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OBJECTIVES: The aim of this study was to assess the long term clinical outcome of patients with achalasia after treatment with botulinum toxin. METHODS: Sixty five patients with achalasia (60 idiopathic, five secondary) were treated with injection of botulinum toxin at the gastroesophageal junction. Dysphagia, chest pain, and regurgitation were scored (0 = no symptoms, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe), with the sum representing the total symptom score, at 0, 7, 30, 120, 240, and 365 days posttreatment. Responders were defined as patients with a 50% decrease in total symptom score at 1 month posttreatment. RESULTS: The 60 patients with idiopathic achalasia had significant improvement in symptoms of dysphagia, chest pain, and regurgitation at 1 and 4 wk posttreatment. At 1 month posttreatment, 42 of 60 patients (70%) were classified as responders. Of 33 patients with at least 1 yr follow-up, 36% continued to have a good or excellent response, whereas 39% underwent a subsequent treatment with botulinum toxin, pneumatic dilation, or myotomy. When symptoms recurred after an initial response, patients responded to a second injection of botulinum toxin in six of seven cases. In four of five patients with secondary achalasia, there was no response to botulinum toxin. CONCLUSIONS: Botulinum toxin injection at the gastroesophageal junction significantly improved symptoms in 70% of patients with idiopathic achalasia at 1 month. Recurrent symptoms responded to repeat botulinum toxin treatment in initially responsive patients. In contrast, most patients with secondary achalasia did not improve after botulinum toxin injection.

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Multifactorial analysis was used to study the influence of rifampicin on the dynamics of synthesis of antibodies belonging to IgM and IgG classes in mice immunized by fraction I of the vaccinal strain EV. Equations and quadric surfaces describing individual dynamics of antibody formation within a wide range of antibiotic doses and time of antibody content determination were developed by the experimental data. It was shown that within the range of the doses corresponding to the therapeutic ones in man rifampicin stimulated antibody formation. It had an inhibitory effect on antibody genesis only when used in the doses many times higher than the therapeutic ones.

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The impact of changes in the ratio of the medium-668 components on growth and synthesis of ergot alkaloids in saprotrophic cultures was studied with mathematical design of the experiment. Medium-668 used for cultivation of strain VNIIA-312A-producing peptide +ergot alkaloids was shown to be balanced with respect to the ratio of all the medium components. An important role of phosphate in control of culture growth and alkaloids synthesis was elucidated. It was demonstrated that by changing the ratio of the medium components it was possible to control accumulation and excretion of the alkaloids which permitted development of the conditions required for product isolation.

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The effect of doxycycline combination with a low molecular immunomodulator of microbial origin on the primary immune response to the vaccine EV antigens was studied in multifactor experiments. Mathematical processing of the data provided construction of polynomial statistic models of the second order describing increased delayed type hypersensitivity (IDTH) and the antibody titer. Analysis of the quasimonofactor models revealed different character of regulation of the cellular and humoral response. Nomograms were plotted for precise quantitative estimation of the dose-time parameters of the regimens for combined use of the antibiotic and immunomodulator providing the required levels of IDTH and the antibody titer.

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Multifactor analysis was applied to combined effect of a low molecular immunomodulator of microbial origin and rifampicin on the primary immune response (increased delayed type hypersensitivity and antibody titer) to the antigens of vaccine EV fraction I. Computer processing of the experimental data provided construction of the 2nd order polynomial models satisfactorily describing cellular and humoral responses in the combined therapy. For increasing the informative capacity of the analysis of the polynomial statistic models it was proposed to develop quasimonofactor relationships reflecting the factor effect on the output with changing of the other factors within the studied ranges. Nomograms (equal level lines at fixed values of one factor) were constructed which provided rapid and correct estimation of optimal values for the regulating parameters (drug doses and administration time). Immunostimulating activity of the microbial immunomodulator was estimated quantitatively and conditions for selective regulation of the cellular and humoral responses were determined.

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To provide constant control of drug resistance in causative agents of surgical infections an automatized data bank based on computer SM-4 was filed at the All-Union Research Institute of Antibiotics. The bank includes information on 1500 objects described by 60 indices referring to the isolated pathogens. For every particular strain there are indicated data on the patients, characteristics of the pathogen biochemical profiles and sensitivity to various antibiotics (28 drugs). The data were obtained during identification of the cultures with automatized microbiological systems. The major functions of the data bank and standard information requests performed on its basis during solving particular epidemiological and clinical problems are described.

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Methodological approaches to investigation of the protective effect of natural immunomodulators are described. The use of multifactorial experiment design, a model of infectious processes and immunomodulators alone or in combination with antibiotics is implied. Theoretical preconditions for rational choosing of the experimental factors and their levels, as well as specific designs are discussed. Potentialities of polynomial statistic model analysis in development of optimal regimens for combined chemoimmunotherapy are shown.

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Experimental design was used in studying the effect of certain qualitative factors on rheological properties of antibiotic hydrogels. It was shown that water solubility of antibiotics and the procedure of their addition to gel bases were important in developing hydrogels. Scanning electron microscopy was used in comparative analysis of antibiotic hydrogels.

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Hard- and software of a distributed system for computer control of experiments on cultivation of microorganisms is described. The system is based on microprocessor techniques and minicomputer CM-4(1420). It provides intensification of microbiological studies due to rational management of experiments, accumulation and long-term storage of experimental data and their processing with specific algorithms for providing additional information on biosynthetic processes and optimization of fermentation conditions.

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Mathematical design of the experiment permitted detection of the action of independent factors of the component composition on antibacterial activity and rheological properties of polymyxin ointment. Optimal compositions of polymyxin ointment based on polyethylene oxide emulsion were scientifically grounded and recommended for further experimental investigation on animals.

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The effect of rifampicin combination with a natural low molecular immunomodulator on the primary immune response to the antigens of tularemia vaccine was studied with the methods of multifactor designing of the experiment. The dependence of the delayed hypersensitivity and antibody titer on doses of the antibiotic and immunomodulator and the time of the immunomodulator administration was manifested by the second order equation. Nomographs for precise quantitative estimation of the doses and regimens providing the maximal delayed type hypersensitivity and antibody titers were plotted.

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The effect of the combined use of doxycycline and glucosaminylmuramyl dipeptide (GMDP) on the primary immune response to antigens of tularemia vaccine was studied on CBA male mice with the use of the multifactorial design of experiment. Antibodies to the blood serum of the immunized animals were determined by the passive hemagglutination test with the use of the tularemia antigen diagnosticum. The delayed type hypersensitivity was estimated by changes in the weight of the extremities of the experimental and control animals treated with the antigen and saline solution, respectively. The multifactorial experiments provided precise quantitative characteristics of the optimal dose-time schedule for the combined use of GMDP and doxycycline.

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Centrifugal extractors of the differential-contact type are widely used all over the world in production of antibiotics. Lately, new extractors were developed by Hitachi (Japan). Model E is of a special interest. In the present study the values of the working zone of the Hitachi extractor, EP-02 Ultrex were determined by the pressure levels and the effect of the main parameters characterizing the apparatus hydrodynamic conditions on the minimum and maximum critical pressure was estimated. The results of the study provide wide variation of the hydrodynamic parameters in determination of the most rational extraction conditions.

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A procedure for calculating sediment distribution on horizontal filtering elements of multileaf filters used for separation of antibiotic suspensions, as well as for calculation of the filtration time in such apparatus is described. The correlations derived on the basis of this procedure may be used for preliminary technological evaluation of the stage of suspension filtration in production of antibiotic powders for injection with the use of closed air-tight apparatus schemes including multileaf filters.

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An optimal fermentation medium for detection of antibiotic-producing cultures among Micromonosporaceae at the stage of primary screening was developed. The method of the experiment factor design with regard both for the qualitative and the quantitative variation of the medium composition was used. The number of the active strains detected with the use of medium M1 amounts to 76.4 per cent of the cultures tested. The same efficiency was observed with simultaneous use of 6 different fermentation media. The use of the new medium significantly decreases the labour-consuming character of the procedure.

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The pharmacokinetics of lincomycin in the blood of 8 patients with osteomyelitis was studied on the drug single and uninterrupted intravenous administration in therapeutic doses. It was found that when the antibiotic was administered continuously according to the routine scheme, its therapeutic blood levels were attained only 1.5 hours after the drug infusion. The optimal regimen of lincomycin uninterrupted infusion providing its constant rate in combination with the single intravenous administration was estimated with the help of the constants of the two-compartment model of lincomycin pharmacokinetics. According to the calculations the rate of the antibiotic administration necessary for providing therapeutic levels should be 2.2 mg/kg in complex with the loading dose equal to 5.4 mg/kg. Practical trials showed that intravenous administration of lincomycin with the above regimen remained within therapeutic range already 10 to 20 minutes after the beginning of the drug infusion. Therefore, from the pharmacokinetic point of view the recommended regimen for lincomycin infusion should be considered preferable to that used presently.

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A technique of "accelerated storage" was used to evaluate promptly the effectiveness of protective (suspension) media for lyophilization and further storage of spores of Actinomyces parvullus 99. The number of survived spores can be predicted using the Arrhenius diagram and the van't Hoff rule. Equine serum without a conserving agent was found to be the most effective protective medium for lyophilizing spores of Act. parvullus, as compared to such media as milk containing no fat or a mixture of 3 per cent solutions of gelatin and glucose.

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The principle of the analysis of concentration-response relationships is valid in the case if the effective course is defined by a logistic function and the drug distribution is approximated by a two-compartment model. The method of calculation the data to construct the curves describing the dependence of the effect on drug concentration in the central and in peripheral compartments was elaborated. The relations between the concentrations of gentamicin and streptomycin and their peripheral neuromuscular blocking effect were investigated experimentally on cats. The blocking action of both drugs is evident at concentrations higher than the drug serum levels after administration of therapeutic doses, gentamicin being more active.

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The basic points in the development of a specialized computer information search system providing ientification of new antibiotics at early stages of their investigation are described. The system of coding the physico-chemical properties of the agents and the spectra of their antimicrobial activity presenting the substance in the information bank is developed. The task of identification is to find in the reference bank according to some specially organized keys such antibiotics which are identical or close by their properties to the substance being identified. Mini-computer of M-6000 type is used as the technical base of the information search system. Preliminary organization of the bank specified by the coding system markedly reduces the requirements to the computer operative memory.

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