Bacteria lactobacillus reuteri strain for making probiotic product, and probiotic product containing it
SUBSTANCE: invention refers to biotechnology, and concerns a lactic bacteria Lactobacillus reuteri DSM 17938 strain stimulating IL-10 production and hence CD4+CD25+TR-cell proliferation used for making a probiotic product. The probiotic product contains Lactobacillus reuteri DSM 17938 strain and additionally medium-chain triglyceride oil.
EFFECT: use of the probiotic product promoted a favorable effect on intestinal colic in a newborn baby.
3 cl, 3 dwg, 1 tbl, 2 ex
The prior art inventions
The technical field to which the invention relates
The present invention relates to certain strains of lactic acid bacteria selected according to their ability to increase levels of the cytokine IL-10, for the prevention and/or treatment of colic, the method of selection of these strains and to products containing such strains.
Description of the prior art
Despite the significant prevalence and prevalence, nature and causes of infant colic remain poorly understood. Description this mother represents the following: the child who was cheerful throughout the day, beginning to frown, face reddens, he pulls the legs, screams and continues to cry for about 2-20 minutes, then attack suddenly ends. Contradictions arise even in the terms used to describe this condition. To include "baby colic", "evening colic", because the pain is mostly confined to the evening, and the three-month colic", because it disappears after approximately three months after birth (Illingworth RS. Difficulties in breastfeeding. In Ronald S. Illingworth, ed. The Normal Child. 10thedn. Harcourt (India) Pvt. Ltd. 1997; 39-44). Different authors use different definitions. Vessel (Wessels) defines colic as an attack of crying for three or more hours per day within three days or more per week for at least three weeks, and this definition is the most widely accepted in the literature (Sondergaard C, Skajaa E, Henriksen TB. Fetal growth and infantile colic. Arch Dis Child Fetal-Neonatal Ed 2000; 83 (1): F44-47). To date, the main possible (causal factors) are divided into three groups: psychosocial, gastrointestinal and nervous disorders development.
Psychosocial factors include the options of normal crying influence on the behavior of atypical upbringing and relationship problems between parents and children.
Gastrointestinal disturbances associated with colic at a certain position of the legs of the infant and the antics during the attack crying. Gastrointestinal factors briefly outlined below.
Improper feeding practices, such as feeding bottles, feeding in a horizontal position or lack of regurgitation after feeding, considered as causal factors. Breastfeeding in the first six months considered to be the only preventive factor. The risk of infant colic 1.86 times higher in children on artificial feeding (Saavedra MA, Dacosta JS, Garcias G, Horta BL, Tomasi E, Mendoca R. Infantile colic incidence and associated risk factors: a cohort study. Pediatr (Rio J) 2003; 79(2): 115-122). Lothe et al. showed that colic is due to sensitivity to whey protein of cow's milk (Lothe L, Lidberg T. Cow''s milk whey protein elicits symptoms of infantile colic in colicky formula-fed infants: A double-blind cross over study. Pediatrics 1989; 83: 262).
In a recent study bilsdale conclusion, what food hypersensitivity can be regarded as the cause of only a small number of cases of infant colic (Hill DJ, Hosking CS. Infantile colic and food hypersensitivity. Pediatr Gastreenterol Nutr 2000; 30 (Suppl): S67-76). Recently, Buchanan showed that the test hypoallergenic milk with infant colic is not backed by sufficient data (Buchanan P. Effectiveness of treatment for infantile colic. Trial of hypoallergenic milk is not supported by strong enough evidence. BMJ 1998; 317(7170): 1451-1452). It is believed that babies with baby colic have a greater risk of allergic diseases. However, in a recent study it was shown that markers of atopy, allergic rhinitis, asthma, stridor and variability of maximum exhalation comparable in infants suffering from infantile colic and without (Castro-Rodriguez JA, Stern DA, Halonen M, Wright AL, Holberg CJ, et al. Relationship between infantile colic and Asthma/ atopy: A prospective study in an unselected population. Pediatrics 2001; 108(4): 878-882).
The authors described the malabsorption of lactose on the basis of samples for the presence of hydrogen in exhaled air (Hyams J, Geerstama M, Etienne N, W. Treem Colonic hydrogen production in infants with colic. J Pediatr 1989; 115: 592). No marked differences in the concentration of hydrogen in the stool of infants suffering from infantile colic or without it. However, it was found that children with higher levels of methane colic occur to a lesser extent, which assumes the role of production of methane in its mitigation (Belson A, Shetty AK, Yorgin PD, Bujanover Y, Peled Y, Dar MH, Riaf S. Coloni hydrogen elimination and methane production in infants with and without infantile colic syndrome. Dig Dis Sci 2003; 48(9): 1762-1766).
It has been shown that gastrointestinal hormones (GIT), such as motilin, vasoactive putting peptide, have pathologically high levels in infants with colic. Lothe et al. showed higher levels from the first days of life in children who later developed colic, assuming pathological physiology of the GIT with baby colic (Lothe L, Ivasson SA, Ekman R, Lindberg T. Motilin and infantile colic: A prospective study. Acta Pediart Scand 1990; 79(4) 410-416).
Based on the impaired development of the nervous system, an assumption was made that abdominal pinched and colic can be the result of hyperperistalsis. This theory is confirmed by the fact that when taking anticholinergics symptoms of colic reduced (Gupta SK. Is colic a gastrointestinal disorder? Curr Opin Pediatr 2002; 14:588-92).
The fact that most infants colic pass to four months of age, confirms neurogenic cause colic (Barr RG. Colic and crying syndromes in infants. Pediatrics 1998; 102(5 suppl E): 1282-6).
Probiotic, by common definition, is a live bacterial feed additive, which has a beneficial effect on the animal host by improving the bacterial balance of the intestines. Although probiotics originally belong to additives to animal feeds for farm animals, their definition can also be applied to humans. Jus the e consumption of probiotics people is in the form of dairy products, containing intestinal species of lactobacilli and bifidobacteria. In the definition of probiotics indicated that their consumption affects the composition of the intestinal microflora.
An assumption was made that the effect of probiotics on the intestinal ecosystem is beneficial to the consumer. The number of possible benefits resulting from changes in the intestinal environment with probiotics, described in the articles and these include: increased resistance to infectious diseases, particularly gastrointestinal, reduced the duration of diarrhea, lower blood pressure, lower concentrations of serum cholesterol, decrease allergies, stimulation of phagocytosis by peripheral blood leukocytes, modulation of gene expression of cytokine, adjuvant effect, regression of tumors and decrease the production of carcinogens or saintereso.
Christensen et al. were the first who reported that probiotic lactic acid bacteria exert their immunomodulatory effects by modulation of the Th1/Th2/Th3/Tr1/Treg-stimulatory capacity of dendritic cells (DC). They showed that the simultaneous cultivation of murine DC and various species ofLactobacillusincludingLactobacillus reuterithey were selectively modelirovanie production of cytokines IL-6, IL-10, IL-12 and TNF-α and activation surface markers dependent on the concentration of All surface markers MHC class II and CD86, activated by lactobacilli, are indicators of maturation of the DC. In particular, significant in these studies was thatL.reuteri(strain 12246) was a weak inducer of IL-12, but with the simultaneous cultivation withL.johnsoniiorL.caseiit selectively inhibited the production of proinflammatory signaling cytokines IL-12, IL-6 and TNF-α, which stimulated the other two species. The production of IL-10 remained unchanged under these conditions.
These obnarujenia led to the conclusion that "L.reuterican contribute to the exogenous modulation of the propagation of the dendritic cells of the intestine, which promotes sustainability to antigens, which don't "danger signal", while not affecting the ability to respond to pathogens that are recognized through such a danger signal, as LPS, "L.reuterimay be a potential mistaway therapy, effective for inhibiting the production of IL-12 and TNF-α (IL-6), and to induce anti-inflammatory IL-10, providing, thus, an alternative therapeutic approach for compensation of proinflammatory environment cytokines intestines, and thus, "there is the possibility of regulating the Th1/Th2/Th3-stimulating ability of the intestine, based on the composition of intestinal microflora, including consumption of probiotics" (Christensen HR, Frokiaer H, Pestka JJ (2002) Lactobacilli differentially modulate expression of cytokines and maturation surface markers n murine dendritic cells. J Immunol 168 171-178).
Smits et al. he continued these studies and showed thatL. reuteriit has the ability to premirovat DC to stimulate the production of regulatory T cells (TR). They used three different kinds ofLactobacilluscultivated at the same timein vitroc DK human monocytic series of differentiation. Used two types of lactic acid bacteria, a strain ofL.reuteriADS 53609) man andL.caseibut didn't take the strain ofL.Plantarumthat was primiraly DC to stimulate the development of TR cells. It was shown that these TR-cells produce elevated levels of IL-10 and are able to inhibit the proliferation of background T cell IL-10-dependent way (Smits HH, Engering A, van der Kleij D, de Jong EC, Schipper K, van Capel TMM, Zaat BAJ, Yazdanbakhsh M, Wierenga EA, van Kooyk Y, Kapsenderg L (2005) Selective probiotic bacteria induce IL-10-producing regulatory T cellsin vitroby modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J Allergy Clin Immunol 115 1260-1267).
One of the first evidence about the effects of oral incomingL. reuterithe owner, essentially, was increased ratio of CD4+/CD8+ cells observed in the ileum of chickens (Walter J. Dobrogosz, NUTRAfoods 2005 4(2/3) 15-28). Valeur et al. continued these observations include the terminal ileum person. They received directin situevidence in humans showing (a) distribution of individual-specific human cellsL.reueri ADS 55730 throughout the intestines of humans and (b) the expression partL.reuteriADS 55730 in the recruitment and/or proliferation of CD4+ T cells, in particular, in the iliac regions of the intestine. They concluded that "the introduction ofL.reutericauses the recruitment of CD4+ T-helper cells to the epithelium of the person. This recruitment may be one of the factors explaining the effect of probiotics this strainL.reuterithe person" (Valeur N, Engel P, Carbajal N, Connolly E, Ladefoged K (2004) Colonization and immunomodulation by Lactobacillus reuteri ATCC 55730 in the human gastrointestinal tract, Appl Environ Environ 70 1176-1181).
Toll-like receptors (TLR) recognize bacterial motifs and activate a set of genes that leads to production of cytokines. Usually TLR considered as sensors of microbial infections, and their role is the induction of the inflammatory response. However, the motifs that are recognized by using a TLR, are not unique to pathogens, but are common motifs that are common to whole classes of microorganisms, and it is not quite clear how the immune system distinguishes between commensal and pathogenic bacteria through TLR. Recent evidence indicate that TLR, in addition to their role in the induction of the inflammatory response, also play a role in the homeostasis of the intestine, recognizing the commensal microflora (Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004 ul 23; 118(2):229-41).
Strains of various species ofLactobacillusincludingL.reuteriwere used in the compositions of probiotics.L.reuteriis one of the natural inhabitants of the gastrointestinal tract of animals, and it is usually detected in the intestines of healthy animals, including humans. It is known that it possesses antimicrobial activity. See, for example, U.S. patent No. 5439678, 5458875, 5534253, 5837238 and 5849289. If cellL.reuterigrown under anaerobic conditions in the presence of glycerol, they produce antibacterial substance known as β-hydroxy-Propionaldehyde (3-hPa).
There are clear and complex relationships between the intestinal immune system and the commensal flora. Recently it was shown that luminally endogenous flora initiates the key process of bacterial origin and adaptive host response through activation of toll-like receptors (TLR) and NOD-receptors located on cells of the intestinal epithelium (Haller D, Jobin C. Interaction between resident luminal bacteria and the host: can a healthy relationship turn sour? J Pediatr Gastroenterol Nutr 2004; 38: 123-36. Rakoff-Naholm S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 2004; 118: 229-241). On models of human cytokines can initiate hyperreflection reaction enteric muscles through the nervous and muscular immune interactions (Milla PJ. Inflammatory cells and the regulation of gut motility. J Pediat Gastroenterol Nutr 2004; 39: S750).
In experimental and clinical studies it was shown that specific strains of probiotics inhibit the proliferation of T-cells and reduce the secretion of a cytokine Th1 and Th2, at the same time, preferably producing suppressor cytokines such as IL-10 and TGF-β (Rautava S, Kalliomaki M, Isolauri E. Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infants. J Allergy Clin Imunol 2002; 109: 119-121). In addition, people-volunteersL. reutericolonizes the gastrointestinal tract of man and is able to exercise together with immunomodulating activity, including restating CD4+ T-helper cells in the epithelium of the ileum person (Valeur N, Engel P, Carbajal N, Connoly E, Laderfoged K. Colonization and immunomodulation by Lactobacillus reutery ATCC 55730 in the human gastrointestimal tract. Appl Environ Environ 2004; 70: 1176-81). The DC maturation is a process that transforms immature DC Mature, antigenpresenting cells, which migrate into the lymph nodes. This process leads to the loss of a strong ability to absorb antigens characteristic of immature DC and to activate the expression of co-stimulatory molecules and various cytokines (Mellman I, Steinman RM: Dendritic cells: specialized and regulated antigen processing machines. Cell 2001, 106:255-8. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ Pulendran B, Palucka K: Immunobiology of dendritic cells. Annu Rev Immunol 2000, 18: 767-811).
Known protocols maturation based on the environment that are considered, DK face after or in EMA presentation of antigens. The best example of this approach is the use of the environment, air-conditioned monocytes (MSM). MSM getin vitrocultivating monocytes and then using cultural supernatant fluid as a source of maturation factors. The main components in the MSM, responsible for the maturation, are Pro-inflammatory cytokines interleukin-1 β (IL-1 β), IL-6 and TNF-α (Reddy A, Sapp M, Feldman M, Subklewe M, Bhardwaj N: A monocyte condidioned medium is more effective than defined cytokines in mediating the terminal maturation of human dendritic cells. Blood 1997, 90: 3640-6). Mature DC produce many cytokines, which stimulate and direct T-cell response. Two of these cytokines are IL-10 and IL-12. These cytokines exert an opposite effect on the direction of the induced T-cell response: IL-12 induces Th1 response type, whereas IL-10 inhibits this response.
Thus, the activation state of the APC (antigenpresenting cells, including DC, determines the type and magnitude of CD4+-cell response. Stop APC in the phase of G0(including epithelial cells in the thymus) may contribute to the development of CD4+CD25+TR-cells. During infection by pathogens detection of bacterial TLR molecules leads to activation of the APC. Then APC produce IL-6 and additional soluble factors, which together block the suppressive effect of TR cells, allowing efficient education is s T E(T-effector cells) cells against the pathogen. Dynamic equilibrium between APC in the phase of resting and activated APC will also be exposed to both TR and TE cells (figure 1).
Pessi et al. (2000) describe the formation of IL-10 in children with allergies after oral administrationLactobacillus rhamnosusGG. But in contrast to the herein invention, in the study described specific strains with the ability to produce large amounts of IL-10, selected for their efficacy against motility disorders and colic (Pessi T, Sutas Y, Hurme M, Isolauri E. Interleukin-10 genetation in atopic children following oral Lactobacillus rhamnosus. GG. Clin Exp Allergy. 2000 Dec; 30(12):1804-8).
The study Hermelijn et al. (2005) shows that premirovanii DK macrophage some differentiation of L. reuteri and Lactobacillus casei, but not Lactobacillus plantarum, manages the development of TR cells. These TR cells were produced elevated levels of IL-10. Unlike the present invention, the authors do not attribute the increase in IL-10 with intestinal motility or colic. Even if it comes strains, the authors mention two different bacterial species, which effectively increase the levels of IL-10. This differs from the present invention, in which indicated that probiotic that will most effectively reduce colic, should be identified and selected on the level of strain, as different strains of the same species have different sposobnostyami to increase the levels of IL-10.
Currently there is no treatment for colic. The accepted treatment of colic consists of pharmacologic and/or nonpharmacologic methods, providing at best a slight decrease symptoms. Typical therapeutic effect on the colic offered to patients is within the four categories, including dietary, physical, behavioral and pharmacological. Diet treatments include professional advice about the various techniques of feeding or the use of hypoallergenic milk, infant formula without soy or lactose and early introduction of solid food (Lothe, L., et al. Cow''s milk formula as a cause of infantile colic: a double-blind study. Pediatrics 1982; 70:7-10; Forsyth B W C. Colic and the effect of changing formulas: a double-blind, multiple-crossover study. J Pediatr 1989; 115,521-6; Treem, W R, et al. Evaluation of the effect of a fiber-enriched formula of infant colic. J Pediatr 1991; 119695-701). However, the use of soy infant formula, any changes in the technique of feeding is not effective for each of the cases of colic. Overview information, studying these recommendations, showed that the use of hypoallergenic infant formula, such as partially hydrated or based on amino acids, can be successful only in about 25% of infants (Lucassen, P L B J, et al. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind? Randomized placebo-controlled trial. Pediatrics 2000; 106:1349-54; Estep, D C, et al. Treatment of infant colic with amino acid-based infant formula: a prelimitary study. Acta Pdiatr 2000; 89: 22-7).
Physical strategy to manage colic includes physical alteration of the positions of the body to facilitate gas/reflux, the wearing of arms, swaddling, applying pressure on the abdomen or massage of the child. Other methods include creating a sense of abstractness to minimize awareness colic baby, such as skating baby on the machine, the use of stimulant trip, vibrator for a cot or baby swing (Lipton E L. Swadding and child care practice: historical, cultural and experimental observations. Pediatrics 1965; 35: 521-67; Byrne J M, Horowitz D. F Rocking as a soothing intervention: the influence of direction and type of movement. Infant Behav Dev 1981; 4:207-18).
Another way is to play sound recordings, which soothes the baby. However, in the medical literature, there is evidence that these methods do not work (Parkin P C, Schwartz C J, Manuel B A. Randomized controlled trial of three inventions in the management of persistent crying of infancy. Pediatrics 1993; 92(2): 197-201). These strategies are, at best, only marginally effective on reducing the symptoms of colic.
Recommendations for behavioural impact for the treatment of colic are the most controversial of the available methods of treatment. Some authors advocate an increase sensory stimulation, while others promote the reduction of such stimulation (A Balon J. Management of infantile colic. Amer Pharm Physician 1997; 55:235-242; Lucassen P L B, Assendeift W J , Gubbels J W, van Eijk T M, van Geldrop W J, Effectiveness of treatments for infantile colic: systematic review. BMJ 1998; 316(5): 1563-9; and Carey W B, “Colic” - primary excessive crying as an infant-environmental interaction. Pediatr Clin North Am 1984; 31: 993-1005). Other recommendations include early response to crying or letting the baby cry, offer dummy, the introduction of a specific schedule of feeding, use of eye contact and entertaining games.
Pharmacological approach to the treatment of colic led to the use of prescription and non-prescription drugs. Currently used prescription drugs include belladonna alkaloids and opiates (camphor tincture of opium), which can provide relief, but is fraught with risks, including extra pyramidal symptoms, respiratory depression and higher. For example, anticholinergic drugs, similar in its action to the action of atropine, such as Hyoscyamine (Levsin® or Gastrosil®), Dicyclomine extend pupils, increase heart rate, reduce salivation, relax spasms of the gastrointestinal and urinary tracts, as well as bronchi. In addition, anticholinergic medications are prescription only drugs on the U.S. market, which, as has been shown many times, effectively treat baby colic, but, unfortunately, 5% of children were treated, can develop side-effect the points, including shortness of breath, apnea, seizures, syncope, asphyxia, coma and muscular hypotonia (Williams J, Watkin-Jones R. Dicyclomine: worrying symptoms associated with its use in some small babies. BMJ 1984; 288:901; Myers J H, Moro-Sutherland D, J Shook E. Anticholinergic poisoning in colicky infants treated with hyoscyamine sulfate. Am J Emerg Med 1997; 15: 532-5). Moreover, it was reported on several cases of death in children treated with dicyclomine (Garriott J C, Rodriguez R, Norton L E. Two cases of death involving dicyclomine in infants. Clinical Toxicol 1984; 22(5): 455-462).
Over-the-counter drugs that have been described as effective for the treatment of infantile colic include several sedative or hypnotic drugs, including supraphysiological dose (high dose) diphenhydramine (Benadryl®), phenobarbital, hydrate chlorine and even alcohol. However, there is a chance of serious side effects associated with several of these agents in children with respiratory disease, thus limiting their widespread use in the treatment of colic (A Balon J. Management of infantile colic. Amer Pharm Physician 1997; 55: 235-242; Gurry D. Infantile colic. Australian Pharm Phys 1994; 23(3): 337-34632).
Safer non-prescription drugs for the treatment of colic include, mainly, the introduction of simeticone or dimethylpolysiloxane, non-absorbable, over-the-counter drug which reduces the amount of intestinal gas bubbles. Simethicone has a very safe profile and often recommended is endued, despite several studies showing that the effectiveness of simethicone in relation to childhood colic is not greater than that of placebo (Metcalf, T J, et al., Pediatrics 1994 July; 94(1): 29-34. Sferra, T J, et al., Pediatr Clin North Am 1996 Aril; 43(2): 189-510. Danielson, B et al., Acta Paediatr scand 1985 May; 74(3): 446-50. Colon, A R, et al., Am Fam Physician 1989 December; 10(6): 122-4). In the most common treatment of colic today is just wait, when the baby will outgrow this condition.
Therefore, currently, there is a need for safe and effective compounds and compositions, and methods that can be effective for treating colic in infants and young children. Compositions and methods of the present invention meets these needs by offering a product that can safely and effectively eliminate the symptoms associated with colic in infants. In patent publication ARE described probiotics for the treatment of gastrointestinal neuromuscular abnormalities, such as colic in infants. As probiotics applicants mention several different kinds of bacteria. On the contrary, in the present invention probiotic for the most effective reduce colic is a specific strain of lactic acid bacteria selected for effectively increasing levels of IL-10, and does not apply to the entire class of bacteria, as the authors of the present invention showed that existence is Tvout significant differences in the stimulation of IL-10 production between strains of the same species.
In 2005, Savino showed that addingL.reuteriADS 55730 significantly improves the symptoms of colic in infants, breast-fed, compared with standard therapy with simeticone within 7 days of treatment. The percentage of response to treatmentL.reuteriwas 95%, while only 7% of infants were answered simethicone. These results were presented at the European Society for the Study of Pediatrics (European Society for Pediatric Research (ESPR)August 31, 2005 September 3, 2005, Siena, Italy (Pediatr Res.2005; 58(2):411). Despite the fact that the results Savino showed a positive effect, he did not determine the relationship between individual strains, contributing to the production of IL-10 and reduced intestinal motility and, therefore, colic. Attached the invention relates to a method of selection of these best strains.
Collins has described that disturbances in motor function provides a variety of symptoms that can occur in the context of inflammation or activation of the immune system in different areas of the intestine and include such ordinary disorders such as esophagitis, gastritis and spontaneous inflammatory bowel disease (IBD). These observations suggest that the motility of the intestines are also susceptible to the immune system. In this context, the motor system can play an important role in protecting the intestine against toxic stimuli present in the lumen (Collins ., The Immunomodulation of Enteric Neuromuscular Function: Implications for Motility and Inflammatory Disorders. Gastroenterology 1996; 111: 1683-1699). This view is reflected, for example, in observation Vantrappen et al., which showed that the excessive growth of bacteria in the small intestine is accompanied by disruption of the normal cyclic digestive motility in the small intestine (Vantrappen G, Jannssens J, Hellemans J, Ghoos Y. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 1977; 9: 1158-1168).
It is well known for many years that elevated levels of IL-10 supression excessively activated immune system. Previously it was also shown that the intestinal motility is controlled by a neurological signals that are associated with the immune system of the intestine, and that colic is a consequence of increased intestinal motility, for example due to excessive growth of bacteria.
In industrialized countries hygienic measures begin from the moment of birth, which violates the newborn's capacity to absorb the microflora of the mother. As a result, the child gets a different microflora. Instead of content, for example,Escherichia coliandLactobacillinewborns receiveStaphylococcus aureusand other skin bacteria.
The inventors have made the unexpected discovery that the excessive growth of skin bacteria excessively activates the immune system of the baby, which leads to excessively-ACTIVIA is Anna the intestinal motility and, as a consequence, colic, more specific intestinal bacteria such asL.reuteriDSM 17938, with the ability to stimulate the production of IL-10 leads to the maturation of the TR system, i.e. proliferation of CD4+CD25+TR cells. Activation of CD4+CD25+ cells leads to calm the intestinal motility and, therefore, favorable effects on infants with colic.
Thanks to these discoveries were selected non-pathogenic bacterial strains on properties that enhance IL-10, and unexpectedly it was found that these properties of the strains correlate with a decrease colic in children. Consequently, the invention relates to the use ofL.reuteriDSM 17938 for obtaining drugs for the prevention and/or treatment of colic and other strains selected in the same way.
Another object of the invention is the products containing these strains, for the introduction of animals, including humans. Other objectives and advantages will be apparent from the following description and the accompanying claims.
The present invention relates to certain strains of lactic acid bacteria selected according to their ability to promote the production of IL-10 and, consequently, the proliferation of CD4+CD25+TR cells for the prevention and/or treatment of colic, to method of selection of these strains and to products containing such strains.
Other objects and characteristics of izobreteny will be apparent from the following description and the accompanying claims.
Brief description of the invention
Figure 1 - estimated the role of certain selected strains of lactic acid bacteria to stimulate the development of CD4+CD25+TR cells.
Figa the production of IL-10 DC cells in a column chart.
Figb the production of IL-10 DC cells in the table.
Detailed description of the invention and the preferred variants of its implementation
Colonization of skin bacteria in the gut and the deficit TR-cells redundantly activate the immune system of a newborn baby, which leads to excessive activation of intestinal motility and, therefore, to colic. A large number of cells of specific intestinal bacteria such asL.reuteriDSM 17938, possessing the ability to stimulate the production of IL-10 leads to the maturation of the TR system, i.e. to the proliferation of CD4+CD25+TR cells. Other strains of lactic acid bacteria, as reported by many researchers previously, induce the production of IL-10, for example Rautava et al. (see above). Activation of CD4+CD25+TR cells leads to moderate intestinal motility and consequently favorable effects on the colic. Unexpectedly it was found that the strains that lead to increased levels of the cytokine IL-10, are also strains that are able to reduce the average time of mourning (example 2).
The present invention relates to strains of lactic acid bacteria, which is selected by the ability to reduce colic, includingL.reuteriDSM 17938. Products such as food, food supplements and baby formulas, medicines or medical equipment containing whole cells or components isolated from these strains can be obtained in accordance with known in this field the recipe and include, as you know, basically, digestible basis plus the strain ofLactobacillusor separated from his component.
Researchin vitrocan be used as a method of selection of strains of lactic acid bacteria the ability to stimulate the production of IL-10 in DC monocytic series differentiation and thereby to induce the development of CD4+CD25+TR cells (Example 1).
The data describe the index in a strong stimulation of IL-10 by using specific strains ofL.reuteriADS 55730 andL.reuteriDSM 17938 and that this regulation is mediated by a substance released into the growth medium of these two specific strains during late log/stationary phase of growth. Two strains ofL.reuteri, by contrast, were not able to stimulate adequate production of IL-10.
To confirm the clinical significance of selected strains for the prevention or treatment of colic additional studies in infants, breast-fed, with a diagnosis of infant colic.
The characteristics of the present invention is Udut clear from the following examples, which should not be construed as limiting the invention.
The study of the ability of probiotic strains to stimulate the expression of IL-10 DC macrophage some differentiation
Immature DC generated from peripheral blood monocytes (Hilkens, C.M.U., P. Kalinski, M. De Boer, and Kapsenberg. 1997. Human dendritic cells require exogenous interleukine-12-inducing factors to direct the development of native T-helper cells toward the Th1 phenotype. Blood 90:1920), cultured in IMDM (Life Technologies, Paisley, UK)containing 10% FCS (HyClone, Logan, state), recombinant human (rh)GM-CSF (500 units/ml; Schering-Plough, Juden, the Netherlands) and rhIL-4 (250 units/ml; Pharma Biotechnologie Hannover, Hannover, Germany) (Kalinski, P., J.H.N. Schuitemaker, C.M.U. Hilkens, E. A. Wierenga, and M.L. Kapsenberg. 1999. Final maturation of dendritic cells is associated with impaired responsiveness to IFN-γ and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. J. Immunol. 162:3231).
Strains to be tested in the experiment areLactobacillus reuteriATCC 55730,Lactobacillus reuteriDSM 17938,Lactobacillus reuteriATCC MOUTH 4660Lactobacillus reuteriATCC MOUTH 4964 available in ATS (Manassas, PCs, Virginia, USA and DSMZ, Braunschweig, Germany). The strains were cultured on Columbia agar (Oxoid, Basingstoke, United Kingdom)containing 6,25% sheep blood. Lactic acid bacteria incubated at 37°C in an atmosphere of 5% CO2. After 3 days the number of bacteria is determined by measuring the optical density at 620 nm (OD620). Usually OD620,equal to 0.35, corresponded to 1×108colony forming units (CFU) for all the test strains.
On day 6 the maturation of immature DC induce using LPS (E. coli; Sigma-Aidrich, Saint Lewis, Morocco) and testlactobacillithe presence of the combination of the cytokines IL-1β (25 ng/ml) and TNF-α (50 ng/ml), used together as maturation factors (cytokines, purchased from Peprotech, rocky hill, NJ).
Production of cytokines IL-12, IL-10 and IL-6 Mature DC is determined by 24-hour stimulation through CD40 legendexpansion of plasmacytoma cells mouse (J558), as described Vieira PL et al. (Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P. Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol 2000; 164: 4507-12). After 24 h supernatant collect and measure the concentration of IL-10 using ELISA. The results, see figure 2. As can be seen from the results, there is a significant difference in the effect of various strains ofLactobacillusand their ability to stimulate the production of IL-10 in DC.
Selected strains of probiotics in comparison with Simethicone in the treatment of infant colic
Babies breastfed, with a diagnosis of infant colic were recruited in the Department of child and adolescent science (University Hospital Trotting Sylvia, Gothenburg). Patients aged 21-90 days, appropriate prenatal to age with weight at birth between 2500 and 4000 g with symptoms to the IKI, meets the criteria Wessel and appeared about 6±1 days prior to registration, are considered for inclusion in the study (Wessel MA, Cobb JC, Jackson EB, Harris GS, Detwiler AC. Paroximal fussing in infancy, sometimes called “colic”.Pediatrics1954; 14: 421-35). All registered infants are exclusively breastfed to reduce the variability of the intestinal microflora due to variations in diet, which could, in turn, cause the response to probiotics. Infants were excluded if they had clinical evidence of chronic disease or gastrointestinal disorders, or if they received antibiotics or probiotics in the week prior to the set.
In this study, infants with colic randomly selected to receive probiotics or Simeticone in the subsequent treatment:
(P1)Lactobacillus reuteristrain ATCC 55730, also called SD2112;
(P2)Lactobacillus reuteristrain DSM 17938 (highlighted DSMZ-Deutshe Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124 Braunschweig) on 6 February 2006, under the Budapest Treaty);
(P3)Lactobacillus reuteristrain ATCC MOUTH 4660; and
L.reuteriadministered at a dose of 108colony forming units (CFU) in 5 drops commercially available MCT oil (medium chain triglyceride oil), 30 minutes after a meal, once a day, for 28 days. MCT oil is obtained in a natural way, and the most common and what source is coconut oil. A large part of MCT oil processed from coconut oil. MCT oil is a clear light colored liquid with a pleasant odor and low viscosity. This oil suspension is stable for 21 months at 2-8°C (as described by the manufacturer, BioGaia AB, Stockholm, Sweden) (alternative source MCT oil is Alkomed R, Karlshamns AB, Karlshamn, Sweden). During the study, parents were informed that they were holding the product in the refrigerator when not in use. Simethicone (S) was given at a dose of 60 mg/day in 3 ml of a commercially available solution (Mylicon Infant Gas Relief Drops, J&J, 7050 camp hill road, Fort Washington, Pennsylvania, 19034-2210, USA) after a meal, twice a day, for 28 days. It is said that when all mothers were asked to follow a diet that excludes dairy milk: to cancel the milk, yogurt, soft and hard cheese, sour cream, butter, cakes. Strict adherence to the diet is monitored through diet diary maintained throughout the treatment period. 7, 14, 21 and 28 day one of the researchers validates the diet.
The ethical Committee of the Institute approved the study Protocol, and infants recorded in the study only after obtaining written informed consent from the parents.
The day that the pediatrician was watching the baby for the first time, defined as - 1 day. In this case, each child underwent a medical examination, and parents were interviewed with the aim of obtaining basic information regarding the type of delivery, birth weight and gestational age, family history of gastrointestinal diseases and atopy. In particular, the latter was considered positive if infants had one or more family members (mother, father and/or older sibling) with atopic eczema, allergic rhinitis or asthma. Moreover, registered any signs and symptoms of atopic disease during the study period. Parents are also invited to register information relating to the average time of crying per day and the number of attacks of colic on the day after collection (day 0). The doctor was randomly attributed baby to any of the studied groups. The introduction of the investigational products was started in 1 day.
Parents were given written information about the study and asked to record the number of bouts of inconsolable crying day and their duration, stool consistency and frequency, as well as any observed side effects (higher, vomiting, skin reactions, and so on), starting from 0 days to 28 day using a structured diary. To ensure that all parents noted the time crying in the same way, and to ensure that drugs etc the Vilna given to infants one of the researchers is always available by phone to help parents.
Each patient examines the same pediatrician at 1, 7, 14, 21 and 28 day.
Of the 120 registered infants, breast-fed, 30 randomly assigned to the treatment ofLactobacillus reuteriATCC 55730 (P1), 30 randomly assigned to the treatment ofLactobacillus reuteriDSM 17938 (P2), 30 randomly assigned to the treatment ofLactobacillus reuteriATCC MOUTH 4660 (P3) and 30 to Simeticone (S). No baby not dropped out because of side effect associated with the experience. Group similar in age, birth weight, gender, type of delivery, family history of atopy or gastro-intestinal diseases and the impact area.
Average time crying in a day is similar in the treatment groups at day 0 and day 1. Showed a significant reduction in daily time crying in infants receivingLactobacillus reuteriATCC 55730 (P1) and DSM 17938 (P2), for 7 days, compared with infants who were treated ATCC MOUTH 4660 (P3) and Simethicone (S). On 14, 21 and 28 day time crying differs significantly between the four treatment groups. The difference between (P1) and (S) by the average time of mourning on the day from beginning to end of the study is 82 minutes, and the difference between (P2) and (S) by the average time of mourning on the day from beginning to end of the study is 83 minutes as on the 28th day (table 1). As vidn the results, four treatment groups of more or less equal before the introduction of the test products. After 7 days, there is a clear difference in favor ofLactobacillus reuteristrains ATCC 55730 and DSM 17938 in comparison with the other two alternatives. After 28 days, the difference has increased.
The time of mourning (value in minutes per day) in groupsL. reuteriand Simeticone
|Babies with colic|
ATCC MOUTH 4660
Although the invention has been described based on specific embodiments, it will be appreciated that countless possible variations, modifications and embodiments, and therefore, all such variations, modifications and embodiments should be considered as included in the essence and the scope of the invention.
1. The bacterial strain Lactobacillus reuteri DSM 17938 used to obtain probiotic product.
2. Probiotic product containing the bacterial strain Lactobacillus reuteri DSM 17938.
3. The product according to claim 2, additionally containing medium chain triglyceride oil.
SUBSTANCE: inoculate contains in a mixture or in a combination, main L-cystein of formula HSCH2CH(NH2)CO2H and at least one B.animalis lactis strain. Said cysteine and at least one B.animalis lactis strain are contained or have the form of at least one frozen granule and/or at least one lyophilizate. The pH value of the solution produced by thawing of at least one granule and/or dissolution, of at least one lyophilizate in the relation making 1 to 2 g of the lyophilizate per 8-10 ml of H2O, makes at least 4. L-cysteine contains in the inoculate in an amount within 1 g per 1·1014 CFU to 1 g per 3.5·1010 CFU, of at least one B.animalis lactis strain or all used B.animalis lactis strains whereas the same are numerous. Using the offered inoculate provides stimulation of B.animalis lactis growth and/or metabolism on a lactic substratum to produce a fermented diary product.
EFFECT: high probiotic value of the product.
21 cl, 9 dwg, 3 tbl, 3 ex
SUBSTANCE: nutrient medium contains yeast water, beef hydrolyzate, sodium chloride, glucose, glycerin, sodium citrate, sodium metabisulphite and distilled water.
EFFECT: invention allows providing optimum conditions for brucellous microbe growth, replication in a transport nutrient medium at any distances.
SUBSTANCE: strain of bacteria Bacillus thuringiensis BIOS-1 VKPM B-10709, possessing insectoacaricidal activity against representatives of leaf-eating and sucking pests, such as representatives of orders Lepidoptera, Coleoptera, Homoptera, Thysanoptera and Acariformes, doing harm to crops, is deposited in All-Russian collection of industrial microorganisms (VKPM), Federal State Unitary Enterprise GosNIIgenetika under number B-10709.
EFFECT: invention makes it possible to increase mortality of representatives of leaf-eating and sucking pests, doing harm to crops.
6 tbl, 2 ex
SUBSTANCE: strain of Bifidobacterium longum is separated from bowels content of healthy baby and is deposited in Government collection of microorganisms of normal microflora (GKNM) FSIS "MNIIEM named after G.N. Gabrichevskiy Rospotrebnadzor " under registration number 230. Strain multiplies in various nutrition mediua with accumulation of production biomass with high concentration of bifidobacteria.
EFFECT: Bifidobacterium longum strain has acid-forming activity, antagonistic activity with respect to pathogenic and opportunistic microorganisms, ferments milk, which makes it possible to apply it for obtaining bifidocontaining production.
2 tbl, 5 ex
SUBSTANCE: method of indicating hospital strains of Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter cloacae involves identification of an isolated pure culture of bacteria, inoculating the identified bacteria on blood-meat infusion agar while washing accumulated bacteria - S.aureus - after 12 hours, and Exloacae and P.aeruginosa - after 8 hours with sodium chloride solution. Electrical resistance of the suspension of bacteria in the sodium chloride solution is determined at bacteria concentration of 500000 in 1 ml in a dc electric field with 2.8 V across the electrodes. If electrical resistance for P.aeruginosa bacteria ranges from 579 to 674 kom, S.aureus 545-642 kom, Exloacae 452-584 kom and epidemiological data on recording five or more disease cases from one infection source, the isolated infectious agent is considered a hospital strain.
EFFECT: invention cuts time for conducting laboratory investigations and detecting circulation of hospital strains in hospitals, use of the invention does not require intraspecific identification of bacteria.
2 tbl, 3 ex
SUBSTANCE: nutrient medium contains enzymeatic hydrolyzate of beef meat, sodium chloride, sodium phosphate bisubstituted, sodium sulfite, Karpuzidi stimulant and purified water in specified component ratio.
EFFECT: invention makes it possible to obtain quality nutrient medium for culturing microbial cells of plague microbe of vaccine strain EB in sufficient quantity during 48 h.
1 tbl, 3 ex
SUBSTANCE: method involves treating a water-based medium containing sulphate-reducing bacteria SRB in industrial aqueous systems of chemical production and oil refining. Inhibition of production of biogenic sulphide with SRB takes place as a result of synergetic action of a biocide component in a first concentration and a metabolic inhibitor in a second concentration. The biocide immediately destroys the first portion of SRB. The biocide component is selected from a group comprising aldehydes, amine-type compounds, halogenated compounds, sulphur compounds, salts of quaternary phosphonium and/or combinations thereof. The metabolic inhibitor inhibits growth of a second portion of SRB without its direct destruction. The metabolic inhibitor component is selected from a group comprising nitrite, molybdate, tungstate, selenate, anthraquinone and/or combinations thereof. Contact between the SRB and the biocide and metabolic inhibitor can take place continuously, intermittently or simultaneously.
EFFECT: method ensures efficient inhibition of production of biogenic sulphide with SRB during combined use of components in considerably lower concentrations than if the biocide or metabolic inhibitor was used separately.
25 cl, 2 dwg, 1 ex
SUBSTANCE: method to produce a probiotic preparation based on sporogenous strains Bac.subtilis and Bac.licheniformis includes their cultivation, mixing of bacterial cells biomasses with protector of microbial cells and subsequent sterile dehydration. For this purpose the method applies the strain Bac.subtilis VKM V-2287 D and the strain Bac.licheniformis VKM V-2414D. Strain biomasses are mixed at the ratio of 1:1. A protector of microbial cells is lactose in amount that provides for cell titre in the finished product after drying of at least 1X1011 CFU/g.
EFFECT: method makes it possible to produce a pluripotential preparation, which may be used to prevent gastrointestinal diseases in farm animals and birds, prevention of stress actions, correction of microflora in intestine in case of digestion processes disturbance.
6 tbl, 2 ex
SUBSTANCE: method to produce a probiotic preparation based on sporogenous strains Bac.subtilis and Bac.licheniformis includes their cultivation, mixing of bacterial cells biomasses with protector of microbial cells and subsequent sterile dehydration. At the same time the method uses the strain Bac. subtilis VKPM V-10172 and the strain licheniformis VPKM V-10135. Biomasses of strains are mixed at the ratio of 1:1. A protector of microbial cells is a gelatine-saccharose protective medium in amount that provides for cell titre in the finished product after drying of at least 2X1012 CFU/g.
EFFECT: method makes it possible to produce a preparation with high efficiency of probiotic component, which ensures higher digestibility of fodders and increases weight gain of farm animals and birds.
3 tbl, 1 ex
SUBSTANCE: invention refers to biotechnology, and can be used for creation of vaccine preparations for colibacillosis in animals. A method for producing colibacillosis anatoxin provides sampling of epizootic Escherichia coli strains able to produce a thermolabile, thermostable and shiga like toxin, separate cultivation on a nutritious broth for 6-7 days, culture inactivation by adding formalin to the concentration 0.3-0.4 % at temperature 37°C for 14 days and mixing in equal volumes, and separation of a bacterial mass by means of sterilisation filtration.
EFFECT: invention provides more efficient prevention of colibacillosis in animals.
1 tbl, 1 ex
SUBSTANCE: invention refers to medicine and aimed at treatment of oesophageal achalasia. The preparation ximedone (1,2-dihydro-4,6-dimethyl,N-(β-oxyethyl)pyramidon-2) is prescribed. The preparation is taken by mouth before meals 3-4 times a day. A daily dose is 30 mg/kg of patient's weight. The course is 30 days.
EFFECT: method enables stabilising contractive activity of smooth muscle fibres of an oesophageal wall.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine and pharmaceutical industry, namely, to anti-tuberculosis medications for peroral application. As active substance, medication contains isoniaside in combination with para-aminosalipilate and is made in form of granules or tablets, each of which has intestine-dissoluble coating.
EFFECT: increase of medication efficiency.
5 cl, 2 ex
SUBSTANCE: invention relates to medicine and is intended for treatment of bile passages dysfunction in children with acute intestinal infections. Used is medication Mebeverine, which is administered per os for one month after acute intestinal infection. Day dose of mebeverine constitutes for children from 3 to 4 years of age - 75 mg per day, for children from 4 to 8 years old - 150 mg per day, for children from 9 to 10 years - 300 mg per day, for children older than 10 years - 450 mg per day.
EFFECT: method makes it possible to normalise indices of bile bladder function and prevent possibilities of formation of its post-infection motility disorders.
SUBSTANCE: novel compounds have general formula (1), or salts thereof:
, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of
, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.
EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.
20 cl, 147 ex, 3 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.
EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.
16 cl, 64 ex, 1 tbl
SUBSTANCE: invention refers to medicine, namely to obstetrics. The method involves preliminary preferred position of placenta aspect. The pregnant women on their 1-2 trimester of pregnancy suffering disordered uteroplacental hemodynamics are prescribed with transdermal exposure to deponite-10. The exposure involves an acupuncture point BM-147 of the leg corresponding to the placenta side and lasts for 12-24 hours. The therapeutic course is 1-2 sessions. The therapeutic course is 1-2 sessions.
EFFECT: method reduces medicament load on a body of the pregnant woman.
SUBSTANCE: group of inventions relates to medicine, particularly, to urology and gastroenterology and concerns treatment of interstitial cystitis or irritable colon syndrome (adaptive colitis) or ulcerative colitis using phenoxyalkyl carbonic acids derivatives. The effective quantity of compound 1:
or of its metabolite - compound 2:
or pharmaceutically acceptable salts thereof, or pro-drug forms, is administered to the patient.
EFFECT: invention ensures high therapeutic efficacy in treatment of the specified diseases due to simultaneous action of the compounds on a number of chemical inflammation mediators.
23 cl, 10 tbl, 10 ex, 5 dwg
SUBSTANCE: invention refers to medicine, namely to physiotherapy. Pre-homogenised medical mud of Tambukan lake is placed in a light- and gas-tight enclosure. Used mud contains mud solution, crystal skeleton and colloid complex at the following ratio of specified ingredients (wt %): crystal skeleton 15.0-25.0, colloid complex 10.0-20.0, mud solution - the rest. The enclosed medical mud is heated to temperature 37-40°C. Then with a syringe, the mud is slowly introduced into rectum of the patient. After introduction of the medical mud, the patient is pronated. Then 10÷20 minutes later, the patient is positioned edgewise. The mud tampon is left in rectum till urge to defecate. The procedures are performed every second day, or 2 days running with one day of break.
EFFECT: method improves clinical effectiveness and provides stable and prolonged remission of intestinal diseases owing to preparation of the mud applied.
7 cl, 5 ex, 1 tbl
SUBSTANCE: group of inventions concerns medicine and aims at treating irritable colon syndrome. The pharmaceutical preparation containing methyl naltrexone is introduced to the medically indigent patient. Said pharmaceutical preparation contains methyl naltrexone, an agent for treating irritable colon syndrome, a pharmaceutically acceptable carrier. A treatment kit contains a package with the preparation of methyl naltrexone and application instructions of the preparation of methyl naltrexone for treating irritable colon syndrome.
EFFECT: invention enables beneficial effect on segmentation and intestinal peristalsis thereby providing controllability of intestinal contractile force.
103 cl, 5 ex, 1 dwg
SUBSTANCE: invention relates to 5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine or to its salt, as well as a pharmaceutical composition which inhibits secretion of gastric acid based on the said compound. Description is given of production of the new compound and a pharmaceutical composition based on the new compound, which can be used in medicine for treating such diseases as gastric ulcer, duodenal ulcer, stomal ulcer, gastroesophageal reflux, Zollinger-Ellison syndrome, symptomatic gastroesophageal reflux, endoscopy negative gastroesophageal reflux, gastroesophageal regurgitation, pharyngolaryngeal paresthesia, Barrett's esophagus, Non-steroidal anti-inflammatory drug (NSAID) induced ulcer, gastritis, gastric hemorrhage, gastrointestinal hemorrhage, peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperchlorhydria, dyspepsia, gastroparesis, senile ulcer, intractable ulcer, heartburn, bruxism, stomach ache, heavy stomach or erosive gastritis.
EFFECT: increased effectiveness of composition and disease treatment.
7 cl, 6 tbl, 29 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to an oral pharmaceutical composition which contains a suspension 0.5-50 wt % of total weight of the composition of a platinum complex (OC-6-43) bis(acetate)-(1-adamantylamino)amine-dichloroplatin (IV) (LA-12) of particle size 100 mcm and less in a pharmaceutically acceptable vegetable, animal, mineral, synthetic or semisynthetic oil and/or oily substance, and a pharmaceutically acceptable excipient. The composition under the invention can be used as a drug for cancer treatment.
EFFECT: invention provides the stable composition high in a complex of tetravalent platinum.
10 cl, 3 ex