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Assessment of microvascular function by use of transdermal iontophoresis: methodological aspects
Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Assessment of the microcirculation is of major importance in understanding the physiology of the vasculature and in assessing te vascular effects of pathological conditions such as diabetes, hypertension and sepsis. Transdermal iontophoresis can be used to non‐invasively introduce vasoactive drugs into the skin. The response to these drugs of the local cutaneous microvasculature can be measured by laser Doppler flowmetry methods. Although these techniques have been used together for over two decades, there are still important methodological issues to be resolved. This work is aimed at optimizing transdermal iontophoresis as a tool for microvascular assessment by focusing on the main methdological issues: non‐specific vasodilatation, drug delivery protocols and analysis of blood flow data.

Non‐specific vasodilatation, an increase blood flow during iontophoresis of non‐vasoactive compounds, is an important problem as it interferes with the response to the administered drug. By investigating this effect in healthy volunteers, we found that the extent of the non‐specific response differs between the positive and negative electrode and that it is dependent on the voltage over the skin andon the ionic strength of the vehicle in which the drug is dissolved. We also found that the extent of the non‐specific response could be reduced by applying local anesthetics and by pre‐treatment with antihistamine drugs. These results suggest that non‐specific effects could be mediated by depolarization or hyperpolarisation of cells, triggering neural and histamine related mechanisms that finally lead to vasodilatation of the local microvasculature.

To prevent non‐specific effects from occurring during the experiments, our results show that the current strength and the total electric charge during iontophoresis should be limited to 0.02 mA and12 mC, respectively. Furthermore, drug solutions at physiological ionic strengths should be used. Under these conditions, adequate responses to the most commonly used drugs, acetylcholine (ACh) and sodium nitroprusside (SNP), are obtained while no significant non‐specific vasodilatation occurs.

The results of our investigations show that blood responses to ACh and SNP applied by a single iontophoretic pulse can well be escribed by conventional dose‐response models, which enables a more powerful analysis and comparison between drugs or possibly patient groups as compared with conventional aalysis methods. Finally, we have incorporated drug transport and physiological response to the local drug concentration during iontophoresis of vasoactve drugs into a single model. Validation of this model using measured responses to ACh and SNP shows that the commonly used assumption that the local drug concentration during iontophoresis is linearly proportional to the electric charge may not be valid.

Abstract [sv]

Mikrocirkulationen, som inbegriper kroppens minsta blodkärl, transporterar syre och näringsämnen till våra celler. Vissa sjukdomar, som diabetes, hjärt‐kärlsjukdom och akut blodförgiftning leder till förändringar hos mikrocirkulationen. Mekanismerna bakom dessa förändringar är delvis okända. Det finns därför ett stort behov av kliniska mättekniker som kan bedöma mikrocirkulationens funktion. Vid jontofores placeras en elektrod tillsammans med ett läkemedel på huden. När en svag elektrisk ström anbringas transporteras läkemedlet ner genom hudlagren. Effekterna av ett kärlaktivt läkemedel som appliceras på detta sätt kan sedan avläsas non‐invasivt med laser Doppler‐teknik. En stor fördel med jontoforesmetoden, förutom att den är non‐invasiv, är att läkemedelsdoserna som tillförs kroppen är mycket små och därmed ger de inte upphov till några systemiska bi‐effekter. I avhandlingen presenteras forskning, vilkas målsättning är att lösa några av de viktiga frågorna kring transdermal jontofores så att tekniken optimeras för att denskall kunna brukas som ett verktyg vid kliniska undersökningar av mikrocirkulationen.

Den första delen ägnas ett fenomen som kallas ospecifik vasodilatation. Det uppstår vid jontofores av substanser som är inte kärlaktiv, som vatten och koksaltlösning. Resultaten från dessa försök indikerar att den ospecifika vasodilatationen beror på framför allt spänningen över huden, vilken i sin tur är relaterad till jon‐koncentrationen hos läkemedelslösningen. Vidare registreras att mekanismen bakom den ospecifika vasodilatationen delvis är neuralt medierad genom att de till stor del år att förhindra med hjälp av lokal bedövning. Dessutom leder förbehandling med anti‐histamina läkemedel till minskade ospecifika reaktioner, vilket också indikerar att lokala inflammatoriska processer är inblandande.

Den andra delen av avhandlingen ägnas att optimera försöksprotokollen för jontofores. Till att börja med utvecklas ett protokoll som ger ett adekvat läkemedelssvar samtidigt som ospecifika effekter minimeras. Det visar sig är möjligt genom att begränsa strömstyrkan och den elektriska laddningen under jontoforesen och genom att använd läkemedelslösningar som har en fysiologisk jonstyrka. Resultaten visar också att blodflödesförändringen som registreras under jontofores av acetylkolin och natriumnitroprussid kan eskrivas med hjälp av konventionella dos‐responsmodeller, vilket möjliggör en mer exakt analys av det mikrocirkulatoriska svaret samt underlättar jämförelse mellan olika läkemedel elle patientgrupper.

Slutligen presenteras en mekanistisk model för det mikrocirkulatoriska svaret vid jontofores. Modellen beskriver läkemedlets transport från elektroden ner genom huden, clearance i huden vilken beror på diffusion och det lokala blodflödet, samt förändringen i blodflöde som sker på grund av läkemedlet. Modellen valideras genom försök på försökspersoner och resultaten visar att förändringarna i blodflödet åstadkommet av acetylklin och natriumnitroprussid med denna modell kan beskrivas på ett exakt sätt. Vidare visar resultaten att det sker en betydande clearance av läkemedel i huden under jontofores. Detta har väsentlig betydelse när man ska uppskatta den lokala jontoforesdosen.

Place, publisher, year, edition, pages
Institutionen för medicin och vård , 2007.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1002
Keyword [en]
Iontophoresis, Microcirculation, Laser-Doppler, Acetylcholine, Sodium nitroprusside, Pharmacodynamics, Pharmacokinetics skin
National Category
Physiology
Identifiers
URN: urn:nbn:se:liu:diva-8831ISBN: 978‐91‐85831‐87‐6 OAI: oai:DiVA.org:liu-8831DiVA: diva2:23539
Public defence
2007-06-04, Patologsalen, Campus US, Linköpings Universitet, Linköping, 12:00 (English)
Opponent
Supervisors
Note
The author changed surname from Droog to Tesselaar in January 2006.Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2009-08-22
List of papers
1. Nonspecific vasodilatation during transdermal iontophoresis: the effect of voltage over the skin
Open this publication in new window or tab >>Nonspecific vasodilatation during transdermal iontophoresis: the effect of voltage over the skin
2003 (English)In: Microvascular research, ISSN 0026-2862, Vol. 65, no 3, 172-178 p.Article in journal (Refereed) Published
Abstract [en]

We used laser Doppler perfusion imaging (LDPI) to study nonspecific vasodilatation during iontophoresis. In iontophoresis studies, nonspecific vasodilatation occurs as a result either of galvanic currents or of the applied voltage over the skin. We made dose–response measurements to study the effect of ionic strength of the vehicle on the nonspecific vasodilatation during iontophoresis of sodium chloride and deionized water, while we monitored the voltage over the skin. We found that anodal and cathodal ionotophoresis induced a voltage over the skin that was dependent on the ionic strength of the test solution. The nonspecific vasodilatation during anodal iontophoresis was less pronounced than during cathodal iontophoresis, and was independent of the voltage over the skin. The nonspecific vasodilatation in cathodal iontophoresis was related to the voltage over the skin, and was possibly mediated by depolarization of local sensory nerves. In experiments using cathodal iontophoresis, therefore, the ionic strengths of the vehicle and the drug are important when vasoactive drugs are examined, as the nonspecific vasodilatation needs to be controlled for. As the vasodilatation that we observed was heterogeneously distributed within the area of iontophoresis, LDPI may provide more accurate measurements than conventional laser Doppler perfusion monitoring.

Keyword
Microcirculation, Skin, Laser-Doppler, Depolarization, Hyperpolarization
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14456 (URN)10.1016/S0026-2862(03)00002-5 (DOI)
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2009-02-19
2. Role of histamine release in nonspecific vasodilatation during anodal and cathodal iontophoresis
Open this publication in new window or tab >>Role of histamine release in nonspecific vasodilatation during anodal and cathodal iontophoresis
Show others...
2004 (English)In: Microvascular research, ISSN 0026-2862, Vol. 67, no 2, 192-196 p.Article in journal (Refereed) Published
Abstract [en]

Nonspecific vasodilatation during iontophoresis is an important confounding factor in experimental pharmacology. In this investigation, we studied the involvement of sensory nerves and histamine-related reactions in causing nonspecific vasodilatation in a model of anodal and cathodal iontophoresis of sodium chloride. Firstly, we applied a mixture of local anesthetic (EMLA) cream to confirm its suppressive effect on nonspecific vasodilatation and to measure its efficacy in three different dosages (duration: 1, 2, and 3 h). We then investigated the role of histamine in nonspecific vasodilatation by giving an oral antihistamine drug (cetirizine) to subjects who had and had not been given EMLA. We found substantial suppression of the nonspecific vasodilatation in all EMLA-treated groups (all dosages) compared with untreated controls (with suppression rates of 60–65%). Dosage had no significant effect. A further suppression of nonspecific vasodilatation was seen after oral cetirizine during anodal and cathodal iontophoresis in both EMLA-treated and untreated groups. The antihistamine effect was most pronounced during anodal iontophoresis. These results suggest a histaminergic increase in perfusion that may be independent of neurogenic mechanisms and depend on polarity (anode or cathode). Local nerve blocks (EMLA) together with cetirizine may therefore be used to reduce nonspecific vasodilatation in both anodal and cathodal iontophoresis.

Keyword
Microcirculation, Iontophoresis, Nonspecific vasodilatation, EMLA, Cetirizine, Histamine, Laser Doppler
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14457 (URN)10.1016/j.mvr.2003.12.002 (DOI)
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2009-08-18
3. A protocol for iontophoresis of acetylcholine and sodium nitroprusside that minimises nonspecific vasodilatory effects
Open this publication in new window or tab >>A protocol for iontophoresis of acetylcholine and sodium nitroprusside that minimises nonspecific vasodilatory effects
2004 (English)In: Microvascular research, ISSN 0026-2862, Vol. 67, no 2, 197-202 p.Article in journal (Refereed) Published
Abstract [en]

Iontophoresis of vasoactive substances is a promising tool for studying pharmacological aspects of the (patho)physiology of the microvasculature. However, nonspecific microvascular responses are a common problem in most protocols used. We studied the effect of current density (mA/cm2), charge density (mC/cm2), drug concentration (mass %) and vehicle concentration (M) on the nonspecific vasodilatation during iontophoresis of sodium chloride, acetylcholine (ACh) and sodium nitroprusside (SNP).

We found that nonspecific vasodilatation depended on current density and charge density in both anodal and cathodal iontophoresis. The responses to ACh and SNP were dependent on current density, charge density and drug concentration. We found that by limiting current density (<0.01 mA/cm2) and charge density (<7.8 mC/cm2) and with adjusted concentrations for drugs and vehicles, it is possible to prevent nonspecific effects during iontophoresis of ACh and SNP, while maximum drug effects (plateaus in the dose–response curves) are still obtained. These new findings are important for future iontophoresis studies in which vasoactive drugs are used to assess microvascular function because the presented approach has advantages compared to older techniques, which mainly have attempted to suppress or compensate for the nonspecific responses during iontophoresis by the use of local anaesthetics or the measurement of drug-minus-vehicle responses, both of which present well-known experimental shortcomings.

Keyword
Microcirculation, Skin, Laser Doppler, Nonspecific vasodilatation, Sodium chloride, Acetylcholine, Nitroprusside
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14458 (URN)10.1016/j.mvr.2003.12.003 (DOI)
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2009-08-17
4. Assessment of microvascular function by study of the dose‐response effects of iontophoretically applied drugs (acetylcholine and sodium nitroprusside): Methods and comparison with in vitro studies
Open this publication in new window or tab >>Assessment of microvascular function by study of the dose‐response effects of iontophoretically applied drugs (acetylcholine and sodium nitroprusside): Methods and comparison with in vitro studies
Show others...
2007 (English)In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 73, no 2, 143-149 p.Article in journal (Refereed) Published
Abstract [en]

Current knowledge about vascular function stems mainly from pharmacological in vitro studies using mounted vascular strips on a strain gauge. We know of no paper that has systematically examined the possibility of assessing the conventional dose–response effects of iontophoresis and laser Doppler investigation of vasoactive substances and compared those relations to data obtained from strips mounted on a strain gauge.

We used the vasoactive substances acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent) and an antagonist (atropine) to enable further investigations in the receptor physiology of iontophoresis.

Dose–response curves from the iontophoresis experiments showed close similarity to those obtained by vascular strips mounted on a strain gauge. The coefficient of variation (CV) of the dose–response factors found in iontophoresis (both inter and intra experimental variability) was low. The iontophoretic effective dose of 50% (ED50) for acetylcholine and nitroprusside had only CVs of 25% and 26%, respectively, compared with 71% and 77% for the vascular strips. Acetylcholine-induced response was antagonized by iontophoresis of atropine. Contrary to expectations, this antagonism was not competitive.

The results show that iontophoresis in combination with laser Doppler technology produces reproducible and reliable dose–response curves that picture the vascular effects of vasoactive drugs.

Keyword
Microvascular circulation, Endothelium, Dose–response, Iontophoresis, Laser doppler
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14459 (URN)10.1016/j.mvr.2006.10.004 (DOI)
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-13Bibliographically approved
5. A time–response model for analysis of drug transport and blood flow response during iontophoresis of acetylcholine and sodium nitroprusside
Open this publication in new window or tab >>A time–response model for analysis of drug transport and blood flow response during iontophoresis of acetylcholine and sodium nitroprusside
2009 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 46, no 4, 270-277 p.Article in journal (Refereed) Published
Abstract [en]

Background/Aims: The analysis of blood flow responses to iontophoresis of vasoactive drugs is often limited to evaluation of maximum responses. In this study, a time-response model is proposed for the blood flow responses to vasoactive drugs applied by iontophoresis.

Methods: The microvascular bed is represented as a single compartment with a zero-order influx of the drugs from the electrode and a first-order clearance due to diffusion and blood flow. The blood flow response to the local drug dose is described using the Emax model.

Results: The model accurately describes the blood flow responses to acetylcholine and sodium nitroprusside during a single iontophoretic current pulse. There is a significant clearance out of the microvascular bed during iontophoresis which depends on the type of drug administered.

Conclusion: The model enables an accurate estimation of response parameters such as ED50 and maximum response, even if the true maximum blood flow is not obtained. The results suggest that due to clearance from the microvascular bed, the local drug dose during a single pulse of current is not linearly proportional to current strength multiplied by pulse duration.

Place, publisher, year, edition, pages
Basel, Switzerland: S. Karger, 2009
Keyword
Time-response model, Iontophoresis, Laser Doppler flowmetry, Acetylcholine, Sodium nitroprusside
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14460 (URN)10.1159/000176042 (DOI)000267091200002 ()
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-13Bibliographically approved

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