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Farmaka a jejich mozïnyâ vztah k ortodontickeâ leâcïbeï. Souborny referaât. Pharmaceuticals - potential effects on orthodontic treatment. Systematic review. MDDr. Jana PtaÂcÏ kovaâ Ortodonticke oddeï

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Farmaka a jejich mozïnyâ vztah k ortodontickeâ leâcïbeï. Souborny referaât. Pharmaceuticals - potential effects on orthodontic treatment. Systematic review. MDDr. Jana PtaÂcÏ kovaâ Ortodonticke oddeï lenõâ Kliniky zubnõâho leâ karïstvõâ LF UP Olomouc Department of Orthodontics, Clinic of Dental Medicine, Medical Faculty of Palacky University, Olomouc Souhrn Mezi leâ cï iva uzï õâvanaâ v CÏ eskeâ republice, u kteryâ ch se podarïilo prokaâ zat vliv na ortodontickou leâ cï bu, poprï. kteraâ meï la vliv i na jineâ faktory jako salivaci cï i hyperplazii gingivy, patrïõâ antibiotika, inhibitory synteâ zy prostaglandinuê, regulaâ tory hladiny vaâ pnõâku v krvi, antiepileptika, imunosupresiva, aplikace ruê stoveâ ho hormonu a parasympatolytika. Ostatnõ cï asto prïedepisovanaâ leâcï iva sice mohou mõât vedlejsïõâuâcï inky, ktereâ se projevujõâ v dutineï uâ stnõâ, avsïak zatõâm u nich nebyl prokaâzaâ n jejich vliv na ortodontickou leâcï bu. PrÏi navrhovaâ nõâ ortodontickeâholeâcï ebneâ ho plaânu by meï la byâ t braâ na v uâ vahu koordinace mezi farmakoterapiõâ, zdravõâm jedince a podmõânkami pro ortodontickou leâcïbu(ortodoncie 2013, 22, cï. 3, s ). Abstract Among pharmaceuticals used in the Czech Republic, in which the effects on orthodontic treatment have been proven or which show impact on other factors (e.g. salivation or gingival hyperplasia) belong antibiotics, inhibitors of prostaglandines synthesis, regulators of blood calcium levels, antiepileptic drugs, immunosuppressives, application of growth hormone and parasympatholytics. Other prescription drugs may have side effects manifesting in oral cavity. However, the influence on orthodontic treatment has not been proved yet. The coordination between pharmacotherapy, health state of a patient, and conditions for orthodontic treatment should be taken into account when planning orthodontic treatment (Ortodoncie 2013, 22, No. 3, p ). KlõÂcÏova slova: leâcï iva, ortodontickaâ leâcïba Key words: pharmaceuticals, orthodontic treatment U vod Farmakoterapie je dnes soucï aâ stõâ kazï dodennõâho zïivota mnoha lidõâ. Je proto nutneâ siuveï domit, zïe uâcï inky jednotlivyâch leâkuê se nejen projevujõâ v lidskeâ m organismu a mohou se vzaâ jemneï doplnï ovat, ale mohou do urcïiteâ mõâry ovlivnit i ortodontickou leâcï bu. V mnoha leâ karïskyâ ch oborech se vyuzï õâvaâ jejich zï aâ doucõâch uâcï inkuê, nicmeâneï v oboru ortodontickeâ m mohou mõât jejich vlastnosti dopad, kteryâ muê zï e neinformovaneâ ho prïinejmensïõâm prïekvapit. I z tohoto duê vodu je vhodneâ sineï kolik duê lezï ityâ ch informacõâ daâ t do souvislostõâ. Introduction Today, pharmacotherapy is a part of everyday life for a lot of people. It is, therefore, necessary to consider the fact that effects of individual drugs manifest not only in a human body (and may complement one another) but may - to some extent - influence the outcomes of orthodontic treatment. Drugs are used in many branches of medicine for their desirable effects, however, in orthodontics those who are not informed may be taken by surprise with their undesirable impact. Therefore we should be aware of the following important information ORTODONCIE Mezile koveâ skupiny, ktereâ mohou ovlivnit ortodontickou leâ cï bu patrïõâ antibiotika, inhibitory synteâ zy prostaglandinuê, regulaâ tory hladiny vaâ pnõâku v krvi, antiepileptika, imunosupresiva, rekombinantnõâ ruê stovyâ hormon a parasympatolytika. CõÂlem tohoto referaâtu je upozornit na mozïneâ vlivy teï chto leâkuê na ortodontickou leâcï bu. Antibiotika JakozÏ to produkty metabolismu mikroorganismuê,cï i synteticky vyraâ beï neâ laâ tky majõâ za cõâl znicï i t puê vodce onemocneï nõâ, nebo omezit jeho ruê st. Indikova ny jsou ve vsï ech prïõâpadech, kdy dojde k porusï enõâ rovnovaâhy vztahuê mezi mikro- a makroorganismem. JedinyÂm zaâstupcem z teâtosï irokeâ sïkaâ ly, u ktereâ ho se zatõâm podarïilo potvrdit vztah k ortodontickeâ mu pohybu zubuê je doxycyklin, patrïõâcõâ do skupiny tetracyklinovyâ ch antibiotik. Jeho vedlejsï õâ mechanismus uâ cï inku spocï õâvaâ v inhibici aktivity metaloproteinaâ z (kolagenaâ zy a gelatinaâ zy) a braâ nõâ kolagenolyâ ze. TõÂm, zï e snizï uje pocï et osteoklastuê, zpomaluje resorpcikorïenuê a alveolaâ rnõâ kostia prïijeho uzïõâvaâ nõâ dochaâ zõâ ke zpomalenõâ ortodontickeâ ho pohybu zubuê [1, 2, 3]. Inhibitory synteâ zy prostaglandinuê Do teâto sï irokeâ skupiny leâcï iv patrïõâ nesteroidnõâ antiflogistika a analgetika-antipyretika. Jejich mechanismem uâcï inku je inhibice vzniku prostanoiduê (prostaglandinuê, prostacyklinuê, a tromboxanuê ), ktereâ v lidskeâm teïle slouzï õâ jako jedny z mediaâ toruê zaâ neï tu. Prostaglandiny vznikajõâ za uâcï asticyklooxygenaâ zy (COX) 1 nebo 2 z kyseliny arachidonoveâ a ovlivnï ujõâ mimo jineâ krevnõâ tlak, agregacidesticï ek, tonus ceâ v, tonus mocï oveâ ho meïchyârïe cï i kostnõâ resorpci. Inhibitory synteâ zy prostaglandinuê deï lõâme na: ANALGETIKA-ANTIPYRETIKA Za stupcem teâ to skupiny je paracetamol. Prakticky nemaâ zïaâ dneâ protizaâ neï tliveâ uâ cï inky a urychluje prïemeï nu prostaglandinuê na meâneï uâcï inneâ formy [4]. Nema vliv na ortodontickyâ pohyb zubuê [5]. MeÏ l by tedy byât leâ kem volby prïibolestech vyskytujõâcõâch se prïiortodontickeâ leâcïbeï [ 5,6]. NESTEROIDNI ANTIFLOGISTIKA ± COX 1 preferencï nõâ: NejcÏ asteï ji uzï õâvanyâm zaâ stupcem je kyselina acetylsalicylovaâ. Jejõ uâ cï inky jsou vedle inhibice agregace trombocytuê snõâzï enõâ pocï tu osteoklastuê a snõâzï enõâ rychlostikostnõâ resorpce. TõÂm dochaâ zõâ ke zpomalenõâ ortodontickeâ ho pohybu zubuê. U cï inek byl prokaâzaâ n ve studii na morcï atech v daâ vce 100mg/kg 2x denneï [5]. Jako doporucï enõâ se uvaâ dõâ co nejvõâce zkraâ tit terapii touto skupinou leâ kuê prïiortodontickeâ leâcïbeï [7]. ± COX neselektivnõâ: Jejich zaâ stupcem je ibuprofen. Inhibuje cyklooxygenaâ zu 1 i2 a tõâm snizï uje pocï et Amongst the drugs which may affect orthodontic treatment we find antibiotics, prostaglandines synthesis inhibitors, blood calcium level regulators, antiepileptic drugs, immunosuppressives, recombinant growth hormone and parasympatholytics. The aim of our report is to comment on potential impact of the drugs mentioned on orthodontic treatment. Antibiotics Antibiotics are either product of microorganisms' metabolism or are produced synthetically. Their purpose is to eliminate originator of a disease or inhibit its growth. They are indicated whenever the balance between microorganism and macroorganism is challenged. Doxycycline, belonging to tetracycline-type antibiotics, is the only medication which is related to orthodontic movement. The side mechanism of its effect inhibits activities of metalloproteinases (collagenase and gelatinase) and impedes collagenolysis. Thus the number of osteoclasts is reduced, root and alveolar bone resorption is slowed down, and orthodontic tooth movement is slower [1, 2, 3]. Prostaglandines synthesis inhibitors This group of pharmaceuticals includes non-steroid antiphlogistics and analgesics-antipyretics. Their purpose is to inhibit creation of prostanoids (prostaglandines, prostacyclines, and thromboxanes) which serve in a human body as mediators of inflammation. Prostaglandines originate with the help of cyclooxygenase (COX) 1 or 2, or from arachidonic acid, and they affect e.g. blood pressure, platelet aggregation, blood vessel tonus, urinary bladder tonus, and bone resorption. Prostaglandines synthesis inhibitors are subclassified into: ANALGESICS-ANTIPYRETICS An example is paracetamol. Paracetamol has virtually no anti-inflammatory effects, and it accelerates transformation of prostaglandines into less effective forms [4]. It has no impact on orthodontic tooth movement [5]. Therefore, paracetamol may become the drug of choice in case of painful orthodontic treatment [5,6]. NON-STEROID ANTIPHLOGISTICS ± COX 1 preferential: The most frequently used is acetylsalicylic acid. Apart from inhibition of thrombocytes aggregation it reduces the number of osteoclasts and slowes down bone resorption. Thus orthodontic tooth movement is slower. The effects were proved in the study with guinea pigs - dose of 100mh/kg 2x daily [5]. However, it is recommended to reduce the therapy with these pharmaceuticals during orthodontic treatment [7]. ± COX non-selective: An example is ibuprofen. Ibuprofen inhibits cyclooxygenase 1 and 2, and thus redu osteoklastuê ikostnõâ resorpci. PrÏijeho uzïõâvaâ nõâ tedy dochaâ zõâ ke zpomalenõâ ortodontickeâ ho pohybu zubuê [5,8]. ± COX 2preferencÏnõÂ:Za stupcem skupiny je meloxikam. U neï j nebyl prokaâzaânzïaâ dnyâ vliv na pocï et osteoklastuê anina ortodontickyâ pohyb zubuê [9]. ± COX 2selektivnõÂ: Za stupciteâ to skupiny jsou leâ cï i va zvanaâ koxiby. Byly vyvinuty pro vysoce selektivnõâ uâcïinek pouze na cyklooxygenaâzu 2 z duê vodu redukce nezïaâ doucõâch uâ cï inkuê zejmeâ na na traâ vicõâ uâ strojõâ. I prïijejich uzïõâvaânõâ vsï ak dochaâ zõâ ke zpomalenõâ ortodontickeâ ho pohybu zubuê [10]. Regula tory Ca Va pnõâk je nezbytnou soucï aâ stõâ v mnoha fyziologickyâ ch pochodech homeostaâ zy lidskeâ ho teï la. Meziregula tory jeho metabolismu patrïõâ neï ktereâ hormony, vitamõâny nebo syntetickaâ leâcï iva zvanaâ bisfosfonaâ ty. ± parathormon: vznikaâ v prïõâsï tõâtnyâch zïlaâzaâ ch a jeho sekrecistimuluje receptor reagujõâcõâ na pokles koncentrace vaâ pnõâku v krvi. Jeho uâcï inek tkvõâ ve zvyâsï enõâ koncentrace vaâ pnõâkovyâ ch a snõâzï enõâ koncentrace fosfaâ tovyâ ch iontuê v krvi. Chronicke kontinuaâ lnõâ podaâ vaâ nõâ parathormonu vyvolaâvaâ resorpcikostiv duê sledku diferenciace a aktivace osteoklastuê a tõâm dochaâzõâ ke zvyâsï eneâ mu ortodontickeâ mu pohybu zubuê, chronickeâ intermitentnõâ podaâ vaâ nõâ stimuluje osteoblasty a vede ke zvyâsï enõâ kostnõâ hmoty, avsï ak vliv na ortodontickyâ pohyb zubuê nebyl zaznamenaâ n. Za lezï õâ tedy na efektu podaâvaânõâleâcï iva [11,12]. ± thyroidnõâ hormony: thyroxin a jeho aktivnõâ forma trijodthyronin hrajõâ vyâ znamnou roliv psychickeâ m a fyzickeâ m vyâ vojicï loveï ka. OvlivnÏ ujõâ metabolismus a aktivitu buneï k, pomaâ hajõâ absorpcivaâ pnõâku v tenkeâ m strïeveï a podõâlõâ se tak na kostnõâ remodelaci. Za rovenï podporujõâ produkci interleukinuê, ktereâ jsou duê lezïiteâ pro stimulaci diferenciace osteoklastuê. PrÏijejich uzïõâvaâ nõâ (studie na krysaâch v daâ vce 5, 10 a 20 mg/kg/ denneï),cï inadmeï rneâ produkcidochaâ zõâ ke zvyâsï eneâ rychlostiortodontickeâ ho pohybu zubuê v zaâ vislosti na podaneâ daâ vce [13,14]. ± kalcitonin: je hormon produkovanyâ parafolikulaârnõâmibunï kamisï tõâtneâ zïlaâ zy. Je vyplavovaâ n prïizvyâsï eneâ hladineï vaâ pnõâku v krvi. Jeho uâ kolem je inhibice cï innosti osteoklastuê a stimulace osteoblastuê cozï maâ v ortodoncii za naâ sledek snõâzïenou rychlost pohybu zubuê [15]. ± estrogeny: jsou hormony ovlivnï ujõâcõâ mimo jineâ kostnõâ metabolismus u zï en. SnizÏ ujõâ kostnõâ resorpci tõâm, zï e braâ nõâ produkcicytokinuê, ktereâ jsou duê lezï i teâ pro diferenciaci osteoklastuê, a tõâm snizï ujõâ irychlost ortodontickeâ ho pohybu zubuê [16]. ± vitamin D3: podporuje vstrïebaâ vaâ nõâ vaâ pnõâku ze strïeva a jeho uklaâ daâ nõâ do kostõâ. Jeho tvorbu stimuluje parathormon. Bylo prokaâ zaâ no, zï e u krys prïilokaâ lnõâm ces the number of osteoclasts as well as bone resorption. Therefore, it results in slower orthodontic tooth movement [5,8]. ± COX 2preferential: An example is meloxicam. No impact on the number of osteoclasts or orthodontic movement has been proved [9]. ± COX 2selective: The group is represented by the so called coxibs. They have a highly selective effect only on cyclooxygenase 2, and side effects (especially on the gastrointestinal system) are negligible. However, their use leads to slower orthodontic tooth movement [10]. Ca regulators Calcium is an essential component in many physiological processes of homeostasis in a human body. Its regulators include some hormones, vitamins, and synthetic pharmaceuticals known as bisphosphonates. ± parathormone: made by parathyroid glands, the secretion is stimulated by the receptor that reacts to decreased calcium concentration in blood. It leads to the increase of calcium ionts concentration and to the decrease of phosphate ionts concentration in blood. Chronic continuous administration of parathormone results in bone resorption due to differentiation and activation of osteoclasts, and thus in increased orthodontic tooth movement. Chronic intermittent administration stimulates osteoblasts, and thus results in increased bone mass. However, it doesn't seem to affect orthodontic tooth movement. The method of application and dosage are important [11, 12]. ± thyroid hormones: thyroxine and its active form triiodothyronine play an important role in psychological and physiological development of a human. They affect cellular metabolism and activity, aid in calcium absorption in small intestine, and thus take part in bone remodelling. They also support production of interleukins that stimulate differentiation of osteoclasts. During the administration (trials with rats used the dose of 5, 10 and 20 mg/kg/a day) or in case of excessive production, orthodontic tooth movement accelerates related to the dose applied [13, 14]. ± calcitonine: produced by parafollicular cells of thyroid gland. It is secreted in case there is an increased level of calcium in blood. It inhibits osteoclasts activity and stimulates osteoblasts which results in slower orthodontic movement of teeth [15]. ± estrogenes: hormones influencing, apart from other things, bone metabolism in women. They decrease bone resorption by inhibiting production of cytokines that are important for differentiation of osteoclasts, and thus they slow down orthodontic movement of teeth [16]. ± vitamin D3: supports absorption of calcium from intestine and its accumulation in bones. Production of vitamin D3 is stimulated by parathormone. It was proved that ORTODONCIE podaâ nõâ snizï uje rychlost ortodontickeâ ho pohybu zubuê vzaâ vislosti na podaneâ daâ vce [20,21]. ± Ca jako doplneï k stravy: dennõâ prïõâjem dospeïleâho cï loveïka by meï l tvorïit mg. Jako doplneïk stravy je vaâ pnõâk doporucï ovaâ n zejmeânazïenaâ m po menopauze a muzïuê m nad 65 let jako prevence osteoporoâ zy. Bylo prokaâ zaâ no, zï e jeho nedostatecï nyâ prïõâjem vede ke zvyâsï enõâ rychlostiortodontickeâ ho pohybu zubuê [22]. ± bisfosfonaâ ty: jsou skupinou leâcï iv indikovanyâch prïi poruchaâ ch kostnõâho metabolismu s nadmeï rnou kostnõâ resorpcõâ. PrÏednostneÏ jsou vychytaâvaâ ny v kostech s vysï sï õâ metabolickou aktivitou. Prokazujõ silnou vazbu na vaâ pnõâk a hydroxyapatit a jsou fagocytovaâ ny osteoklasty, kde poteâ spousï teï jõâ jejich apoptoâ zu. Terapie bisfosfonaâ ty muê zï e byâ t komplikovaâ na vznikem osteonekroâ zy cï elisti, kde podstatou komplikace je porucha vaskularizace kostnõâ tkaâ neï. Bisfosfona ty snizï ujõâ rychlost pohybu zubuê a zaâ rovenï istupenï resorpce korïenuê [17, 18, 19]. Antiepileptika Epilepticky zaâ chvat je definovaâ n jako silnaâ synchronizovanaâ aktivita urcïiteâ skupiny neuronuê. CõÂlem antiepileptik je zvyâsïit krïecï ovyâ praâ h. MezinejcÏ asteï jise vyskytujõâcõâ nezïaâ doucõâ uâ cï inky ve stomatologickeâ oblasti patrïõâ vyâ raznaâ hyperplazie gingivy podmõâneï naâ plakem prïipodaâ vaâ nõâ fenytoinu, prïõâpadneï vzaâ cneï ifenobarbitalu. ( Pozn.: K hyperplazii gingivy kromeï antiepileptik dochaâ zõâ takeâ u cykosporinu - viz nõâzï e a blokaâ toruê Ca kanaâ lu [23]). U kolem ortodontisty by meïlobyât usnadneï nõâ pacientovy hygieny a jako obecnaâ doporucï enõâ jsou braâ na tato kriteria: neextrakcï nõâ terapie, uzïõâvaânõâ ortodontickyâ ch zaâ mkuê s nõâzkyâ m profilem, pouzï õâvaâ nõâ kanyl mõâsto krouzïkuê, ukoncï ovaâ nõâ Essix dlah nad uâ rovnõâ gingivy a neuzïõâvaâ nõâ fixnõâch retaineruê [24,25]. Imunosupresiva Specificka imunitnõâ obrana je spojena s proliferacõâ lymfocytuê. K jejõâmu potlacï enõâ se uzï õâvajõâ inhibitory s ruêznou selektivitou. ± Antagoniste interleukinu 1 a 6 a tumor nekrotizujõâcõâho faktoru (TNF): snizï ujõâ zaâ neï tlivou odpoveï d' - tõâm takeâ snizï ujõâ rychlost pohybu zubuê a kostnõâ remodelaci [26]. ± Cyklosporin A: potlacï uje prïenos signaâluê na lymfocyty, zvysï uje osteoklastickou aktivitu a zpuê sobuje lokaâ lnõâ osteopenii alveolaâ rnõâho vyâbeï zï ku. Zrychluje takeâ ortodontickyâ pohyb zubuê. Jako jeho vedlejsïõâ uâcï inek se projevuje hyperplazie gingivy [27]. ± Kortikosteroidy: inhibujõâ tvorbu cytokinuê, prostaglandinuê a TNF. Takte zï dochaâ zõâ k potlacï enõâ zaâneï tliveâ odpoveï di[28], avsï ak zvysï ujõâ rychlost ortodontickeâho pohybu zubuê, zvysï ujõâ rychlost resorpce korïenuê. NavõÂc in rats, when administered topically, orthodontic tooth movement slows down depending on the dose [20, 21]. ± Ca as a nutritional supplement: recommended daily allowance in adults should be between 1000 and 1300 mg. Calcium in the form of nutritional supplement is recommended for women after menopause and for men over the age of 65 as osteoporosis prevention. Insufficient allowance of Ca was proved to result in accelerated orthodontic tooth movement [22]. ± bisphosphonates: the group of pharmaceuticals indicated in bone metabolism disorder and in excessive bone resorption. They are primarily found in bones with higher metabolic activity. They establish a very strong bond with calcium and hydroxyapatite, and they are phagocytized by osteoclasts, in which they later cause apoptosis. Therapy using bisphosphonates may be complicated by osteonecrosis of a jaw which is the result of disorder in vascularization of bone tissue. Bisphosphonates slow down teeth movement as well as root resorption [17, 18, 19]. Anti-epileptic drugs Epilepsy seizure is a strong synchronous activity of a particular group of neurons. Medication aims to increase seizure threshold. The most frequent side effects in dental medicine include excessive hyperplasia of gingiva related to plaque due to administration of phenytonine, rarely also of phenobarbital. ( Note: Hyperplasia of gingiva is also connected to cyclosporine (see below) and inhibitor of Ca channel [23]). An orthodontist should help patients to facilitate oral hygiene; the recommendations include: non-extraction therapy, use of orthodontic brackets with a low profile, use of tubes instead of bands, finishing of Essix splints above the level of gingiva, no use of fixed retainers [24, 25]. Immunosuppressives Specific immuno-protection is related to lymphocytes proliferation. To suppress the proliferation, inhibitors with different selectivity are used. ± Antagonists of interleukin 1 and 6 and tumor necrosis factor (TNF): they suppress inflammatory reaction, and thus they also slow down movement of teeth and bone remodeling [26]. ± Cyclosporine A: suppresses transfer of signals to lymphocytes, increases ac
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