Background: Two of the excipients in intravenous formulations of amiodarone, polysorbate 80 and benzyl alcohol, have been shown to cause hypotension. A newer formulation of amiodarone, which contains cyclodextrin, is devoid of these excipients. Objective: To evaluate the change in mean arterial pressure when utilizing 2 intravenous amiodarone formulations. Methods: This was a retrospective cohort analysis conducted at an academic medical center. Patients received intravenous amiodarone containing either polysorbate 80/benzyl alcohol (control) or cyclodextrin (cyclodextrin). Patients received these formulations based on a standard institutional protocol of 1 mg/min for 6 hours, followed by 0.5 mg/min for at least 18 hours or until discontinued by the provider. All data were collected from the medical record and included changes in blood pressures, time to lowest systolic blood pressure, concurrent antihypertensive use, and number of patients requiring treatment for hypotension. Results: A total of 160 patients (120 control, 40 cyclodextrin) were included. There was a statistically significant difference in mean arterial pressure between the groups receiving the control formulation of amiodarone compared with the cyclodextrin formulation across the 24-hour maintenance phase infusion (P < 0.001). There was a significant difference between formulations with regard to the change in mean arterial pressure during the 0- to 6-hour and 12- to 18-hour time blocks. There was a statistically significant difference in the number of patients receiving fluid boluses for treatment of hypotension (P = 0.001). Conclusions: The excipients in the formulation of intravenous amiodarone may have a significant role in the hypotensive effects seen throughout the duration the maintenance phase infusion.

<p>Razvoj savremenih sistema za ciljanu aplikaciju farmakolo&scaron;ki aktivne supstance zasniva se na postojanju interakcija između funkcionalnih grupa makromolekula i povr&scaron;inski aktivne materije &scaron;to omogućava kontrolisano oslobađanje, smanjenu toksičnost i bolji režim doziranja leka. Prisustvo tenzida, kako se jos povr&scaron;inski aktivne materije nazivaju, u niskim koncentracijima može značajno da izmeni konformaciju makromolekula i viskozitet sistema, i samim tim pro&scaron;iri mogućnosti primene modifikovanjem svojstava. Stoga je poznavanje fizičko-hemijskih osobina vodenih rastvora makromolekul-povr&scaron;inski aktivna materija neophodno radi dobijanja adekvatnog finalnog proizvoda unapređenih osobina uz primenu optimalnih koncentracija pomoćnih supstanci. U radu su prikazani rezultati ispitivanja uticaja natrijum lauril sulfata, predstavnika anjonskih tenzida, odnosno polioksietilen (20) sorbitan monooleata, kao &scaron;iroko kori&scaron;ćenog nejonskog tenzida na fizičko-hemijske osobine vodenih rastvora makromolekula karbomera 940 i ksantan gume. U cilju potpunog razumevanja ovih sistema, čiste komponente su prvo analizirane infracrvenom spektroskopijom primenom Fourierove tranformacije. Pona&scaron;anje karbomera 940 odnosno ksantan gume u prisustvu tenzida, ispitano je kombinacijom različitih tehnika (viskozimetrije, konduktometrije, tenziometrije, spektroskopije, spektrofluorimetrije, skenirajuće elektronske mikroskopije) koje pružaju uporedive rezultate. Određene vrednosti interakcionih parametara, potvrdjuju hipotezu o postojanju međudejstva između karbomera 940/ksantan gume i ispitivanih tenzida i ukazuju da povećanje koncentracije makromolekula u rastvoru uslovljava &scaron;irenje opsega interakcije. Tenzidom indukovane promene konformacije ksantan gume odnosno karbomera 940 potvrđene su i na mikroskopskom nivou. Takođe, rezultati uticaja ispitivanih tenzida na osobine vodenih rastvora sme&scaron;a karbomera 940 i ksantan gume dobijeni su istim tehnikama. Međudejstvom dva različita polimera bez dodatne sinteze na jeftin i brz način mogu se postići željene karakteristike sistema. Na osnovu eksperimentalnih rezultata definisani su matematički modeli primenom metodologije odzivnih povr&scaron;ina i vi&scaron;estruke linearne regresije, čija je validnost statistički potvrđena te se mogu primeniti u optimizaciji i predviđanju fizičko-hemijskih osobina vodenih rastvora analiziranih binarnih sistema.</p> / <p>The possible interactions between polymers and surfactants are of great interest in the development of drug delivery systems, where they improve therapeutic efficiency by the controlled release and reduced toxicity. The addition of even a small amount of surfactant could change the physico-chemical properties of polymer dispersions in terms of viscosity and stability of the system and, consequently, enlarge possibilities for their application. Therefore, understanding the physico-chemical properties of polymer-surfactant aqueous solutions are necessary in order to optimize the formulation of these compounds and consequently to get product with acceptable properties and desired effect. In this thesis the physico-chemical changes of carbomer 940 and xanthan gum influenced by different surfactants were investigated. Widely used anionic surfactant sodium dodecyl sulfate, and nonionic polyoxyethylene (20) sorbitan monooleate were used. In order to completely understand the mechanism of interaction the pure polymers and surfactants were tested by Fourier transform infrared spectrometer. The behaviour of carbomer 940 as well as xanthan gum in the presence of examined surfactants were analysed by the combination of different techniques such as viscometry, conductometry, tensiometry, spectrophotometry, fluorimetry and scanning electron microscopy. The obtained results confirmed the existence of interactions between carbomer 940 / xanthan gum and tested surfactants. Furthermore, the interaction parameters were determined and the polymer saturation points for both surfactants increased with the increase in carbomer 940 and xanthan gum content, respectively. Additionally, the surfactant induced microstructural changes of carbomer 940 as well as xanthan gum were confirmed. Moreover, the physico-chemical properties of the mixture of carbomer 940 and xanthan gum influenced by the addition of anionic and nonionic surfactant were examined by the same techniques. Without additional synthesis the desired characteristics of the system could be achieved by optimizing the interaction between two different polymers. The obtained results were analysed by response surface methodology and multiple linear regression analysis. The defined mathematical models could be used to optimize and predict physico-chemical properties of aqueous solutions of the tested binary systems.</p>

<p>Uloga micela u razvoju farmaceutskih oblika zasniva se na njihovom potencijalu da kao transportni sistemi povećaju bioraspoloživost lekovite supstance i unaprede njen farmakokinetski profil. Micele mogu da modifikuju propustljivost biolo&scaron;kuh membrana, omoguće kontrolisano oslobađanje lekovite supstance iz farmaceutskog oblika, stabilizuju lekovitu supstancu, itd. Kombinovanje različitih surfaktanata kao gradivih jedinica omogućava konstruisanje micela sa poželjnim fizičko-hemijskim karakteristikama. Takođe, me&scaron;ovite micele između čijih gradivnih jedinica postoje sinergističke interakcije se formiraju na nižim koncentracijama surfaktanata u poređenju sa monokomponentnim micelama. U doktorskoj disertaciji je ispitana termodinamička stabilnost binarnih me&scaron;ovitih micela Brij S10 i Brij S20 surfaktanata sa polisorbatom 20, polisorbatom 60 i polisorbatom 80 kao kosurfaktantima. Analiziran je uticaj građe odabranih nejonskih surfaktanata na fizičko-hemijske parametre i stabilnost njihovih me&scaron;ovitih micela. Vrednosti kritične micelarne koncentracije su dobijene spektrofluorimetrijskim merenjima. Da bi se analizirao uticaj temperature na termodinamičku stabilnost micela, merenja su vr&scaron;ena na sledećim temperaturama: 273.15 K, 283.15 K, 293.15 K, 303.15 K i 313.15 K. Rezultati su tumačeni sa aspekta teorije regularnih rastvora (regular solution theory &ndash; RST), uz primenu Porterove jednačine. Na osnovu rezultata istraživanja, predloženi su modeli monokomponentnih i binarnih me&scaron;ovitih micela. Utvrđeno je da u svim analiziranim binarnim me&scaron;ovitim sistemima postoji dodatna entropija. Može se doneti zaključak da pretpostavka RST o isključivo entalpijskoj prirodi dodatne Gibsove energije nije primenljiva na ispitivane binarne sisteme. Utvrđeno je da postojanje razlike u dužini hidrofobnih segmenata monomera dodatno stabilizuje me&scaron;ovitu micelu. Sa porastom temperature, ovaj stabilizacioni efekat entropijskog porekla postaje izraženiji. Prisustvo dvostruke veze u ugljovodoničnom lancu polisorbata 80 doprinosi povećanoj rigidnosti njegovih molekula. Rezultat je smanjena termodinamička stabilnost me&scaron;ovitih micela koje sadrže polisorbat 80 u poređenju sa me&scaron;ovitim micelama koje sadrže njegov zasićeni homolog, polisorbat 60. Utvrđeno je da razlika u dužini polarnih segmenata monomera koji grade me&scaron;ovitu micelu utiče na stepen hidratacije micele, a time i na njenu stabilnost.</p> / <p>The role of the micelles in pharmaceutical formulation lies in their ability to, when used as drug delivery systems, increase the bioavailability of the drug and enhance its pharmacokinetic profile. Micelles may modify the permeability of biomembranes, enable controlled release from drug delivery systems, stabilize the drug, etc. By combining different surfactants as building units it is possible to engineer micelles with favorable physicochemical characteristics. Also, the mixed micelles between whose building units synergistic interactions exist are formed on lower concentrations of surfactants in comparison to single-component micelles. In the doctoral dissertation the thermodynamic stability of binary mixed micelles built of Brij S10 and Brij S20 with polysorbate 20, polysorbate 60 and polysorbate 80 as co-surfactants is examined. The influence of the structure of selected nonionic surfactants on physicochemical parameters and the stability of their mixed micelles is analyzed. Critical micelle concentration values were obtained by spectrofluorimetric measurements. In order to analyze the influence of the temperature on the micelles&rsquo; thermodynamic stability, measurements were conducted on following temperatures: 273.15 K, 283.15 K, 293.15 K, 303.15 K and 313.15 K. Obtained results were studied using regular solution theory (RST) and Porter&rsquo;s equation. Based on the research results, models of both single-component and binary mixed micelles are introduced. It is deduced that in all analyzed binary mixed systems the excess entropy exists. A conclusion can be made that the assumption of RST regarding solely enthalpic nature of the excess Gibbs energy is not applicable to investigated binary systems. The difference in the length of the hydrophobic segments of monomers additionally stabilizes the mixed micelle. With the increase in the temperature, this stabilizing effect of the entropic nature is more noticeable. The existence of the double bond in polysorbate 80 hydrocarbon chain contributes to the increased rigidity of its molecules. As a result, the thermodynamic stability of the mixed micelles containing polysorbate 80 is lesser than the stability of the mixed micelles containing its saturated homologue, polysorbate 60. It is determined that the difference in length of polar segments of mixed micelle monomers affects the micelle hydration and therefore, its stability.</p>

<p>Surfaktanti imaju značajnu primenu u farmaciji i medicini. Ove supstance se primenjuju u farmakoterapiji, koriste se za solubilizaciju hidrofobnih lekova, a pojedina ispitivanja pokazuju da mogu unaprediti bioraspoloživost određenih aktivnih supstanci. U poslednje vreme se sve vi&scaron;e pažnje posvećuje ispitivanju sme&scaron;a surfaktanata, po&scaron;to je utvrđeno da sistemi dva ili vi&scaron;e surfaktanta često pokazuju poželjnija svojstva od pojedinačnih surfaktanata za aplikaciju u farmaciji i medicini. U ovoj disertaciji su ispitivani binarni sistemi osam anjona žučnih kiselina i dva nejonska surfaktanta (polisorbat 40 i polisorbat 80). Ciljevi su određivanje vrednosti kritičnih micelarnih koncentracija ispitivanih sme&scaron;a surfaktanta, utvrđivanje međudejstva između različitih surfaktanta u njihovim me&scaron;ovitim micelama, kao i ispitivanje uticaja stukture ispitivanih surfaktanata na fizičko-hemijske karakteristike me&scaron;ovitih micela. Rezultati pokazuju da ispitivane sme&scaron;e imaju znatno niže vrednosti kritičnih micelarnih koncentracija od anjona žučnih kiselina. Sme&scaron;e anjona žučnih kiselina i polisorbata 40 imaju manje vrednosti eksperimentalnih kritičnih micelarnih koncentracija, od izračunatih, idealnih, vrednosti, &scaron;to ukazuje na postojanje sinergističkih interakcija u me&scaron;ovitim micelama. Sme&scaron;e anjona žučnih kiselina i polisorbata 80 imaju uglavnom veće vrednosti kritičnih micelarnih koncentracija od idealnih vrednosti, &scaron;to može biti posledica postojanja antagonističkih interakcija između gradivnih jedinica me&scaron;ovitih micela. Vrednosti interakcija, koje dovode do neidealnog pona&scaron;anja sistema surfaktanata, su određene računanjem vrednosti interakcionog parametra, &beta;_1,2, prema regular solution theory. Sistemi anjona žučnih kiselina i polisorbata 40 imaju negativne vrednosti interakcionog parametra, dok sistemi anjona žučnih kiselina i polisorbata 80 imaju uglavnom pozitivne vrednosti interakcionog parametra. Poređenjem fizičko-hemijskih parametara me&scaron;ovitih micela je utvrđeno da postojanje privlačnih međudejstava između hidrofilnih delova različitih surfaktanata najverovatnije potiče od vodoničnih veza koje se formiraju između hidrofilnih grupa anjona žučnih kiselina i polioksietilenskih delova. Pozitivne vrednosti &beta;_1,2 parametra su najverovatnije posledica sterno krute cis dvostruke veze oleinske kiseline u molekulu polisorbata 80, usled čega se lipofilni deo ovog nejonskog surfaktanta teže pakuje u jezgru me&scaron;ovitih micela. Pretpostavlja se da zbog toga dolazi do formiranja dimera anjona žučnih kiselina u me&scaron;ovitim micelama u kojima se javljaju odbojne interakcije između negativno naelektrisanih karboksilatnih grupa.</p> / <p>Surfactants have important application in pharmacy and medicine. These substances are applied in pharmacotherapy, they are used for hydrophobic drug solubilisation, and certain investigations indicate they can improve bioavailability of certain active substances. Lately, investigations of surfactant mixtures have gained a lot of attention, since it was found that systems of two or more surfactants often show more desirable properties than the individual surfactants, for application in pharmacy and medicine. In this dissertation, binary systems of eight bile acid anions and two nonionic surfactants (polysorbate 40 and polysorbate 80) were investigated. The aims were to determine values of critical micelle concentrations of investigated surfactant mixtures, interactions between different surfactants in their mixed micelles, and to investigate the influence of the structure of investigated surfactants on physico-chemical characteristics of mixed micelles. The results indicate that investigated mixtures have significantly lower values of critical micelle concentrations than bile acid anions. Mixtures of bile acid anions and polysorbate 40 have&nbsp; lower values of experimentally obtained critical micelle concentrations than the calculated, ideal, values, indicating the existence of synergistic interactions in mixed micelles. Mixtures of bile acid anions and polysorbate 80 have mainly higher values of critical micelle concentrations than the ideal values, what could be due to the existence of antagonistic interactions between building units of mixed micelles. The values of the interactions, attributing to the nonideal behaviour of the surfactant systems were obtained by calculating the values of the interaction parameter, &beta;1,2 , according to the regular solution theory. Systems of bile acid anions and polysorbate 40 have negative values of the interaction parameter, while systems of bile acid anions and polysorbate 80 have mainly positive values of interaction parameter. By comparing the physico-chemical parameters of mixed micelles, it was determined that existence of attractive interactions between hydrophilic parts of different surfactants most probably originates from the hydrogen bonds, which are formed between hydrophilic groups of bile acid anions and polyoxyethylene parts. Positive values of &beta;1,2 parameter are most probably due to sterically rigid cis double bond of oleic acid in polysorbate 80 molecule, causing the lipophilic tail of this nonionic surfactant to pack less easily in the core of mixed micelles. It is hypothesised that this influences formation of dimers of bile acid anions in mixed micelles, where repulsive interactions emerge between negatively charged carboxylate groups.</p>

<p>Binarne me&scaron;ovite micele su značajne u farmaceutsko-farmakolo&scaron;kim primenama, u kojima lek kao povr&scaron;inska aktivna supstanca može da bude gradivna jedinica binarne micelle (promena bioraspoloživosti, mehanizam resorpcije itd.). Takođe su važne i me&scaron;ovite micele kod kojih su gradivne jedinice biosurfaktanti (biokompatibilni solubilizatori lekova). U kozmetičkoj, prehrambenoj i industriji detergenata me&scaron;ovite micele su uveliko zastupljene. Važno je nalaženje binarnih sistema surfaktanata koji u me&scaron;ovitim micelama poseduju sinergističko međudelovanje (negativna vrednost interakcionog parametra). Takva binarna sme&scaron;a surfaktanata ima nižu vrednost kritične micelarne koncentracije od hidrofobnije komponente sme&scaron;e. U prvom delu rada je ispitivan uticaj dužine hidrofobnog segmenta homolognih Tween-ova iz me&scaron;ovitih micela sa Triton-om X100 na interakcioni parametra ( i, j &beta; ) i dodatnu Gibbs-ovu energiju (GE ), takođe ispitivao se i uticaj temperature na stabilnost proučavanih me&scaron;ovitih micela (273,15-328,115 K). Kritične micelarne koncentracije čistih surfaktanata i njihovih binarnih sme&scaron;a su određeni spektrofluorometrijski uz primenu pirena kao probnog molekula. Nađeno je da na svakoj ispitivanoj temperaturi povećanje dužine zasićenog alifatičnog niza polisorbata povećava stabilnost me&scaron;ovite micele ( , 0 i j &beta; &lt; i GE &lt; 0 ) u odnosu na idealnu me&scaron;ovitu micelu. Prisustvo C9 dvostruke veze u ostatku oleinske kiseline Tween-a 80 umanjuje sinergistički efekat ovog polisorbata u odnosu na Tween 60, koji ima hidrofobni segment sa istim brojem C atoma, ali bez olefinske veze. Dodatna slobodna entalpija ispod temperature 298.15 K određena je entropijskim doprinosem, a iznad 298.15 K entalpijskim doprinosom. U drugom delu rada ispitivane su binarne sme&scaron;e surfaktanata Tween 85/Triton X100 i Tween 85/Triton X165 u vodenom rastvoru u intervalu temperature od 273.15 K do 323.15 K. Pri temperaturama od 273.15 K i 283.15 K između različitih gradivnih jedinica binarnih me&scaron;ovitih micela postoje sinergističke interakcije na čiju veličinu ne utiče razlika u dužini polioksietlienskih nizova Triton-a X100 i Triton-a X165. Na većim vrednostima temperature duži polioksietilenski niz Triton-a X165 pokazuje stabilizirajuči efekat u me&scaron;ovitoj miceli sa Tween-om 85 u odnosu na me&scaron;ovite micele Tween 85/Triton X100. Kod ispitivanih binarnim me&scaron;ovitim micela ne može se prihvatiti aproksimacija regularnih sme&scaron;a o nula vrednosti dodatne entropije formiranja binarne me&scaron;ovite micele.</p> / <p>Binary micelles are important in pharmaceutical-pharmacological applications, in which drug as surface active substance can be building unit of binary micelle (influencing bioavailability change, change of resorption mechanism etc.). Mixed micelles in which building units are biosurfactants (biocompatible drug solubilizers) are also important. In cosmetics, food and detergent industry mixed micelles are widely present. It is important to find binary surfactant systems having synergistic interactions (negative value of interaction parameter). That binary surfactant mixture has lower critical micelle concentration value than more hydrophobic component of the mixture. In the first parth of this work, influence of hydrophobic segment length of homologues Tweens in mixed micelles with Triton X-100 on the interaction parameter value ( i, j &beta; ) and an excess Gibbs energy (GE ) was investigated. Also, influence of temperature on the stability of investigated mixed micelles has been investigated (273.15-328.15 K). Critical micelle concentration values of pure surfactants and their binary mixtures were determined spectrofluorimetrically using pyrene as a probe molecule. It was found for every investigated temperature that increase in length of saturated aliphatic side chain of a polisorbate increases the stability of investigated mixed micelles (&beta; &lt; and GE &lt; 0 ) compared to ideal mixed micelles. Presence of the C9 double bond in oleic acid residue of Tween 80 reduces synergistic effect of this polysorbate compared to Tween 60 which contains hydrophobic segment with the same number of C atoms but without olefin bond. Excess free enthalpy below the 298.15 K is determined with entropic contribution, but above 298.15 K with enthalpic contribution. In the second parth of this work, binary surfactant mixtures of Tween 85/Triton X100 and Tween 85/Triton X165 have been investigated in water solution in the temperature range from 273.15 K to 323.15 K. At the temperatures of 273.15 K and 283.15 K between different building units of binary mixed micelles synergistic interactions exist, which size is not affected by difference in length of the polyoxyethylene chains. At higher temperatures, longer polyoxyethylene chain of Triton X165 shows more stabilizing effect in mixed micelle with Tween 85 than in mixed micelles of Tween 85/Triton X100. For investigated binary mixed micelles, regular solution theory approximation about zero value of excess entropy of binary mixed micelle formation cannot be accepted.</p>

<p>Da bi se dobio sistem surfaktanata željenih osobina moguće je hemijski modifikovati već postojeće molekule povr&scaron;inski aktivnih supstanci, a druga mogućnost je konstrukcija binarnih sme&scaron;a surfaktanata. U farmaceutskoj i prehrambenoj industriji uveliko se primenjuju binarne sme&scaron;e povr&scaron;inski aktivnih molekula. Ukoliko je binarna me&scaron;ovita micela termodinamički stabilnija od hipotetičke idealne binarne me&scaron;ovite micele, onda je kritična micelarna koncentracija binarne sme&scaron;e surfaktanata niža čak i od hidrofobnije gradivne jedinice me&scaron;ovite micele, &scaron;to znači da je za isti efekat povr&scaron;inske aktivnosti potrebna manja količina binarne sme&scaron;e nego čistog surfaktanta. Različite gradivne jedinice binarne micele u micelarnoj pseudofazi mogu formirati specifične regije koje mogu vezivati lekove određenih strukturnih karakteristika. Pogodno je da jedna gradivna jedinica bude krute konformacije, npr. soli žučnih kiselina, dok je druga gradivna jedinica konformaciono pokretljiva (ugljovodonični nizovi iznad C10). Na taj način se povećava zapremina hidrofobne micelarne faze u odnosu na zapreminu hidrofobne micelarne faze monokomponentne micelle konformaciono krutog surfaktanta, &scaron;to povećava solubilizacioni kapacitet me&scaron;ovite micele u odnosu na monokomponentnu micelu krutog surfaktanta. Povećanjem dužine ugljovodoničnog niza konformaciono pokretnog surfaktanta povećava se stepen unutra&scaron;nje pokretljivosti u hidrofobnom domenu me&scaron;ovite micele, &scaron;to takođe povećava verovatnoću prihvatanja molekula gosta. Micelarni sistemi, kako monokomponentnih micela tako i binarnih me&scaron;ovitih micela dodatno se mogu termodinamički stabilizovati povećanjem jonske jačine rastvora. Za hidrataciju katjona tro&scaron;e se molekuli vode iz sistema, &scaron;to povećava efekat desolvatizacije hidrofobne povr&scaron;ine surfaktanata, pa se zbog toga pospe&scaron;uje samoasocijacija.</p> / <p>To obtain the surfactant system with the desired properties it is possible to chemically modify existing molecules of surface active agents. The other possibility is the construction of binary mixtures of surfactants. Binary mixtures of surface active molecules are widely used In the pharmaceutical and food industry. If the binary mixture micelle is more thermodynamically stable than the hypothetical ideal binary mixed micelle, then the critical micellar concentration (CMC) of the binary mixture of surfactants is even lower than the CMC of the more hydrophobic building block of the binary mixture. That means that for the same effect of surface activity less the amount of the binary mixture than the pure surfactants is required. The different building blocks of binary micelles in micelar pseudophase can form specific regions that can bind drugs of certain structural characteristics. It is suitable that one building block is of a rigid conformation, i.e. bile acid salts, while the second building block is of a flexible conformation (above C10 hydrocarbon arrays). In this way the volume of the hydrophobic micellar phase is increased in relation to the volume of the hydrophobic micellar phase of the monocomponent micelles of conformationally rigid surfactant, which increases the capacity of solubilisation of the mixed micelles, compared to the mono-component surfactant micelle of the rigid conformation. By increasing the length of the hydrocarbon array of the the conformational flexible surfactant, the degree of internal mobility in the hydrophobic domain of mixed micelles is also increased, which also increases the likelihood of acceptance of guest molecules. Micellar systems, of both monocomponent micelles and mixed micelles can be additionally thermodynamically stabilized by increasing the ionic strength of the solution. The hydration of cations uses the molecules of water from the system, which increases the effect of desolvatisation of the hydrophobic surface of the surfactants, and therefore promotes self-association.</p>