inducers.

 There is only one report in the literature about an attempt at immunocorrective therapy of HFRS with a thymogen that combines the properties of a stimulator of the cellular immunity unit and an interferon inducer. However, the expected therapeutic effect in comparison with the control group was not obtained (Clinical and immunological monitoring of the effectiveness of the use of thymogen in HFRS. V.I. Roshchupkin et al., 1989, p. 181-182).

 In the patent literature and open publications, we could not find information on the use of iodantipyrine for the treatment of patients with HFRS.

 The technical result is a reduction in the duration of periods and individual symptoms of the disease.

 The proposed method of treatment is as follows: for the treatment of HFRS patients, iodantipirin is prescribed in the early stages of the disease, not later than 5 days of illness, orally - in the first four days, 0.2 g (2 tablets) 3 times a day, in the next 5 days 0.1 g (1 tablet) 3 times a day. General course 9 days. This treatment is carried out against the background of conventional therapy, including isotonic solutions of glucose and sodium chloride, ascorbic acid, antihistamines, antiplatelet agents, diuretics.

Iodantipyrine (1-phenyl-2,3-dimethyl-4 iodopyrazolone) belongs to the group of non-steroidal anti-inflammatory drugs derived from pyrazolone, has anti-inflammatory, antiviral, immunostimulating and interferonogenic properties. The drug is an active inducer of alpha and beta interferons, significantly increases the activity of fibroblasts and induces their antiviral resistance, delays the penetration of the virus into the cell due to the stabilizing effect on biological membranes, and significantly stimulates the production of antibodies. A clinical study of the drug as a tool for the treatment and prevention of tick-borne encephalitis, influenza and other acute respiratory viral infections in adults has been conducted. Good clinical and laboratory results were obtained that made it possible to recommend iodantipyrine for widespread use (Actual issues of focal infections, 1998, pp. 244-245). Iodantipirin is economically available, it can be purchased in the pharmacy network and always be with you, since it does not require special conditions for storage,
To assess the effectiveness of therapy, patients were divided into two groups. The first group - 67 patients received only conventional pathogenetic therapy and made up the control group. The second - out of 74 patients, in addition to conventional therapy, received iodantipyrine. The object of study was patients with a moderate and severe form of the disease, since with a mild form there are no pronounced immunopathological and clinical manifestations of the disease.

As criteria for the effectiveness of therapy, we used the following indicators: 1) clinical - duration of fever, pain, duration of oliguria, 2) biochemical - peak levels of urea and creatinine, 3) the dynamics of some indicators of immunity - a subpopulation of CD ₃ . CD ₄ , CD ₈ lymphocytes, phagocytic index, B-lymphocytes, 4) dynamics of indicators of interferon status - serum IFN, alpha-IFN.

 Assessing the positive effect of immunomodulating therapy, we primarily relied on clinical criteria for effectiveness.

 As can be seen from table 1, in patients with moderate severity of HFRS who received iodantipyrine, the duration of symptoms such as fever, oliguria, lower back pain, and stomach pain was significantly less than in patients from the control group. A significant decrease in the peak values of urea and creatinine in the experimental group was also revealed. In patients with severe HFRS who received the test drug, the duration of fever and lower back pain also significantly differed. The difference in the duration of oliguria, abdominal pain, and headache in patients of both groups was unreliable. Peak creatinine was significantly lower in the experimental group, and urea did not have a significant difference (table 2).

 Iodantipirin in the dosage regimen we developed was well tolerated by patients; no side effects and allergic reactions were reported. Although it should be noted that its oral administration may be limited in cases with the presence of severe vomiting in patients.

The results obtained in the study of CD ₃ , CD ₄ , CD ₈ lymphocytes, phagocytic index, B-lymphocytes, showed that the dynamics of cellular immunity indicators depended on the severity of patients with HFRS.

As can be seen from tables 3 and 4, immunological parameters in the oliguric period did not significantly differ in the groups. In the polyuric period, an increase in the relative number of CD ₃ , CD ₄ lymphocytes was observed with moderate and severe form of HFRS. As for the level of CD ₈ lymphocytes, the data obtained are somewhat contradictory: in moderate form this indicator did not significantly differ in both groups, and in severe form in the experimental group the indicator was significantly lower than in the control. Phagocytosis of neutrophils in the experimental group in the polyuric period was characterized by high phagocytic index. Reliably high values of B-lymphocytes were revealed. In the period of convalescence in moderate form, the relative number of subpopulations of CD ₃ , CD ₄ , CD ₈ lymphocytes remains significantly higher in the experimental group and approaches the values of healthy individuals. The phagocytic index and B-lymphocytes in this period did not significantly differ in the groups. In severe form, a general tendency toward normalization of cellular immunity indices was observed, but there was no statistically significant difference in both groups.

 Thus, in general, according to the analysis of the above characteristics of cellular immunity in the two studied groups of patients, we can talk about the presence of the immunomodulating effect of iodantipirin in the category of patients with moderate to severe disease.

 With the early appointment of iodantipirin, a significantly rapid increase in the activity of the IFN system was revealed.

 As can be seen from table 5, with a moderate form of HFRS, there were no significant differences in the increase in titer of serum IFN in comparable groups in the oliguric and polyuric periods. By the time of discharge, the level of serum IFN in the experimental group was significantly lower than in the control. The increase in the ability of leukocytes to produce alpha-IFN occurred later to the period of convalescence in the experimental group.

 In severe HFRS, the level of serum IFN during all periods of the disease remained high in both groups and did not significantly differ. The level of alpha-IFN was reduced in comparison with the same indicator in patients with a moderate form of the disease. During the convalescence period, the level of alpha-IFN tended to increase, which was more pronounced in the experimental group, but the indicators did not significantly differ (table 6).

 High titers of serum IFN in the midst of the disease, apparently, are associated with high interferonogenic activity of blood cells and other systems involved in the pathological process, as well as high interferonogenic activity of the HFRS virus itself.

 In the oliguric period, a decrease in the ability of leukocytes to produce alpha-IFN was observed, probably this is due to the inhibitory effect of the HFRS virus on the production of alpha-IFN. The increase in the ability of leukocytes to produce alpha-IFN during the recovery period was consistent with the known data on the normalization of indicators of cellular and humoral immunity at the same time.

 Thus, the early administration of iodantipyrine contributed to a greater increase in the interferonsynthetic ability of leukocytes in moderate to severe HFRS, but in moderate form this ability was more pronounced.

 Examples of specific applications of the proposed method of treatment.

 Example 1

 Patient P., 30 years old, was treated in the 8th department of CIB 4 from October 5 to October 26, 1999. Clinical diagnosis: Hemorrhagic fever with renal syndrome, moderate.

 The diagnosis was confirmed by the serological method (increase in titer of antibodies and HFRS virus in paired sera 1: 256-1: 1024).

He was admitted to the hospital on the 4th day of illness. In the anamnesis: the disease began acutely, with a rise in temperature to 39 ^o C, chills, headache. On the 3rd day of the disease, pain in the lumbar region, nausea, weakness appeared. He took antipyretics at home. On October 4, he went to the local doctor and was hospitalized on October 5.

 Epidemiological history: Periodically went to the garden site, noted cases of infection (HFRS) among neighbors in the garden. There is no history of chronic diseases.

An objective examination at the time of admission of the patient to the hospital - the patient is in a serious condition, conscious, severe intoxication, body temperature 38.8 ^o C.

 Hyperemia of the skin of the face, neck, upper body, injection of sclera. Enanthema in the soft sky. On the lateral surfaces of the trunk, a small point rash.

 The vesicular breathing, the cardiac sounds are muffled, tachycardia up to 96 beats per minute, blood pressure = 120/60 mm RT. Art. Palpation of the abdomen - moderate soreness in the area of the projection of the kidneys, severe soreness when striking the lumbar region.

 The patient was prescribed infusion therapy - hypertonic glucose solution, ascorbic acid, desensitizing drugs. From October 6 (on the 5th day of illness), the patient was prescribed iodantipirin 0.2 g (2 tablets) 3 times a day, and from October 10 to 0.1 g (1 tablet) 3 times a day. General course 9 days.

On October 6, the patient's condition remained severe, the temperature remained up to 38.9 ^o C, pain in the lumbar region, decreased urine. The next day, the temperature dropped to 37.3 ^o C, and from October 8, it returned to normal. The manifestations of intoxication and pain were gradually reduced. Daily diuresis on October 6 was 800 ml, on October 7 - 850 ml, on October 9 - 900 ml, and on October 10 - about 2 liters, then polyuria developed up to 3.2 liters per day, which lasted 5 days. The period of recovered diuresis proceeded normally, without complications, and the patient was discharged in satisfactory condition.

 Laboratory data from October 6th.

General blood test - hemoglobin 162 g / l, red blood cells 5.3 • 10 ¹² / l, white blood cells 6.5 • 10 ⁹ / l, stab 3%; segmented nuclear 70%, lymphocytes -13%, eosinophils 2%, monocytes 12%, platelets 69 • 10 ⁹ / l, ESR 5 mm / h, IPI 89%, blood coagulation time 4 '15 ".

 Biochemical analysis of blood: creatinine 132 μmol / l, urea 8.2 mmol / l, ALT 26 IU / l, ACT 30 IU / l, total bilirubin 4.8, thymol sample 2.7.

Urinalysis: relative density 1018, protein 0.66% ₀ , hyaline cylinders - single.

October 8 (on the 7th day of illness) - azotemia (creatinine 280 μmol / l, urea 14.1 mmol / l), in the analysis of urine - relative density 1010, protein 3.3% ₀ , red blood cells 0-1 in the field of view .

 After 9 days of treatment (October 15) - blood creatinine 110 μmol / L, urea 6.0 mmol / L. Urinalysis: relative density 1014, negative protein, 0-1 epithelium in the field of view.

Immunity indicators
In the oliguric period: CD ₃ 43.4%, CD ₄ 29%, CD ₈ 30%, B-lymphocytes 14%, phagocytic index 40%.

In the polyuric period (after the end of treatment with iodantipyrine): СО ₃ 50%, CD ₄ 34%, CD ₈ 30%, B-lymphocytes 10%, phagocytic index 56%.

In the period of convalescence: СО ₃ 61%, CD ₄ 40%, CD ₈ 35%, B-lymphocytes 18%, phagocytic index 67%.

Indicators of interferon status:
In the oliguric period: serum IFN 87 IU / ml, alpha-IFN 130 IU / ml.

 In the polyuric period (after the end of treatment with iodantipyrine): serum IFN-130 IU / ml, alpha-IFN-175 IU / ml.

 In the period of convalescence: serum IFN 87 IU / ml, alpha-IFN 260 IU / ml.

 As can be seen from the above observation, the appointment of iodantipyrine in the complex treatment of a patient with moderate form of HFRS had a positive effect on the clinical course of the disease, on cellular immunity and indicators of interferonogenesis.

 Example 2

 Patient N., 43 years old, medical history 8768, was hospitalized in the CIB of 4 Ufa from October 6 to November 1, 1999.

 Clinical diagnosis: "Hemorrhagic fever with renal syndrome, severe course. Complication - ITS-11 degrees, DIC syndrome. The diagnosis was verified by the serological method: in paired sera in MFA, the titer of antibodies to HFRS virus increases 1: 16-1: 1024.

Received on the 3rd day of illness. He became acutely ill with an increase in body temperature up to 40 ^o C, chills, lower back pain, and also impaired vision and short-term nosebleeds. After examination by a local doctor, he was hospitalized in CIB 4.

 In the epidemiological history - he constantly went to the garden plot in the Demsky district, noted cases of HFRS among neighbors in the garden plot.

 Complaints at admission: body aches, back pain, weakness, dizziness, headache, blurred vision, nausea.

 Objectively: the condition is severe, lethargic, hyperemia of the skin of the face, neck, upper third of the chest, hemorrhages in the sclera, and a small-pointed hemorrhagic rash on the skin of the chest. In the lungs weakened vesicular breathing, respiratory rate of 22 per minute. Heart sounds are muffled, the rhythm is correct, the pulse is 110 beats per minute, blood pressure is 100 / 70-90 / 70 mm Hg. Art. The tongue is dry, covered with a white coating. The abdomen on palpation is soft, painful in the area of the projection of the kidneys. The symptom of lumbar effusion is positive on both sides.

 Given the severity of the condition, the patient was hospitalized in the intensive care unit. Infusion therapy was prescribed - 10% glucose solution with insulin, 4% sodium bicarbonate solution, prednisone 90 mg intravenously, desensitizing drugs. From October 7 (on the 4th day of illness), iodantipyrine was prescribed in a daily dosage of 0.6 g, and from October 11, 0.3 g per day. The total duration of therapy is 9 days.

Laboratory data from October 6:
Complete blood count: hemoglobin 161 g / l, red blood cells 4.9 • 10 ¹² / l, white blood cells 6.9 • 10 ⁹ / l, ESR 20 mm / h, platelets 190 • 10 ⁹ / l, stab 4%, segmented 76 %, lymphocytes 10%.

General analysis of urine: relative density 1060, protein 3.3% ₀ , red blood cells 4-6 in the field of view, cylinders in large numbers.

 The creatinine level is 103.2 μmol / L, and urea is 6.3 mmol / L.

 On October 7, the patient's condition remained severe, hypotension of 80/70 mm Hg was observed. Art., daily diuresis was 450 ml.

On the day of the appointment of iodantipyrine, a decrease in body temperature to 37.4 ^o C was noted, and on the next day its normalization. On the 6th day of illness, October 9, daily diuresis was 350 ml, vomiting was observed up to 5 times a day, abdominal pain.

 Thus, the duration of the febrile period was 4 days, oliguria - 4 days. The highest level of azotemia was observed on October 13, on the 10th day of the disease (creatinine 428 mmol / l, urea 24 mmol / l), but the daily diuresis on this day was already 3 liters.

 After iodantipyrine therapy, laboratory indicators were as follows.

Complete blood count: hemoglobin 122 g / l, red blood cells 3.8 • 10 ¹² / l, white blood cells 8.8 • 10 ⁹ g / l, ESR 10 mm / h, platelets 325 • 10 ⁹ g / l, lymphocytes 42%, stab 4%.

Urinalysis: relative density 1005, protein 0.006% ₀ , white blood cells 0-1-0 in the field of view, red blood cells 0-1-2 in the field of view.

Creatinine level 88 μmol / L, urea 5.0 mmol / L
Immunogram data:
Oliguric period - CD ₃ 37%, CD ₄ 24%, CD ₈ 25%, B-lymphocytes 11%, phagocytic index 49%.

The polyuric period is CD ₃ 39%, CD ₄ 24%, CD ₈ 26%, B lymphocytes 15%, phagocytic index 32%.

The convalescence period is CD ₃ 43%, CD ₄ 29%, CD ₈ 31%, B-lymphocytes 17%, phagocytic index 52%.

 The patient was discharged in satisfactory condition under the supervision of a local doctor.

 As can be seen from the above example, the appointment of iodantipyrine in the complex treatment of a patient with severe HFRS had a positive effect on the clinical course of the disease and indicators of cellular immunity.

 Iodantipyrine, apparently having an antiviral effect, affects the level of viremia, as evidenced by a more rapid decrease in temperature. One of the mechanisms of action of iodantipyrine is the delay in the penetration of the virus into the cell and the induction of the synthesis of interferon, antibodies, resulting in an interruption of the pathological process.

 Based on our data, it can be concluded that a dynamic assessment of changes in indicators of cellular immunity and interferon status revealed the importance of these disorders in understanding the mechanisms of the pathogenesis of HFRS. The noted positive effect when using iodantipyrine allows pathogenetically substantiating the feasibility of using interferon inducers as part of the complex treatment of patients with moderate and severe HFRS.

Claims (1)

 A method of treating hemorrhagic fever with renal syndrome with an immunocorrective drug against the background of conventional therapy, characterized in that iodantipyrine is used as an immunocorrective drug in the early stages of the disease, not later than 5 days of illness and for 9 days, with the daily dose of 0 6 g, followed by a dose of 0.3 g.

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