Combined Hydroxyethyl Starch Luteolin Nanocrystals for Effective Anti-Hyperuricemia Effect in Mice Model.

Introduction: Although flavonoid compounds exhibit various pharmacological activities, their clinical applications are restricted by low oral bioavailability owing to their poor solubility. Nanocrystals (NCs) represent an excellent strategy for enhancing the oral bioavailability of flavonoids. Hydroxyethyl starch (HES), a biomaterial compound used as a plasma expander, could be an ideal stabilizer material for preparing flavonoid NCs. Methods: HES was used to stabilize flavonoid nanocrystals (NCs), using luteolin (LUT) as a model drug. After full characterization, the freeze-drying and storage stability, solubility, intestinal absorption, pharmacokinetics, and in vivo anti-hyperuricemic effect of the optimized HES-stabilized LUT NCs (LUT-HES NCs) were investigated. Results: Uniformed LUT-HES NCs were prepared with mean particle size of 191.1±16.8 nm, zeta potential of about -23 mV, drug encapsulation efficiency of 98.52 ± 1.01%, and drug loading of 49.26 ± 0.50%. The freeze-dried LUT-HES NCs powder showed good re-dispersibility and storage stability for 9 months. Notably, compared with the coarse drug, LUT-HES NCs exhibited improved saturation solubility (7.49 times), increased drug dissolution rate, enhanced Caco-2 cellular uptake (2.78 times) and oral bioavailability (Fr=355.7%). Pharmacodynamic studies showed that LUT-HES NCs remarkably lowered serum uric acid levels by 69.93% and ameliorated renal damage in hyperuricemic mice. Conclusion: HES is a potential stabilizer for poorly soluble flavonoid NCs and provides a promising strategy for the clinical application of these compounds. LUT-HES NCs may be an alternative or complementary strategy for hyperuricemia treatment.

Lysine-mediated hydroxyethyl starch-10-hydroxy camptothecin micelles for the treatment of liver cancer.

Liver cancer is a malignant tumor with extremely high morbidity and mortality. At present, traditional chemotherapy is still the most commonly used therapeutic approach. However, serious side effects lead to the treatment of liver cancer is not ideal. Therefore, it is imperative to develop a new drug delivery system based on nanotechnology and liver cancer microenvironment. In this study, a pH/reduction/α-amylase multi-sensitive hydroxyethyl starch-10-hydroxy camptothecin micelles (HES-10-HCPT-SS-Ly) targeting over-expressed amino acid (AA) transporters on the surface of liver cancer cell by applying lysine were successfully synthesized. The prepared micelles showed regular structure, suitable particle size, and intelligent drug release property. Compared with conventional HES-10-HCPT micelles and 10-HCPT injection, HES-10-HCPT-SS-Ly micelles demonstrated better in vitro anti-proliferative capability toward human liver cancer Hep-G2 cells and greater antitumor efficiency against nude mouse with Hep-G2 tumor. These findings suggest that HES-10-HCPT-SS-Ly micelles may be a promising nanomedicine for treatment of liver cancer.

6% Hydroxyethyl starch (HES 130/0.4) diminishes glycocalyx degradation and decreases vascular permeability during systemic and pulmonary inflammation in mice.

BACKGROUND: Increased vascular permeability is a pathophysiological hallmark of sepsis and results in increased transcapillary leakage of plasma fluid, hypovolemia, and interstitial edema formation. 6% hydroxyethyl starch (HES 130/0.4) is commonly used to treat hypovolemia to maintain adequate organ perfusion and oxygen delivery. The present study was designed to investigate the effects of 6% HES 130/0.4 on glycocalyx integrity and vascular permeability in lipopolysaccharide (LPS)-induced pulmonary inflammation and systemic inflammation in mice. METHODS: 6% HES 130/0.4 or a balanced electrolyte solution (20 ml/kg) was administered intravenously 1 h after cecal ligation and puncture (CLP) or LPS inhalation. Sham-treated animals receiving 6% HES 130/0.4 or the electrolyte solution served as controls. The thickness of the endovascular glycocalyx was visualized by intravital microscopy in lung (LPS inhalation model) or cremaster muscle (CLP model). Syndecan-1, hyaluronic acid, and heparanase levels were measured in blood samples. Vascular permeability in the lungs, liver, kidney, and brain was measured by Evans blue extravasation. RESULTS: Both CLP induction and LPS inhalation resulted in increased vascular permeability in the lung, liver, kidney, and brain. 6% HES 130/0.4 infusion led to significantly reduced plasma levels of syndecan-1, heparanase, and hyaluronic acid, which was accompanied by a preservation of the glycocalyx thickness in postcapillary venules of the cremaster (0.78 ± 0.09 µm vs. 1.39 ± 0.10 µm) and lung capillaries (0.81 ± 0.09 µm vs. 1.49 ± 0.12 µm). CONCLUSIONS: These data suggest that 6% HES 130/0.4 exerts protective effects on glycocalyx integrity and attenuates the increase of vascular permeability during systemic inflammation.

Comparison of the pharmacokinetics of two formulations of hydroxyethyl starch in healthy horses.

A lower molecular weight and molar substitution formulation (130/0.4) of hydroxyethyl starch solution has been shown to have a more sustained effect on COP and similar hemodynamic effects as a higher molecular weight and molar substitution formulation (600/0.75) in healthy horses. In humans, these pharmacodynamic characteristics are coupled with more rapid clearance and decreased adverse coagulation effects and accumulation. The objective of this study was to determine and compare the pharmacokinetics of these two formulations in horses. Eight healthy horses were given a 10 mL/kg bolus of each formulation (600/0.75 and 130/0.4) of hydroxyethyl starch solution in a randomized crossover design. Blood was collected, and plasma was harvested for plasma levels over 24 h. Pharmacokinetic parameters for each horse were estimated from a noncompartmental analysis. Treatment with 600/0.75 resulted in a higher initial plasma concentration (C0 ), systemic half-life (t1/2 ), and overall drug exposure (AUC0-inf ) in addition to decreased elimination rate (ß), volume of distribution (Vd), and clearance (CL), compared to treatment with 130/0.4 (P < 0.001). The pharmacokinetic findings combined with previous pharmacodynamics findings suggest that 130/0.4 can provide similar benefits to 600/0.75 with a lower risk of accumulation in the circulation.

Raman-based detection of hydroxyethyl starch in kidney allograft biopsies as a potential marker of allograft quality in kidney transplant recipients.

In brain-dead donor resuscitation, hydroxyethyl starch (HES) use has been associated with presence of osmotic-nephrosis-like lesions in kidney transplant recipients. Our aim was to determine whether the presence of HES in protocol renal graft biopsies at three months (M3) after transplantation is associated with renal graft quality. According to the HES administered to the donor during the procurement procedure, two groups of patients were defined according graft exposition to HES: HES group, (N = 20) and control group (N = 6). Detection and relative quantification of HES was performed by Raman spectroscopy microimaging on M3 protocol renal graft biopsies. Statistical analyses were used to investigate the association between Raman data and graft characteristics. HES spectral signal was revealed negative in the control group, whereas it was positive in 40% of biopsies from the HES group. In the HES group, a stronger HES signal was associated with a lower risk of graft failure measured by the Kidney Donor Risk Index (KDRI) and was correlated with the allograft kidney function. Thus, HES accumulation in donor kidney, as probed by Raman biophotonic technique, is correlated with the quality of donor kidney and consequently the graft renal function and graft survival.

Hydroxyethyl starch-10-hydroxy camptothecin conjugate: synthesis, pharmacokinetics, cytotoxicity and pharmacodynamics research.

10-hydroxy camptothecin (10-HCPT) is an antitumor agent effective in the treatment of several solid tumors but its use is hampered by poor water solubility, low lactone stability, short plasma half-life and dose-limiting toxicity. In this study, 10-HCPT-hydroxyethyl starch (HES) conjugate was prepared to overcome these limits of 10-HCPT. The solubility of 10-HCPT conjugate was 0.72 mg/ml, about 100 times to free 10-HCPT. The 10-HCPT conjugate showed good sustained release effect in phosphate-buffered saline (PBS), rat plasma and liver homogenate. Meanwhile, 10-HCPT-HES conjugate achieved much lower IC50 and higher cytotoxicity effects than the free 10-HCPT on Hep-3B liver cancer cells. The pharmacokinetics results of 10-HCPT-HES conjugate demonstrated that the biological half-life of 10-HCPT was increased from 10 min to 4.38 h and the bioavailability was 40 times higher than the commercial 10-HCPT injection. The pharmacodynamics results indicated that 10-HCPT-HES conjugate had a better antitumor efficiency against nude mouse with Hep-3B tumor than the commercial 10-HCPT injection, and the inhibition ratio of tumor was 83.9 and 27.8%, respectively, at the same administration dosage. These findings suggest that 10-HCPT-HES conjugate is a promising drug delivery system providing improved long circulating effect, greater stability and better antitumor effect.

Hydroxyethyl starch and granulocyte transfusions: considerations of utility and toxicity profile for patients and donors.

Hydroxyethyl starch (hetastarch) is a synthetic glucose compound with extensive clinical use as a volume expander. Because of its red blood cell-sedimenting properties, hetastarch plays a major role in preparation of granulocyte products. Recent concerns have been raised about the use of hetastarch in critically ill patients for the development of renal injury and other severe adverse events. In contrast, granulocyte donors receive much less of this compound during collection procedures, and over many years, minimal toxicity has been documented in these individuals. Furthermore, granulocyte products contain very little hetastarch, and ill effects on renal function have not been associated with their administration. This review assesses available information about the toxicity profile of hetastarch in critically ill patients requiring a volume expander as well as granulocyte donors and recipients. Because of the lack of toxicity in these latter two groups, hetastarch should be available for preparation of granulocyte products and their administration.

Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use.

OBJECTIVE: To review and summarize the pharmacokinetics and pharmacodynamics of hydroxyethyl starch (HES), as well as reported risks and benefits of HES infusion, and to provide administration and monitoring recommendations for HES use in dogs and cats. DATA SOURCES: Veterinary and human peer-reviewed medical literature, including scientific reviews, clinical and laboratory research articles, and authors' clinical experience. SUMMARY: HES solutions are the most frequently used synthetic colloid plasma volume expanders in human and veterinary medicine. The majority of research in human medicine has focused on the adverse effects of HES infusion, with emphasis on acute kidney injury and coagulation derangements. The studies often differ in or fail to report factors, such as the type, amount, interval, and concentration of HES administered; the patient population studied; or concurrent fluids administered. Currently, there is no definitive clinical evidence that the reported adverse effects of HES use in human medicine occur in veterinary species. There is little information available on HES administration techniques or simultaneous administration of additional fluids in human and veterinary medicine. The rationale for HES use in small animals has been largely extrapolated from human medical studies and guidelines. A controlled approach to intravenous fluid resuscitation using crystalloid and HES volumes titrated to reach desired resuscitation end point parameters is outlined for small animal practitioners. CONCLUSION: The extrapolation of data from human studies directly to small animals should be done with the knowledge that there may be species variations and different pharmacokinetics with different HES solutions. Veterinary reports indicate that bolus and continuous rate infusions of 6% hetastarch solutions at moderate doses are well tolerated in feline and canine subjects. Further research in domesticated species is necessary to better define and expand the knowledge regarding use of HES solutions in small animal medicine.

Protein HESylation for half-life extension: synthesis, characterization and pharmacokinetics of HESylated anakinra.

Half-life extension (HLE) is becoming an essential component of the industrial development of small-sized therapeutic peptides and proteins. HESylation(®) is a HLE technology based on coupling drug molecules to the biodegradable hydroxyethyl starch (HES). In this study, we report on the synthesis, characterization and pharmacokinetics of HESylated anakinra, where anakinra was conjugated to propionaldehyde-HES using reductive amination, leading to a monoHESylated protein. Characterization using size exclusion chromatography and dynamic light scattering confirmed conjugation and the increase in molecular size, while Fourier transform infrared spectroscopy showed that the secondary structure of the conjugate was not affected by coupling. Meanwhile, microcalorimetry and aggregation studies showed a significant increase in protein stability. Surface plasmon resonance and microscale thermophoresis showed that the conjugate retained its nanomolar affinity, and finally, the pharmacokinetics of the HESylated protein exhibited a 6.5-fold increase in the half-life, and a 45-fold increase in the AUC. These results indicate that HESylation(®) is a promising HLE technology.

[Properties and clinical implications of middle molecular weight low substitution hydroxyethyl starch solution].

In this review article, the properties and clinical implications of middle molecular weight low substitution hydroxyethyl starch (HES) solution are summarized. This preparation shows larger volume effect and longer duration compared to the currently available low-molecular weight HES solution and will be available in the near future in Japan. Effects on renal function and coagulation system are supposedly dependent on the persistence of larger HES molecule in the body and this middle molecular weight low substitution HES preparation may be advantageous to the older HES preparation due to its rapid metabolism. This preparation has been successfully used in the goal-directed fluid management in the early recovery program after surgery and will offer several advantages in fluid management when introduced in Japan.

Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review.

PURPOSE: To systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage. METHODS: MEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation. RESULTS: Forty-eight studies were included: 37 human studies with a total of 635 patients and 11 animal studies. The most frequent indication for fluid infusion was surgery accounting for 282 patients (45.9%). HES localization in skin was shown by 17 studies, in kidney by 12, in liver by 8, and in bone marrow by 5. Additional sites of HES deposition were lymph nodes, spleen, lung, pancreas, intestine, muscle, trophoblast, and placental stroma. Among major organs the highest measured tissue concentration of HES was in the kidney. HES uptake into intracellular vacuoles was observed by 30 min after infusion. Storage was cumulative, increasing in proportion to dose, although in 15% of patients storage and associated symptoms were demonstrated at the lowest cumulative doses (0.4 g kg(-1)). Some HES deposits were extremely long-lasting, persisting for 8 years or more in skin and 10 years in kidney. Pruritus associated with HES storage was described in 17 studies and renal dysfunction in ten studies. In one included randomized trial, HES infusion produced osmotic nephrosis-like lesions indicative of HES storage (p = 0.01) and also increased the need for renal replacement therapy (odds ratio, 9.50; 95% confidence interval, 1.09-82.7; p = 0.02). The tissue distribution of HES was generally similar in animals and humans. CONCLUSIONS: Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful.

Development and application of a UPLC-MS/MS method for the pharmacokinetic study of 10-hydroxy camptothecin and hydroxyethyl starch conjugate in rats.

With the purpose to carry out the pharmacokinetic studies of 10-hydroxy camptothecin (10-HCPT) and hydroxyethyl starch (10-HCPT-HES) conjugate, an ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated. The analytes, 10-HCPT and the internal standard, Diphenhydramine hydrochloride were extracted with ethyl acetate-isopropanol (95:5, v/v) and separated on an ACQUITY UPLC™ BEH C18 column using a mobile phase composed of acetonitrile and water (containing 0.1% formic acid) with a linear gradient program. With positive ion electrospray ionization (ESI), the analytes were monitored on a triple quadrupole mass spectrometer in the multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over the concentration ranges of 0.5-2500ng/mL. The intra- and inter-day precisions were less than 9.8% and 10.8%, respectively. The accuracy was within 12.1%. The mean recoveries of 10-HCPT at three concentrations of 2.5, 100, 2000ng/mL were higher than 87.2%. Commercial 10-HCPT injection and 10-HCPT-HES conjugate were administered intravenously at an equal dose of 10-HCPT at 0.5mg/kg. The biological half-life of conjugate was increased significantly from 10min to 3.15h and the bioavailability was 40 times higher than 10-HCPT injection. Consequently, the proposed UPLC-ESI-MS/MS method was proved to be sensitive, specific and reliable to analyze 10-HCPT in biological samples; 10-HCPT and HES conjugate is a promising strategy for delivery of 10-HCPT with prolonged half time and improved bioavailability.

Carbohydrate plasma expanders for passive tumor targeting: in vitro and in vivo studies.

The objective of this study was to investigate the suitability of carbohydrate plasma volume expanders as a novel polymer platform for tumor targeting. Many synthetic polymers have already been synthesized for targeted tumor therapy, but potential advantages of these carbohydrates include inexpensive synthesis, constant availability, a good safety profile, biodegradability and the long clinical use as plasma expanders. Three polymers have been tested for cytotoxicity and cytokine activation in cell cultures and conjugated with a near-infrared fluorescent dye: hydroxyethyl starches (HES 200 kDa and HES 450 kDa) and dextran (DEX 500 kDa). Particle size and molecular weight distribution were determined by asymmetric flow field-flow fractionation (AF4). The biodistribution was investigated non-invasively in nude mice using multispectral optical imaging. The most promising polymer conjugate was characterized in human colon carcinoma xenograft bearing nude mice. A tumor specific accumulation of HES 450 was observed, which proves it's potential as carrier for passive tumor targeting.

Pharmacokinetics and safety of 6 % hydroxyethyl starch 130/0.4 in healthy male volunteers of Japanese ethnicity after single infusion of 500 ml solution.

PURPOSE: This phase I study was performed in volunteers of Japanese ethnicity to compare pharmacokinetic data after infusion of 6 % hydroxyethyl starch (HES) 130/0.4 with historical data of Caucasians. METHODS: In an open-label, uncontrolled, single-center study, 12 healthy male Japanese volunteers received single intravenous infusions of 500 ml 6 % HES 130/0.4 (Voluven 6 %; Fresenius Kabi Deutschland, Bad Homburg, Germany) over 30 min. RESULTS: Plasma concentration of 6 % HES 130/0.4 was highest at end of infusion (5.53 ± 0.55 mg/ml) and decreased following a biphasic manner. Total plasma clearance and rapid and slow elimination half-lives obtained by a two-compartment model were 1.14 ± 0.16 l/h, 1.12 ± 0.26 h, and 9.98 ± 2.38 h, respectively, and the volume of distribution was 4.76 ± 0.64 l. Mean area under the concentration-time curve was 26.7 ± 3.75 mg/ml h. The total amount of HES excreted into urine was 59.4 % of the applied dose. Hemodilution was observed in all 12 subjects as indicated by a decrease of hemoglobin from 15.5 ± 0.4 g/dl at baseline to 13.8 ± 0.4 g/dl after the end of infusion. Adverse events in this study refer to changes of laboratory parameters and were assessed as not clinically relevant. CONCLUSION: Single administration of a 500 ml solution of 6 % HES 130/0.4 was confirmed to be safe and tolerable in healthy male Japanese subjects. A rapid renal excretion was observed within 24 h after drug administration, accounting for 96 % of the total amount excreted. A comparison with pharmacokinetic data derived from Caucasians did not reveal significant differences to Japanese and confirmed the good tolerability in both ethnic groups.

Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies.

BACKGROUND: Intravenously infused hydroxyethyl starch (HES) can be found in urine, plasma and tissues. HES remaining in plasma and tissues is thought to increase the risk of clinical complications. HES solutions of lower molecular weight and substitution have been developed to increase urinary excretion and reduce plasma persistence. However, their effect on tissue uptake of HES has not been investigated in human subjects. OBJECTIVE: Our objective was to test the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES. DATA SOURCES: Computer searches were performed of MEDLINE; EMBASE; the Cochrane Library; meeting abstract databases in surgery, anaesthesiology and intensive care; ClinicalTrials.gov; and Google. Supplementary sources were reference lists and electronic tables of journal contents. No time period or language restrictions were imposed. STUDY SELECTION: Clinical studies were eligible for inclusion in the meta-analysis, if data were reported both for cumulative urinary excretion of HES over 24 hours after infusion and for plasma HES concentration at 24 hours. DATA EXTRACTION: Data were extracted on 24-hour urinary excretion of HES, 24-hour HES plasma concentration, plasma volume, HES molecular weight and substitution, study design, type and demographics of subjects, indication for fluid infusion, and HES infusion regimen. Tissue uptake of HES was computed as the difference between the infused dose and the sum of urinary excretion and residual plasma HES at 24 hours. DATA SYNTHESIS: Twenty-five clinical studies totalling 287 subjects were included. Tissue uptake of low-molecular-weight HES (≤200 kD) was 42.3% (95% confidence interval [CI] 39.6, 45.0) compared with 24.6% (CI 17.8, 31.4) for high-molecular-weight HES (p < 0.001). Similarly, tissue uptake of lower-substitution HES (≤0.5) was 42.4% (CI 39.5, 45.3) versus 26.6% (CI 19.6, 33.6) for higher-substitution HES (p < 0.001). Among the three most often investigated single HES solutions, tissue uptake of 130/0.4 (42.6%; CI 35.0, 50.2) and HES 200/0.5 (43.3%; CI 39.4, 47.2) closely coincided, whereas uptake of HES 450/0.7 (22.2%; CI 14.8, 29.6) was lower (p = 0.001 and p < 0.001, respectively). CONCLUSIONS: This meta-analysis did not support the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES. Further clinical studies of HES tissue uptake are needed.

[Hydroxyethylstarch-induced pruritus: an understimated side effect of its application also in ENT diseases]. / Hydroxyethylstärke-induzierter Pruritus: Eine unterschätzte und hartnäckige medikamentöse Nebenwirkung auch bei HNO-ärztlichen Erkrankungen.

Chronic pruritus may be caused by drugs such as colloid infusions with hydroxyethylstarch (HES). HES-induced pruritus can be diagnosed by typical patient's history, clinical characteristics, confirmed application of HES and its cutaneous tissue storage obtained by electron microscopy. Pruritus occurs on the whole body and significantly impairs patient's quality of life. It persists daily in high and constant intensity. After several to 15 months in average pruritus decreases gradually and finally ceases when the HES deposits are degraded. Topical and systemic treatments are only of symptomatic value. HES-induced pruritus is severe, protracted and mostly therapy-refractory. Limiting the dose and the duration of HES application may help reducing this intractable side effect.

Relevance of non-albumin colloids in intensive care medicine.

Current guidelines on initial haemodynamic stabilization in shock states suggest infusion of either natural or artificial colloids or crystalloids. However, as the volume of distribution is much larger for crystalloids than for colloids, resuscitation with crystalloids alone requires more fluid and results in more oedema, and may thus be inferior to combination therapy with colloids. This chapter describes the currently available synthetic colloid solutions [i.e., dextran, gelatin and hydroxyethyl starch (HES)] in detail, and critically discusses their specific effects including potential adverse effects. Literature was selected from medical databases (including Medline and the Cochrane library), as well as references extracted from the available publications. Dextrans appear to have the most unfavourable risk/benefit ratio among the currently available synthetic colloids due to their relevant anaphylactoid potential, risk of renal failure and, particularly, their major impact on haemostasis. The effects of gelatin on kidney function are currently unclear, but potential disadvantages of gelatin include a high anaphylactoid potential and a limited volume effect compared with dextrans and HESs. Modern HES preparations have the lowest risk of anaphylactic reactions among the synthetic colloids. Older HES preparations (hetastarch, hexastarch and pentastarch) have repeatedly been reported to impair renal function and hemostasis, especially when the dose limit provided by the manufacturer is exceeded, but no such effects have been reported to date for modern tetrastarches compared with gelatin and albumin. However, no large-scale clinical studies have investigated the impact of tetrastarches on the incidence of renal failure in critically ill patients. When considering the efficacy and risk/benefit profile of synthetic colloids, modern tetrastarches appear to be most suitable for intensive care medicine, given their high volume effect, low anaphylactic potential and predictable pharmacokinetics. However, the impact of tetrastarch solutions on mortality and renal function in septic patients has not been fully determined, and further comparison with crystalloids in prospective, randomized studies is required. Such studies are currently ongoing and their results should be awaited before drawing final conclusions on the HES preparations.

Hydroxyethyl starches: different products--different effects.

With the development of a new generation of hydroxyethyl starches (HES), there has been renewed interest in their clinical potential. High doses of first- and second-generation HES were associated with adverse effects on renal function, coagulation, and tissue storage, thereby limiting their clinical applicability. Newer HES products have lower molar substitution and in vivo molecular weight, resulting in more rapid metabolism and clearance. In this review article, the differences between HES generations are highlighted, with particular emphasis on the improved safety profile of the third generation products. These improvements have been achieved with no loss of efficacy, and they contradict the assumption that efficacy of HES solutions is directly linked to plasma concentration. The impact of source material on structure and pharmacokinetics is highlighted, and the role of the carrier solution is critically assessed.