Нутритивная профилактика аллергии к белкам коровьего молока у детей раннего возраста
Нутритивная профилактика аллергии к белкам коровьего молока у детей раннего возраста
Захарова И.Н., Лаврова Т.Е., Стоволосов И.С. Нутритивная профилактика аллергии к белкам коровьего молока у детей раннего возраста. Педиатрия (Прил. к журн. Consilium Medicum). 2018; 2: 17–23.
DOI: 10.26442/2413-8460_2018.2.10-23
DOI: 10.26442/2413-8460_2018.2.10-23
DOI: 10.26442/2413-8460_2018.2.10-23
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DOI: 10.26442/2413-8460_2018.2.10-23
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Аннотация
В статье показан современный подход к профилактике аллергических заболеваний у детей раннего возраста. Описаны механизмы формирования пищевой толерантности с учетом современного понимания развития иммунной системы. Продемонстрированы основные исследования и обзоры, подчеркивающие важность современного подхода к профилактике аллергических заболеваний: контролируемого представления антигена и модуляции микробиоты кишечника на примере результатов международного многоцентрового исследования PATCH. В исследовании, включавшем 1047 детей, изучалось профилактическое действие смеси на основе частично гидролизованного белка коровьего молока, обогащенной олигосахаридами. Показано, что прием исследуемой смеси в течение 6 мес у детей с высоким риском аллергических заболеваний приводит к снижению риска атопического дерматита до 5-летнего возраста. Эффективность нутритивной профилактики зависит от сроков введения прикорма: выраженное профилактическое действие наблюдалось при введении прикорма в период окна пищевой толерантности. Формирование толерантности к белкам коровьего молока было подтверждено повышением количества дендритных клеток и регуляторных Т-клеток, а также снижением специфического иммуноглобулина G1 к белкам коровьего молока. На фоне приема исследуемой смеси продемонстрировано становление микробиоты кишечника, близкой по составу к таковой у детей на грудном вскармливании с преобладанием бифидобактерий.
Ключевые слова: дети раннего возраста, аллергия к белкам коровьего молока, профилактика, толерантность, частично гидролизованный белок, пребиотические олигосахариды.
Key words: infants, cow milk proteins allergy, prevention, tolerance, partially hydrolyzed protein, oligosaccharides.
Ключевые слова: дети раннего возраста, аллергия к белкам коровьего молока, профилактика, толерантность, частично гидролизованный белок, пребиотические олигосахариды.
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Key words: infants, cow milk proteins allergy, prevention, tolerance, partially hydrolyzed protein, oligosaccharides.
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26. Von Berg A, Filipiak-Pittroff B, Schulz H et al. Allergic manifestation 15 years after early intervention with hydrolyzed formulas--the GINI Study. Allergy 2016; 71 (2): 210–9.
27. Alexander DD, Cabana MD. Partially hydrolyzed 100% whey protein infant formula and reduced risk of atopic dermatitis: a meta-analysis. J Pediatr Gastroenterol Nutr 2010; 50: 422–30.
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29. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Turck D et al. Scientific and technical guidance for the preparation and presentation of an application for authorisation of an infant and/or follow‐on formula manufactured from protein hydrolysates. EFSA J 2017; 15 (5): 4779.
30. Szajewska H, Horvath A. A partially hydrolyzed 100% whey formula and the risk of eczema and any allergy: an updated meta-analysis. World Allergy Organ J 2017; 10 (1): 27.
31. Moro G et al. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the rst six months of age. Arch Dis Child 2006; 91 (10): 814–9.
32. Arslanoglu S, Moro GE, Boehm G et al. Early neutral prebiotic oligosaccharide supplementation reduces the incidence of some allergic manifestations in the first 5 years of life. J Biol Regul Homeost Agents 2012; 26 (Suppl. 3): 49–59.
33. Grüber C, van Stuijvenberg M, Mosca F et al, MIPS 1 Working Group. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J Allergy Clin Immunol 2010; 126: 791–7.
34. Osborn DA. Prebiotics in infants for prevention of allergy. Cochrane Database Syst Rev 2013; 3: CD006474.
35. Van Esch, BCAM et al. A dietary intervention with non-digestible oligosaccharides and partial hydrolysed whey protein prevents the onset of food allergic symptoms in mice. Pharma Nutrition, 2016.
36. Boyle RJ et al. Prebiotic-supplemented partially hydrolysed cow's milk formula for the prevention of eczema in high-risk infants: a randomized controlled trial. Allergy 2016; 71 (5): 701–10.
37. Tang M. Influence of early feeding patterns on eczema development in high-risk children. EAACI PAAM abstracts, 2017.
38. Wopereis H et al. Intestinal microbiota in infants at high risk for allergy: Effects of prebiotics and role in eczema development. J Allergy Clin Immunol 2017.
2. Host A, Halken S. Cow's milk allergy: where have we come fr om and wh ere are we going? Endocr Metab Immune Disord Drug Targets 2014; 14 (1): 2–8.
3. Bousquet J et al. Vorhersageallergischer Erkrankungen im Säuglingsalter. Aktuelle Probleme der päd. Allergologie 1983; p. 43–54.
4. West CE et al. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. J Allergy Clin Immunol 2015; 135 (1): 3–13.
5. Keag OE et al. Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis. PLoS Med 15(1): e1002494
6. Jakobsson HE et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 2014; 63 (4): 559–66.
7. Rutayisire E et al. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. BMC Gastroenterol 2016; 16 (1): 86.
8. Cuppari C et al. Mode of delivery and atopic phenotypes: Old questions new insights? A retrospective study. Immunobiology 2016; 221 (12): 1418–23.
9. Wambre E et al. Oral Tolerance Development and Maintenance. Immunol Allergy Clin North Am 2018; 38 (1): 27–37.
10. Weiner HL et al. Oral tolerance. Immunol Rev 2011; 241: 241–59.
11. Dubois B, Chapat L, Goubier A et al. Innate CD41CD251 regulatory T cells are required for oral tolerance and inhibition of CD81 T cells mediating skin inflammation. Blood 2003; 102: 3295–301.
12. Kim KS, Surh CD. Induction of immune tolerance to dietary antigens. Adv Exp Med Biol 2015; 850: 93–118.
13. Kim KS, Hong SW, Han D et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 2016; 351: 858–63.
14. Matheson MC, Allen KJ, Tang ML. Understanding the evidence for and against the role of breastfeeding in allergy prevention. Clin Exp Allergy 2012: 42: 827–51.
15. Новик Г.А. Формирование пищевой толерантности у детей с аллергией к белкам коровьего молока. Лечащий врач. 2014; 6. / Novik G.A. Formirovanie pishhevoj tolerantnosti u detej s allergiej k belkam korov'ego moloka. Lechashhij vrach. 2014; 6. [in Russian]
16. Turati F, Bertuccio P, Galeone C et al. Early weaning is beneficial to prevent atopic dermatitis occurrence in young children. Allergy 2016; 71: 878–88.
17. Ricci G, Cipriani F. Which advises for primary food allergy prevention in normal or high-risk infant? Pediatr Allergy Immunol 2016; 27: 774–8.
18. Taylor-Robinson DC et al. Do early-life exposures explain why more advantaged children get eczema? Findings from the U.K. Millennium Cohort Study. Br J Dermatol 2016; 174 (3): 569–78.
19. Kajosaari M. Atopy prevention in childhood: the role of diet. Prospective 5-year follow-up of high-risk infants with six months exclusive breastfeeding and solid food elimination. Ped Aller Immun 1994; 5 (Suppl. 6): 26–8.
20. Poysa L, Korppi M, Remes K, Juntunen-Backman K. Atopy in childhood and diet in infancy. A nine-year follow-up study. I. Clinical manifestations. Allergy Proc 1991; 12: 107–111.
21. Merrett TG, Burr ML, Butland BK et al. Infant feeding and allergy: 12-month prospective study of 500 babies born into allergic families. Ann Allergy 1988; 61(6 Part II): 13–20.
22. Muraro А et al. EAACI Food Allergy and Anaphylaxis Guidelines: managing patients with food allergy in the community. Allergy 2014; 69: 1046–57.
23. Vandenplas Y, De Greef E, Devreker T. Treatment of Cow's Milk Protein Allergy. Pediatr Gastroenterol Hepatol Nutr 2014; 17 (1): 1–5.
24. Greer FR et al. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008; 121 (1): 183–91.
25. Boyce JA et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010; 126 (Suppl. 6): S1-58.
26. Von Berg A, Filipiak-Pittroff B, Schulz H et al. Allergic manifestation 15 years after early intervention with hydrolyzed formulas--the GINI Study. Allergy 2016; 71 (2): 210–9.
27. Alexander DD, Cabana MD. Partially hydrolyzed 100% whey protein infant formula and reduced risk of atopic dermatitis: a meta-analysis. J Pediatr Gastroenterol Nutr 2010; 50: 422–30.
28. Boyle RJ et al. Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ 2016; 352: i974.
29. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Turck D et al. Scientific and technical guidance for the preparation and presentation of an application for authorisation of an infant and/or follow‐on formula manufactured from protein hydrolysates. EFSA J 2017; 15 (5): 4779.
30. Szajewska H, Horvath A. A partially hydrolyzed 100% whey formula and the risk of eczema and any allergy: an updated meta-analysis. World Allergy Organ J 2017; 10 (1): 27.
31. Moro G et al. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the rst six months of age. Arch Dis Child 2006; 91 (10): 814–9.
32. Arslanoglu S, Moro GE, Boehm G et al. Early neutral prebiotic oligosaccharide supplementation reduces the incidence of some allergic manifestations in the first 5 years of life. J Biol Regul Homeost Agents 2012; 26 (Suppl. 3): 49–59.
33. Grüber C, van Stuijvenberg M, Mosca F et al, MIPS 1 Working Group. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J Allergy Clin Immunol 2010; 126: 791–7.
34. Osborn DA. Prebiotics in infants for prevention of allergy. Cochrane Database Syst Rev 2013; 3: CD006474.
35. Van Esch, BCAM et al. A dietary intervention with non-digestible oligosaccharides and partial hydrolysed whey protein prevents the onset of food allergic symptoms in mice. Pharma Nutrition, 2016.
36. Boyle RJ et al. Prebiotic-supplemented partially hydrolysed cow's milk formula for the prevention of eczema in high-risk infants: a randomized controlled trial. Allergy 2016; 71 (5): 701–10.
37. Tang M. Influence of early feeding patterns on eczema development in high-risk children. EAACI PAAM abstracts, 2017.
38. Wopereis H et al. Intestinal microbiota in infants at high risk for allergy: Effects of prebiotics and role in eczema development. J Allergy Clin Immunol 2017.
2. Host A, Halken S. Cow's milk allergy: where have we come fr om and wh ere are we going? Endocr Metab Immune Disord Drug Targets 2014; 14 (1): 2–8.
3. Bousquet J et al. Vorhersageallergischer Erkrankungen im Säuglingsalter. Aktuelle Probleme der päd. Allergologie 1983; p. 43–54.
4. West CE et al. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. J Allergy Clin Immunol 2015; 135 (1): 3–13.
5. Keag OE et al. Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis. PLoS Med 15(1): e1002494
6. Jakobsson HE et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 2014; 63 (4): 559–66.
7. Rutayisire E et al. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. BMC Gastroenterol 2016; 16 (1): 86.
8. Cuppari C et al. Mode of delivery and atopic phenotypes: Old questions new insights? A retrospective study. Immunobiology 2016; 221 (12): 1418–23.
9. Wambre E et al. Oral Tolerance Development and Maintenance. Immunol Allergy Clin North Am 2018; 38 (1): 27–37.
10. Weiner HL et al. Oral tolerance. Immunol Rev 2011; 241: 241–59.
11. Dubois B, Chapat L, Goubier A et al. Innate CD41CD251 regulatory T cells are required for oral tolerance and inhibition of CD81 T cells mediating skin inflammation. Blood 2003; 102: 3295–301.
12. Kim KS, Surh CD. Induction of immune tolerance to dietary antigens. Adv Exp Med Biol 2015; 850: 93–118.
13. Kim KS, Hong SW, Han D et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 2016; 351: 858–63.
14. Matheson MC, Allen KJ, Tang ML. Understanding the evidence for and against the role of breastfeeding in allergy prevention. Clin Exp Allergy 2012: 42: 827–51.
15. Новик Г.А. Формирование пищевой толерантности у детей с аллергией к белкам коровьего молока. Лечащий врач. 2014; 6. / Novik G.A. Formirovanie pishhevoj tolerantnosti u detej s allergiej k belkam korov'ego moloka. Lechashhij vrach. 2014; 6. [in Russian]
16. Turati F, Bertuccio P, Galeone C et al. Early weaning is beneficial to prevent atopic dermatitis occurrence in young children. Allergy 2016; 71: 878–88.
17. Ricci G, Cipriani F. Which advises for primary food allergy prevention in normal or high-risk infant? Pediatr Allergy Immunol 2016; 27: 774–8.
18. Taylor-Robinson DC et al. Do early-life exposures explain why more advantaged children get eczema? Findings from the U.K. Millennium Cohort Study. Br J Dermatol 2016; 174 (3): 569–78.
19. Kajosaari M. Atopy prevention in childhood: the role of diet. Prospective 5-year follow-up of high-risk infants with six months exclusive breastfeeding and solid food elimination. Ped Aller Immun 1994; 5 (Suppl. 6): 26–8.
20. Poysa L, Korppi M, Remes K, Juntunen-Backman K. Atopy in childhood and diet in infancy. A nine-year follow-up study. I. Clinical manifestations. Allergy Proc 1991; 12: 107–111.
21. Merrett TG, Burr ML, Butland BK et al. Infant feeding and allergy: 12-month prospective study of 500 babies born into allergic families. Ann Allergy 1988; 61(6 Part II): 13–20.
22. Muraro А et al. EAACI Food Allergy and Anaphylaxis Guidelines: managing patients with food allergy in the community. Allergy 2014; 69: 1046–57.
23. Vandenplas Y, De Greef E, Devreker T. Treatment of Cow's Milk Protein Allergy. Pediatr Gastroenterol Hepatol Nutr 2014; 17 (1): 1–5.
24. Greer FR et al. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008; 121 (1): 183–91.
25. Boyce JA et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010; 126 (Suppl. 6): S1-58.
26. Von Berg A, Filipiak-Pittroff B, Schulz H et al. Allergic manifestation 15 years after early intervention with hydrolyzed formulas--the GINI Study. Allergy 2016; 71 (2): 210–9.
27. Alexander DD, Cabana MD. Partially hydrolyzed 100% whey protein infant formula and reduced risk of atopic dermatitis: a meta-analysis. J Pediatr Gastroenterol Nutr 2010; 50: 422–30.
28. Boyle RJ et al. Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ 2016; 352: i974.
29. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Turck D et al. Scientific and technical guidance for the preparation and presentation of an application for authorisation of an infant and/or follow‐on formula manufactured from protein hydrolysates. EFSA J 2017; 15 (5): 4779.
30. Szajewska H, Horvath A. A partially hydrolyzed 100% whey formula and the risk of eczema and any allergy: an updated meta-analysis. World Allergy Organ J 2017; 10 (1): 27.
31. Moro G et al. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the rst six months of age. Arch Dis Child 2006; 91 (10): 814–9.
32. Arslanoglu S, Moro GE, Boehm G et al. Early neutral prebiotic oligosaccharide supplementation reduces the incidence of some allergic manifestations in the first 5 years of life. J Biol Regul Homeost Agents 2012; 26 (Suppl. 3): 49–59.
33. Grüber C, van Stuijvenberg M, Mosca F et al, MIPS 1 Working Group. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J Allergy Clin Immunol 2010; 126: 791–7.
34. Osborn DA. Prebiotics in infants for prevention of allergy. Cochrane Database Syst Rev 2013; 3: CD006474.
35. Van Esch, BCAM et al. A dietary intervention with non-digestible oligosaccharides and partial hydrolysed whey protein prevents the onset of food allergic symptoms in mice. Pharma Nutrition, 2016.
36. Boyle RJ et al. Prebiotic-supplemented partially hydrolysed cow's milk formula for the prevention of eczema in high-risk infants: a randomized controlled trial. Allergy 2016; 71 (5): 701–10.
37. Tang M. Influence of early feeding patterns on eczema development in high-risk children. EAACI PAAM abstracts, 2017.
38. Wopereis H et al. Intestinal microbiota in infants at high risk for allergy: Effects of prebiotics and role in eczema development. J Allergy Clin Immunol 2017.
________________________________________________
2. Host A, Halken S. Cow's milk allergy: where have we come fr om and wh ere are we going? Endocr Metab Immune Disord Drug Targets 2014; 14 (1): 2–8.
3. Bousquet J et al. Vorhersageallergischer Erkrankungen im Säuglingsalter. Aktuelle Probleme der päd. Allergologie 1983; p. 43–54.
4. West CE et al. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. J Allergy Clin Immunol 2015; 135 (1): 3–13.
5. Keag OE et al. Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis. PLoS Med 15(1): e1002494
6. Jakobsson HE et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 2014; 63 (4): 559–66.
7. Rutayisire E et al. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. BMC Gastroenterol 2016; 16 (1): 86.
8. Cuppari C et al. Mode of delivery and atopic phenotypes: Old questions new insights? A retrospective study. Immunobiology 2016; 221 (12): 1418–23.
9. Wambre E et al. Oral Tolerance Development and Maintenance. Immunol Allergy Clin North Am 2018; 38 (1): 27–37.
10. Weiner HL et al. Oral tolerance. Immunol Rev 2011; 241: 241–59.
11. Dubois B, Chapat L, Goubier A et al. Innate CD41CD251 regulatory T cells are required for oral tolerance and inhibition of CD81 T cells mediating skin inflammation. Blood 2003; 102: 3295–301.
12. Kim KS, Surh CD. Induction of immune tolerance to dietary antigens. Adv Exp Med Biol 2015; 850: 93–118.
13. Kim KS, Hong SW, Han D et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 2016; 351: 858–63.
14. Matheson MC, Allen KJ, Tang ML. Understanding the evidence for and against the role of breastfeeding in allergy prevention. Clin Exp Allergy 2012: 42: 827–51.
15. Новик Г.А. Формирование пищевой толерантности у детей с аллергией к белкам коровьего молока. Лечащий врач. 2014; 6. / Novik G.A. Formirovanie pishhevoj tolerantnosti u detej s allergiej k belkam korov'ego moloka. Lechashhij vrach. 2014; 6. [in Russian]
16. Turati F, Bertuccio P, Galeone C et al. Early weaning is beneficial to prevent atopic dermatitis occurrence in young children. Allergy 2016; 71: 878–88.
17. Ricci G, Cipriani F. Which advises for primary food allergy prevention in normal or high-risk infant? Pediatr Allergy Immunol 2016; 27: 774–8.
18. Taylor-Robinson DC et al. Do early-life exposures explain why more advantaged children get eczema? Findings from the U.K. Millennium Cohort Study. Br J Dermatol 2016; 174 (3): 569–78.
19. Kajosaari M. Atopy prevention in childhood: the role of diet. Prospective 5-year follow-up of high-risk infants with six months exclusive breastfeeding and solid food elimination. Ped Aller Immun 1994; 5 (Suppl. 6): 26–8.
20. Poysa L, Korppi M, Remes K, Juntunen-Backman K. Atopy in childhood and diet in infancy. A nine-year follow-up study. I. Clinical manifestations. Allergy Proc 1991; 12: 107–111.
21. Merrett TG, Burr ML, Butland BK et al. Infant feeding and allergy: 12-month prospective study of 500 babies born into allergic families. Ann Allergy 1988; 61(6 Part II): 13–20.
22. Muraro А et al. EAACI Food Allergy and Anaphylaxis Guidelines: managing patients with food allergy in the community. Allergy 2014; 69: 1046–57.
23. Vandenplas Y, De Greef E, Devreker T. Treatment of Cow's Milk Protein Allergy. Pediatr Gastroenterol Hepatol Nutr 2014; 17 (1): 1–5.
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Авторы
И.Н.Захарова*1, Т.Е.Лаврова2, И.С.Стоволосов2
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования»
Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1;
2 ООО «Нутриция». 143421, Россия, Московская обл., Красногорский р-н, 26-й км автодороги «Балтия»,
бизнес-центр «Рига Ленд», стр. 1
*zakharova-rmapo@yandex.ru
1 Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, st. Barrikadnaia, 2/1;
2 Nutricia. 143421, Russian Federation, Moscow region, Krasnogorskii area, Baltia highway, 26th km, business-centre “Riga Land”, building 1
*zakharova-rmapo@yandex.ru
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования»
Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1;
2 ООО «Нутриция». 143421, Россия, Московская обл., Красногорский р-н, 26-й км автодороги «Балтия»,
бизнес-центр «Рига Ленд», стр. 1
*zakharova-rmapo@yandex.ru
________________________________________________
1 Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, st. Barrikadnaia, 2/1;
2 Nutricia. 143421, Russian Federation, Moscow region, Krasnogorskii area, Baltia highway, 26th km, business-centre “Riga Land”, building 1
*zakharova-rmapo@yandex.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.