The Sverdlovsk Oblast Research and Practice Association “Phthisiopulmonologiya”

THE "PHTISIO-BIOFON" DEVICE CLINICAL TEST REPORT

Ekaterinburg 2001ã

Content

Introduction

1. Subject, materials and research methods
2. Studying the “PHTISIO-BIOFON” device radiation exposure effects on the main laboratory tests data of pulmonary TB patients

1. Blood tests
2. Immunology tests
3. Biochemical tests

3. Clinical characteristics of the “PHTISIO-BIOFON” device radiation exposure effects on the pulmonary TB patients undergoing antibacterial therapy
1. Clinical observations group-wise
2. Dynamics of the intoxication symptoms in the pulmonary TB patients during chemotherapy combined with infra-red radiation (IRR) exposure.
3. Clinical X-ray dynamics in the pulmonary TB patients during chemotherapy combined with IRR exposure.

Synopsis

Report 30 pages, 9 tables, 16 reference sources

The “PHTISIO-BIOFON” device, medicobiological efficacy and safety.

Subject of the study: medical appliance “PHTISIO-BIOFON” and pulmonary TB patients.

Objective: appraisal of the “Phtysio-Biphone” device radiation exposure impact on the pulmonary TB patients receiving standard antibacterial therapy.

The following goals have been attained in the course of the study:

1. Development of the “PHTISIO-BIOFON” radiation exposure tactics for pulmonary TB patients
2. Determination of the basic laboratory criteria for appraisal of the “Phtysio-Biphone” radiation exposure effect on the pulmonary TB patients
3. Administering standard chemotherapy in combination with the “Phtysio-Biphone” radiation exposure to pulmonary TB patients.
4. Appraisal of the “Phtysio-Biphone” radiation exposure effect during pulmonary TB treatment.

The research involved microbiological, biochemical, clinical, immunology and X–ray examination methods and experimental statistics.

The study yielded the following results:

Development of the “PHTISIO-BIOFON” radiation exposure method permitting to enhance the efficacy of the standard chemotherapy administered to pulmonary patients.

Established effectiveness of “PHTISIO-BIOFON” IR radiation exposure in combination with standard TB medications (95% cases).

Use of the "PHTISIO-BIOFON" IR exposure in treatment of pulmonary TB patients allows to eliminate intoxication symptoms 1,5-2 times as fast.

Use of the "PHTISIO-BIOFON" IR device in treatment of TB patients allows to reduce the duration of the MBT release period by 98% as compared to the reference group.

During use of the "PHTISIO-BIOFON" IR device in treatment of patients spreading the drug-resistant MBT strains in 55% cases a decline in the intoxication symptoms and specific manifestations was observed.

Main laboratory criteria permitting performance control over the "PHTISIO-BIOFON" devices were established.

Introduction

Among the endless variety of infectious pathologies TB is one of the most common and formidable human chronic health threat. A sharp deterioration of the TB epidemiology has been observed in the Russian Federation in recent years manifesting itself through rise of incidence and lethality statistics (M.I Perelman, N.A. Brazhenko, M.V. Shilova).

Chemotherapy still remains the main TB treatment method. At present time the WHO recommends simultaneous use of 4 or even 5 anti-TB preparations. Recent trends are toward persistence in the disease process with the tendency to becoming chronic and increasingly drug resistant (R.P. Selitskaya). Primary drug-resistance is observed in 25% fresh pulmonary TB cases, secondary – in 30-40% with this parameter approaching 70% in chronic cases (E.S. Severin, I.E. Zykova, Yu. N. Khomyakov). These facts bear witness to insufficient effectiveness of administered therapy.

Side-effects of the anti-TB preparations are one of the main reasons for low effectiveness of the chemotherapy. A comprehensive clinical research has established that side-effects most often develop as a reaction to a specific TB medication, i.e. isoniazid, rifampicine, streptomycine. Structurally 45.7% cases are toxic reactions, 37% are allergic cases and 17.3% are complex reactions. (V.I. Chukanov, V.Yu. Mishin, O.T. Comissarova). Various pathogenetic means can be employed to reduce the side-effects in patients including physiotherapeutical methods. Though, the challenge of reducing the chemotherapy time and drug burden still remains a topical issue. (R.P. Selitskaya)

Use of streamlined antibacterial therapy policies is aimed at elimination of the infectious component, while existing immune disorders far from disappearing sometimes even worsen which in turn has a negative impact on the disease outcome.(V.I. Litvinov)

Thus growth of TB incidence is associated with appearance of resistant forms of mycobacteria, accompanied by immunity impairment and rise in toxico-allergic reactions to the main TB drugs which hinders chemotherapy efforts.

The existing situation forces to seek new TB treatment approaches. The XXI century calls for entirely new approaches in tuberculosis therapy without undue prejudice against the significance of efficient chemotherapy (A.G. Chuchalin).

The most reasonable resolution of the issue is strengthening the patient’s general immunity and specific tuberculous mycobacteria resistance enhanced by impairing the viability of the infectious agent (E.C. Severin).

In this connection of particular interest is "PHTISIO-BIOFON" a medical appliance produced by the Government-owned enterprise “Izhevsky Mekhanichesky Zavod” which is designed for treatment of TB patients in combination with standard chemotherapy.

The objective of this study was appraisal of pulmonary TB patient exposure to the “PHTISIO-BIOFON” radiation used in combination with common antibacterial therapy.

On order to achieve the objective the following tasks were assigned:

1. Development of a radiation exposure method for pulmonary TB patients
2. Determination of the primary laboratory criteria for evaluating the device exposure impact on the pulmonary TB patients.
3. Administration of the device IR therapy in combination with TB drugs
4. Appraisal of the device efficacy in pulmonary TB treatment.

The study involved microbiological, biochemical, clinical, immunology and X-ray examination methods and experimental statistics.

The used methods and the reference sources are given in the respective paragraphs of this report.

The study in question was carried out at the premises of the Sverdlovsk Oblast Research and Practice Association “Phthisiopulmonologiya” following the decision of the Pulmonology Apparatus and Appliances Commission of the Ministry of Health Committee for Innovative Medical Equipment (Sitting Minutes ¹2 of 02/17/2000). The field test of the "PHTISIO-BIOFON" device was carried out for “Izhevsky Mekhanichesky Zavod” according to Agreement ¹1996 of 04/18/2000.

1. Subject. Materials and study methods

The matter for this scientific enquiry was fresh pulmonary TB cases and the "PHTISIO-BIOFON" medical apparatus manufactured by the State-owned enterprise “Izhevsky Mekhanichesky Zavod”.

All the patients received an easy-to-understand explanation of the “Biophone” IR-therapy method. The treatment was administered to various age groups. Clinical characteristics are given in paragraph 3 of this Report. The apparatus of the “Biophone” series are electronic devices generating information-modulated non-thermal intensity electromagnetic radiation in the IR range of 0,8-30mkm wavelength and 0,1-1mWt power (hereinafter referred to as IRR, otherwise infra-red radiation). The IRR effect is based upon change of the electrostatic potential at the cellular membranes of the affected microorganisms. This rated radiation of high selectivity has the ability to inhibit the activity of pathogenic microorganisms.

This apparatus has received a positive patent-worthiness account from the State Research Institute for Patent Investigation.

The inquiries into the device capabilities carried out at the State Research Center for Applied Microbiology and the Research and Production Enterprise “Bionix” showed that IR emission of the “Biophone” appliances inhibits the viability of microorganisms. The membrane barrier function of microorganisms is affected most notably as employment of the luminoindependent chemoluminescence method demonstrated an increased penetration of non-specific matters from the surroundings into the cell. The devices of this series are efficiently used for treatment of urogenital infections.

The in vitro experiments and in vivo experiments on animals carried out by ourselves attested to inhibiting IRR effect on the viability of virulent mycobacteria tuberculosis (MBT). Observation revealed an instant dependence between the microorganism virulence and the IRR inhibiting effect. Use of the "PHTISIO-BIOFON" device in treatment of experimental tuberculosis helps to decrease the manifestation intensity of specific lesions. Use of IRR in combination with the isoniazid therapy of experimental tuberculosis boosts the chemotherapeutical effect of the drug.

The experimental laboratory material included blood, serum, tracheobronchial secretion and M.tubrculosis cultures of the patients.

For appraisal of IRR effect the main laboratory criteria, clinical X-ray examination methods and data statistics were used. The laboratory diagnostics included hematology, immunology, biochemical and microbiological examination methods.

Hematology parameters analyzed:

• Leukocyte count (standard count method in the Goryaev chamber)
• ESR (by standard Panchenko micromethod)
• Hemoglobin count method (standard hemoglobincyanide method)
• Leukogram (Romanovski-Gimse staining)

Condition of the immune system determines both the severity of the tuberculosis process and effectiveness of the administered chemotherapy. In the long run various types of immunocompetent cell imbalances up to and including immunodeficiency are viewed as unfavorable prognostic factors and serve as the evaluation criteria for meaningfulness and effectiveness of the administered chemotherapy. In connection with this during clinical tests of the "PHTISIO-BIOFON" device the immunogram was analyzed by the following main parameters:

• Relative and absolute quantity of T-lymphocytes and their subpopulations (the teophylline-sensitive and -resistant) by the Gondal et al. spontaneous rosette formation with ram erythrocytes method (as modified by K.A. Lebedeva and I.D. Ponyakina)
• Relative and absolute number of B-lymphocytes by the rosette formation with mouse erythrocytes method (as modified by K.A. Lebedeva and I.D. Ponyakina)
• Phagocytosis activity of neutrophils in the NST-test by latex incubation method
• Circulating immune complexes in the blood serum by the precipitation method in 3.5% solution of polyetheleneglycol with subsequent colormetering in spectrophotometer by Haskov V. et al technique as modified by Yu.A. Grinevich and A.N. Alferov
• Average molecules determinaion was carried out in SF-46 spectrophotometer to evaluate the degree of endogenic intoxication
• TB antibodies titre in blood serum by the Middlebrook-Dubeau method, by means of passive hemaglutination reaction using the diagnosticum of the Leningrade Vaccine and Serum Research Institute, as the TB antibodies quantity dymamics being in instant dependence on the clinical X-ray data can serve as a reliable criterion in observation of the TB process.

Biochemical data characterize the basic physiological functions of the system and provide important parameters helping to monitor the safety of the patient exposure to IRR. Change in the parameters reflecting the functional condition of the liver and kidneys is a symptom of intoxication. The following monitoring parameters were adopted:

• Determination of total blood serum protein by the Biuret method (“Rajchem” reagents)
• Determination of the globulin-thymol-lipids content through a standard thymol turbidity test in veronal buffer
• Determination of blood serum protein fractions by standard paper electrophoresis method
• Determination of ÀëÀÒ and ÀñÀÒ ferment activity with “Rajchem” reagents
• Bilirubin determination by standard L. Jendrassjk, R. Cleghom method involving the daizoreaction technique
• Urea and creatinine determination by standard methods

Throughout the course of treatment the laboratory monitoring was accompanied by X-ray monitoring of the parameters with keeping individual records for each patient. The X-ray examination was carried out in conformity to the planned schedule. The X-ray examination was carried with the help of Siemens TUR D-800 apparatus and involved a general lungs roentgenogram and when necessary a targeted roentgenogram and tomography of the individual lung parts. In complicated cases bronchial examination by means of fibrebronchoscopy was carried out. Since negative sputum test serves as one of the treatment effectiveness parameters, special focus was placed on microbiological examination of the patients. The following examination pattern was adopted: 3 pre-treatment bacteriological tests by the irritant inhalation method with culturing onto two nutrient mediae (Levenstein-Jensen and Novaya) followed by luminescence bacterioscopy with the help of the “Lumam-IZ” microscope and a full monthly bacteriological examination during treatment.

The mycobacteria tuberculosis culturing was accompanied by culture identification and drug sensitivity determination. The isolated mycobacteria cultures were tested by absolute concentrations on the dense culturing media “Novaya” for sensitivity to the major contra-TB medications: tubazide (1, 5, 25, m g/ml), streptomycine (5, 10, 50, m g /ml), rifampicine ( 20, 50, m g /ml), kanamycine (30, 50, m g /ml), tibon (2, 5 m g /ml).

Identification of the isolated cultures was done by the cultural and biochemical methods: through assessment of growth peculiarity and growth rates on various culturing mediae in different ambient temperature, pigment formation, Tween-80 hydrolysis.

2. Looking into the “PHTISIO-BIOFON” device radiation exposure effects on the main laboratory data of pulmonary TB patients

In accordance with the initial examination program and in conformity to the laboratory criteria set for inquiry into the impact of the "PHTISIO-BIOFON" device radiation on the hematology, immunology and biochemical parameters, blood sampling in the exposure study group of patients (62 individuals) and the reference group (34 persons) was carried out before exposure and then every ten days. Clinical characteristics of the patient body are given in paragraph 3.1 of this report.

2.1. Blood tests

Hematology examinations is a common clinical practice. Total blood count provides a readily obtained, cost-effective and informative tool.

For assessment of the IRR exposure effects on the blood count in the pulmonary TB patients we employed standard methods, mentioned in paragraph 1 of this report.

The obtained results are shown in Table1

The analysis of the obtained data revealed no significant difference in blood counts between the IRR exposure and the reference groups of patients

Table 1
The hematology parameters for the pulmonary TB patients

2.2. Immunology tests.

In order to assess the impact of the "PHTISIO-BIOFON" device radiation on the immunology data blood sampling in the exposure group of patients (62 individuals) and the reference group (34 persons) was run in conformity to the determined criteria before exposure and then every other decade as was initially planned.

The standard test methods used are mentioned in paragraph 1 of this report.

The obtained data are shown in Table 2

Table 2
Immunology data for the pulmonary TB patients

The analysis of the obtained data revealed no significant difference in immunology test data between the “Biophone” IRR exposure and the reference groups of patients

2.3 Biochemical tests

In accordance with the initial examination program and in conformity to the criteria determined for inquiry into the impact of the "PHTISIO-BIOFON" device radiation on the hematology, immunology and biochemical parameters blood sampling in the study exposure group of patients (62 individuals) and the reference group (34 persons) was carried out before exposure and then every decade.

The used standard test methods are mentioned in paragraph 1 of this report.

The obtained data are given in Table 3.

Table 3
Biochemical data for the pulmonary TB patients

The analysis of the obtained data did not reveal any significant difference in the major biochemical parameters between the exposure and the reference groups of the pulmonary TB patients.

Thus, based on the data analysis results it is safe to assume that the “Biophone” IRR does not have any adverse impact on the main blood, immunological and biochemical data of the pulmonary TB patients.

3. Clinical characteristics of IRR exposure effects on the pulmonary TB patients receiving antibacterial therapy

The patients received standard treatment involving the full range of TB medications.

Frequency and duration of exposure to the "PHTISIO-BIOFON" emission conformed to the instruction worked out by ourselves.

1 day – 4 exposures with a 6 hours interval; 2^nd day – 3 sessions with an 8 hours interval; in the 3d through 7^th day period 2 sessions daily with a 12 hours interval; starting on the 8^th day and through the 30^th day one daily exposure.

Exposures were administered individually to each patient. Total number of treatment sessions amounting to 10 in every case. All the patients received a comprehensible explanation of the “Biophone” therapy essence. Treatment was administered to patients form 16 to 63 years of age with a variety of accompanying pathologies.

3.1. Clinical observations group-wise

The study embraced 96 patients with various forms of fresh pulmonary TB cases.

The main group included 62 patients, who received a comprehensive tuberculostatic treatment combined with exposure to the “Biopone” device emission. The group’s sex ratio was 83.3% males (n=52) and 16.7% females (n=10).

The reference group comprised 34 patients, undergoing treatment with the tuberculostatic medications withut exposure to the “Biophone” emission. The check group sex ratio was 82.4% males (ï=28) and 17.6% (ï=á) female patients.

Table 4 contains the age data for the pulmonary TB groups

Table 4
TB patients age data

As is evident from the table data the majority of the patients in both the groups were between 31-50 years of age, 77.% in the study group and 70.6% in the reference group.

TB form distribution of the patients is shown in Table 5

Table 5
Clinical TB forms in the pulmonary patients

As is evident from the table above the majority of the study group patients 32.3% had a disseminated form of TB. The second in strength were the infiltrative TB patients 30.0%, with 29.4% and 38.2% in the reference group respectively.

The main TB case severity criteria are presence of tissue destruction and MBT release. The criteria-wise distribution of the TB patients is shown in Table 6.

Table 6
Distribution of patients by the tissue destruction and MBT release criteria

As is obvious from the table above 46.3% patients in the study group revealed presence of MBT in sputum while 40% had caverns in the lung tissue (49,9% and 40,6% in the reference group respectively).

3.2. Dynamics of the intoxication symptoms in the pulmonary TB patients during chemotherapy combined with radiation exposure.

Treatment effectiveness of the primary pulmonary TB patients was appraised by a set of criteria: speed of intoxication symptoms disappearance, X-ray of the lung process dynamics, MBT release discontinuance time as well as laboratory blood and immune reaction tests.

Intoxication symptoms provide an important case severity criterion. For laboratory criteria leukocytes, lymphocytes count and ESR were assumed.

The 4.0 – 7.0 ´ 10⁹/l leukocyte count was regarded as normal, the 7.0-9.0´ 10⁹/l as a moderate increase; over 9.0´ 10⁹/l as a considerable rise.

The 27-30% lymphocyte count in peripheral blood was considered normal. A drop to 22% was viewed as moderate lymphopenia and below 22% as considerable lymphopenia.

A 10-12mm/h ESR was considered normal, ESR below 25mm/h was viewed as a moderate rise in sedimentation speed, above 25mm/h as a pronounced growth.

The study and reference group patients were divided into three categories by the degree of intoxication symptoms. The first category comprised the patients with satisfactory condition. The patients with weak intoxication symptoms in form of slight indisposition, sweatiness, weakness, sporadic subfebrility, up to 25mm/hr ESR and up to 8.0´ 10⁹/l leukocytes on the laboratory side constituted the second category. The third category of patients included the cases with febrile temperature, leukocyte count in excess of 8.0´ 10⁹/l and considerable ESR rise (over 25mm/hr). The level of intoxication symptoms is directly related to the process severity. These symptoms are most pronounced during the infiltrative and disseminated forms o TB.

The symptom dynamics for the pulmonary TB patients of the study and reference groups is shown in Table 7.

As a result of the integrated treatment including exposure to the “Biophone” apparatus emission the number of asymptomatic patients in the study group grew within a month from 12.9% to 83.9% followed by a rise to 91.9% in two months (see Table 7)

Weak intoxication symptoms were noted in 59.7% patients before the start of treatment in 9.7% cases after a month-long therapy and in 8.1% patients after two months.

During the first month of treatment the percentage of patients with pronounced intoxication symptoms decreased five-fold becoming 6.5% . By the end of the second months none of the patients had such symptoms.

By the end of the first TB treatment month the intoxication symptoms were absent only in 52.9% cases in the reference group, weak symptoms were noted in 35.5% patients (Table 7), well pronounced symptoms in 11.8% patients. After a two month long treatment only 88.3% patients in this group proved asymptomatic.

The comparative analysis of the intoxication symptoms data showed that well pronounced intoxication symptoms were diagnosed in the study group 1.5 times as often as in the reference group (p<0.05). Within one month from the start of treatment considerably pronounced intoxication manifestations were present only in 6.5% study group cases and in 11.8% reference group cases (p<0.1).

Table 7
Intoxication symptoms dynamics in the pulmonary TB patients undergoing treatment

The majority of cases in both the groups were characterized by weak intoxication manifestations with the percentage amounting to 59.7% and 58.8%.

Within a month after the start of treatment this ratio changed notably. In the group where the patients received integrated TB therapy in combination with the “Biophone” exposure the protion of cases characterized by weak intoxication symptoms dropped from 59.7% to 9.4% whereas in the reference group the change was from 58.8% to 35.5% (p<0.05).

As follows from the data (Table 7) in the group where patients received the “Biophone” exposure therapy a quicker and more notable regression of the intoxication symptoms happens at the initial stage of TB treatment. After two months of treatment the intoxication symptoms were coped up with in 83.9% cases of the study group and only in 52.5% cases of the check group (p<0.5). By the end of institutional treatment the groups did not differ much in this parameter.

3.3. Clinical X-ray dynamics in the pulmonary TB patients during chemotherapy combined with IRR exposure

Treatment effectiveness of the primary pulmonary TB patients was appraised by a set of criteria: including X-ray of the lung process dynamics and MBT release discontinuance. The employed methods are described in paragraph 1 of this Report.

The X-ray of the lung process dynamics is shown in Table 8

Table 8
Process X-ray dynamics

The main group showed a quicker X-ray dynamics of (from 41% to 1.6%). Decrease from 8.3% to 2.9% in the check group.

The analysis of the lung process dynamics X-ray revealed that pronounced and moderate resolution of focal and infiltrative lung lesions took place in 70.2% cases of the study group and in 18.5% cases of the reference group.

The groups did not differ notably in the perspective of destruction caverns healing, during a six months long observation.

The microbiological research data obtained by MBT culturing are given in Table 9.

Table 9
MBT release dynamics

Inquiry into the MBT release cessation time revealed that MBT release cessation within the first month of treatment occurs positively more frequently in the study group than in the check group. As is evident from Table 9 MBT release cessation was achieved by the end of the first month of therapy in 74.2% cases of the study group and in 33.3% cases of the reference group.

Summary

As the result of the study it was found that:

A "PHTISIO-BIOFON" apparatus exposure method has been developed permitting to enhance treatment of pulmonary patients receiving standard chemotherapy.

The "PHTISIO-BIOFON" device IRR exposure has been found effective in combination with TB medications (average 95%).

Use of the "PHTISIO-BIOFON" IRR exposure in the pulmonary TB therapy allows to eliminate the intoxication symptoms 1.5-2 times as quickly.

Use of the "PHTISIO-BIOFON" IRR exposure in the pulmonary TB therapy permits to shorten the MBT release cessation time on the average by 98% in comparison to the check group.

It was found that use of the "PHTISIO-BIOFON" IRR exposure in the pulmonary TB therapy administered to patients releasing drug-resistant MBT leads to elimination of the intoxication symptoms and specific manifestations in 55% cases.

There were determined main laboratory criteria allowing development of the "PHTISIO-BIOFON" device performance control parameters.

List of reference sources

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