The levels of cognitive processes development in preschool children receiving vitamin-mineral complexes ALFAVIT Kindergarten and reference complex  (hereinafter the reference drug "X") were studied during and after a course of tested preparations. Cognitive processes in children after four-month course of vitamin administration were characterized. A comparative analysis between the groups of children taking different vitamins and minerals was made. Neuro-psychological development dynamics of preschool children receiving vitamins was studied. The effect of course admission of vitamin-mineral complexes on the ENT-status of preschool children in the winter-spring period was evaluated. The characteristic profile of safety (tolerance) of the studied complexes in their long-term (course) administration was done.
Despite the well-defined sanitary and hygienic standards of nutrition for children in preschool institutions, the issues related to food quality, especially in the winter and spring always remain valid. According to some reports, lack of vitamins is a permanent year-round factor . Predominance of foods, subjected to heat treatment of products made using high technologies (long-term storage products, as well as refined vegetables and fruits grown in greenhouse conditions) makes the provision of the child's body with vitamins, macro-and micronutrients solely through food an unreal task. This problem becomes even more acute among children of preschool age, when adequate formation of psycho-physiological functions of the child requires a sufficient intake of vitamins and minerals, and nutritional disorders can affect not only the physical functions, but also intelligence . All this requires a reasonable correction of vitamin and mineral status of preschool children.
To study the effect of vitamin-mineral complex ALFAVIT Kindergarten and reference drug "X" on development of cognitive processes of preschool-age children, the state of the neurological status and the prevalence of otorhinolaryngological pathologies, as well as the evaluation of safety profile during a long-term course intake of investigated multivitamin complexes.
Materials and methods
Vitamin-mineral complex ALFAVIT Kindergarten (SGR number 126.96.36.199.U.3931.5.06 dd. 06.05.2006, manufacturer AKVION JSC, Russia), the reference drug "X".
A clinical study was conducted in a preschool educational institution № 178 ("Rossiyanochka) in the city of Arkhangelsk. Duration of administration of investigated vitamin-mineral complexes was 4 months. 60 children of preschool age (5-6 years) received vitamin-mineral complexes, of which 30 children (study group) received ALFAVIT Kindergarten and 30 children (control group) received the reference drug "X".
The study used the following methods:
1. Psycho-pedagogical survey according to methodology of professor EA Strebeleva , which allows to identify the basic parameters of mental and verbal child development and to conduct a pedagogical examination of children’s hearing and includes a number of subtests:
a) "Inclusion in a row" – identification of development level of the child's orientation and cognitive activity – namely, orientation in amounts.
b) "Ladder" – identifying the level of design skills development, ability to work with memory on the model.
c) "Finish a drawing" – clarification of the level of development of generalized ideas about the properties and qualities of the real and imagined objects.
g) "Classification of images based on functionality," "grouping of pictures based on the mode of action", "Account", "Find the time of the year", "A series of scene images” – subtests, reflecting the level of development of visual-figurative thinking.
"Account" – identifying the level of development of quantitative concepts and skills of the child to perform counting operations in mental terms, i.e. the level of development of elements of logical thinking.
"Find the time of the year" – determine the level of formation of ideas about the seasons.
"A series of scene images" – clarification of the ability to understand the sequence of events depicted in the picture.
The methodology of estimating
Children received the highest possible rating - 4 points - in case of a task acceptance, understanding of problem conditions and its correct implementation, 3 points - if a child accepted and understood the assignment, but could not independently perform it at once, generalize, or solve a problem, or make a coherent story, 2 points – if the child accepted the task, but did not understand the conditions of the problem, 1 point - the child did not understand the purpose, or had inadequate performance, in terms of training.
2. Neurological examination. A comparative evaluation of dynamic muscle strength, motor activity, motor dexterity, reflexes, hyperkinesias, gait, posture, autonomic reactions on the background of long-term intake of the studied vitamin-mineral complexes.
3. ENT examination. Conducted to identify acute and worsening of chronic ENT pathologies because of high prevalence of ENT diseases in the Arkhangelsk region.
Statistical analysis was done using the Mann-Whitney and Fischer's angular transformation (Sidorenko EV, 2004).
Results and discussion
Russian pharmaceutical market is replete with a variety of multivitamin preparations in combination with minerals and microelements (unfortunately, mostly preparations are imported). Some of them are focused on certain age groups or particular pathological conditions (elderly, people with cardiovascular, neurological diseases, eye diseases etc.). However, the variety of balanced multivitamin-mineral complexes targeted at preschool children is very limited. At the same time, this period of childhood (3-7 years) is significant in terms of preparing children for the upcoming cognitive, psychological and physical stress encountered in school educational institutions. In this regard, it seems urgent to research and study the possibility of a prolonged prophylactic use of balanced vitamin-mineral complexes for preschool children in preparation for school period.
Pediatricians and parents often have a natural question: what multivitamin preparation to choose? The number of ingredients in the composition of these preparations could be several dozens. On the first glance, there is nothing wrong with that: the doctor is saved from unnecessary prescriptions and the child has no need to take multiple drugs. However, the interactions of vitamins, minerals, metals and microelements among themselves as well as in the body have not been sufficiently studied. Therefore, the number of foreign and domestic scientists, in particular, professor NA Korovin, caution against excessive use of multivitamin preparations in combination with microelements and minerals . Interactions between vitamins and minerals occur at the chemical and physiological levels. Therefore we cannot simply mix the ingredients of multivitamin preparations, because due to chemical reactions, some of them may become inactive. As a result, the actual amount of vitamins or microelements in such complexes may be much smaller than claimed, even though the production process limits direct contact between the ingredients. Accounting for these pharmaceutical features is extremely necessary and important for clinical and pharmacological choice of vitamin-mineral complex. One of these is the original Russian vitamin-mineral complex ALFAVIT Kindergarten, which is specially balanced and optimally adapted for children from 3 to 7 years. The composition and dosage of ALFAVIT Kindergarten is developed by Institute of Nutrition, taking into account the physiological needs of the child's body in vitamins and minerals, and pharmaceutical interactions between vitamins and minerals, which certainly enhance the pharmacodynamic efficacy . Vitamin-mineral complex ALFAVIT Kindergarten is designed to prevent hypovitominosis and lack of minerals, for ensuring harmonious neuropsychological development and adequate growth of children in preschool period. It is known that vitamins play an important role in the development of higher mental functions of the child . For example, vitamin B1 (thiamine) plays an important role in carbohydrate, protein and fat metabolism and is essential for neural regulation. Vitamin B6 (pyridoxine) is necessary for normal functioning of the nervous system. Vitamin B5 (pantothenic acid) plays an important role in the regulation of redox processes. Vitamin B12 (cyanocobalamin) is necessary to normalize the neurological function and hematopoiesis. It is assumed that biotin, which is one of the most powerful vitamin catalysts has regulating effects in nerve functioning. Thyroid hormones, which are based on iodine, also play vital roles because they provide growth, physical and intellectual and cognitive development in children. Chromium contributes to the structural integrity of nucleic acids, promotes excretion of toxins, salts, heavy metals, radionuclides, and is involved in cerebral blood flow.
In connection with the abovementioned, we conducted a clinical study of effects of balanced vitamin-mineral complex ALFAVIT Kindergarten and reference drug "X" on the development of neuro-psychological processes in preschool children.
During the study of cognitive processes in children before administration of vitamin preparations, some differences were found between the main group (the ALFAVIT Kindergarten) and the comparison group (the drug "X") on a number of subtests of EA Strebeleva methodic, namely: "Classification of images based on function" "grouping of pictures based on the mode of action", "Find the time of the year", "A series of scene images," which reflect the level of visual-figurative thinking. Scores on these subtests in children of the main group slightly exceeded the results of children in comparison group. However, the statistical data processing showed that differences in levels of visual-figurative thinking of children in these groups was not significant (p <0,003).
The study of cognitive processes of children after receiving a course of tested vitamin-mineral complexes has shown a trend in increase of the number of correct answers in both groups on subtests: "Find the time of the year", " Finish a drawing "," Count". Scores of children in the main group were 14% higher than the results of children in comparison group, and the difference in the level of development of cognitive processes was significant (p<0,001).
Assessment of the dynamics of cognitive processes in each group revealed that the number of children in the study group (ALFAVIT Kindergarten), which successfully solved sub-tests "Four Seasons", "The grouping of pictures on the mode of action," "Finish a drawing", was significantly greater after course of vitamins (p<0,005). Positive dynamics of cognitive function development of children in the study group after reception of ALFAVIT Kindergarten was 61 %, which fully corresponds with the direction of pharmacodynamic action of the studied vitamin-mineral complex. The remaining indicators did not show significant differences. The number of children in the comparison group (the drug "X") which solved subtests: "Inclusion in a row," "Ladder", "Classification images for Functionality", "The grouping of pictures on the mode of action", "Account" , "Four Seasons", "Finish a drawing" was slightly lesser (40 %) before intake of vitamins (p<0,003).
Given that the total number of children in the study group (ALFAVIT Kindergarten), which successfully accomplished given tasks, prior to receiving the vitamin-mineral complex was 26 % and after four months of regular admission this number increased to 87 % (61 % increase) and in the comparison group (drug "X") it was originally estimated at 30 % and increased to 70 % (40 %), one can assume that the stimulating factor that influenced the level of cognitive processes development, was intake of a balanced vitamin-mineral complexes by children and the implementation of developmental programs related to preparing children for school.
Analysis of the parent complaints was conducted, on the basis of which it seems appropriate to note that in the group of children which received vitamin-mineral complex ALFAVIT Kindergarten fewer complaints of violations of speech (68 %) also decreased the number of somnological disorders (74 %) and slightly decreased the number of complaints of headaches (20 %) were reported. The dynamic neurological examination showed a trend in increase of the number of children with improved motor dexterity, gait, facial expression, reduction of speech deviations, reduced number of children with autonomic disturbances (hyperhidrosis, vascular reaction). As can be seen, positive changes dominated the neurological status dynamics of children, of which the reduction of speech and somnological disorders were statistically significant. This indicators are especially important in preparing children for school period.
In the group of children who took the drug "X", frequency of headache complaints, sleep disturbances, excess mobility of children also decreased, but there were no changes in violations of speech, restlessness, irritability, and inattention.
Before the administration of investigated preparations there were no differences in prevalence of individual nosological forms in the studied groups (at the level of statistical significance of p<0.05 by Student's t-test). In general, the prevalence of diseases was higher in the study group - children who took ALFAVIT Kindergarten during the study (1289,6 ‰ and 1025,6 ‰, respectively, p<0,005). The re-examination showed a reduction in the incidence of diseases in both groups, with significant decrease in both groups: the main group (the ALFAVIT Kindergarten) – by 17,2 %, in control (drug "X") – by 9,1 %, p<0,005. After vitamin therapy the study group had higher prevalence of diseases than the control group (1068,2 ‰ and 931,8 ‰, respectively, p<0,05). Reducing the incidence of disease was mainly due to a decrease in the incidence of middle ear diseases (exudative otitis media in two stages of its progression – catarrhal and secretive). Reduction of exudative otitis media occurred in both groups: in the study group (ALFAVIT Kindergarten) the reduction was 71,2 % in the control (drug "X") – 49,4 %, but statistically significant (p<0.05) decrease only was noted only in the study group. For the rest of nosological forms changes were minor and statistically insignificant.
Reduction in the incidence of exudative otitis could be logically explained on the basis of the pathogenesis of this disease, which is based on dysfunction of the auditory tube. The latter occurs for many reasons. The main ones for this age group include: mechanical obstruction of the pharyngeal opening by adenoids, and frequent respiratory infections, because of which there is not enough time to recover mucociliary transport in auditory tubes. Reduction of incidence of acute respiratory infections leads, firstly, to reduction of pharyngeal tonsil volume, and secondly, to the recovery of mucociliary transport in eustachian tubes, which accounts for their normal functioning and decreases the frequency of exudative otitis media. The same should not be expected for other studied diseases, which is confirmed by the results of statistical data. One might expect a reduction in the prevalence of diseases such as hypertrophy of adenoid and tonsils, chronic tonsillitis, since the basis of their pathogenesis is chronic inflammation (along with other mechanisms), resulting from contamination of mucous membrane by pharynx viruses and bacteria. Course application of vitamin-mineral complex ALFAVIT Kindergarten, of course, leads to increased local and general immunity, the normalization of pharyngeal microbiota, but the formation of these diseases has a longer period than the duration of the vitamin administration. It is important to note that after application of multi-vitamin preparation ALFAVIT Kindergarten leads to significant decrease in the proportion of children with 2nd stage hypertrophy of the adenoid tonsils (from 100 % to 33,3 %).
Thus, prophylactic course application of ALFAVIT Kindergarten helps to reduce the incidence of diseases of upper respiratory tract in children of preschool age, but it should be recognized that the prevention of chronic diseases of the ear, nose and throat requires comprehensive, long-lasting (the first days of kindergarten), systematic arrangements aimed at reducing the incidence of acute respiratory diseases.
Safety profiles (tolerability)
The question of tolerability always arises in pediatric practice during selection of multivitamin, because of importance to minimize the possibility of allergic reactions. In this context, we studied the safety profile of the tested vitamin-mineral complexes. During the course of administration of ALFAVIT Kindergarten there were 2 cases of allergic dermatosis, and 1 case in drug "X" group, and therefore the administration of drugs in these children has been discontinued. Other side effects throughout the entire course of treatment with the studied drugs were noted.
Prolonged courses of prophylactic (4-month) intake of a balanced vitamin-mineral complex ALFAVIT Kindergarten is characterized by objective improvements in cognitive functions in preschool children, decrease of ENT pathologis, positive changes in overall neurological status of children and favorable safety profile (tolerability), which allows us to recommend its course admnistration (according to the scheme: 3-month course, one-month break, followed by arepeated 3-month course) in the scope of complex medical-prophylactic preparation of children to school period.
 The composition of the reference vitamin-mineral complex (one-tablet): vitamin A - 400 mcg, vitamin D - 10 mg, vitamin E - 5 mg, vitamin B1 - 0,7 mg, vitamin B2 - 0,8 mg, vitamin B6 - 0,9 mg, vitamin B12 - 1 mcg, nicotinamide - 9 mg, pantothenic acid - 3 mg, folic acid - 20 mcg, vitamin C - 40 mg, iron - 10 mg, zinc - 5 mg, Copper - 1 mg, manganese - 1 mg, Chromium - 20 mcg, Selenium - 25 mcg, Iodine - 70 mcg