Biomedical subjects
H Schott
Publications and source records attributed to H Schott.
Effect of Inorganic Additives on Solutions of Nonionic Surfactants
The salt effects of 10 transition metal cations on nonionic surfactants were investigated by the action of their salts (nine nitrates, two sulfates) on the cloud point (CP) of octoxynol 9. All cations investigated raised the CP of octoxynol 9 by complexation with its ether groups, which represents salting in. However, aside from Ag+, these CP increases were no larger than those caused by Li+ and by di- and trivalent cations not belonging to the transition metal group, even though the transition metal cations have a greater capacity for forming complexes. This unremarkable, average salting-in capacity of most transition metal cations is attributed to competition for their coordination sites between the ether groups of the surfactant and water. With the exception of silver, the solid nitrates of all transition metals examined form stable solid hydrates containing three to nine molecules of water of crystallization, which indicates a high affinity of the cations for water. Only AgNO3 forms no stable solid hydrates. The low affinity of Ag+ for water results in a commensurately higher capacity for binding the ether groups of the surfactant. This was shown by the facts that AgNO3 produced the largest CP increases and that it was the only salt to reversibly precipitate an insoluble adduct with octoxynol 9 from concentrated solutions. The only salt that oxidized the surfactant when its solution was heated in a nitrogen atmosphere and illuminated during CP measurements was Fe(NO3)3. Oxidative degradation produced small but progressive CP reductions. Copyright 1997Academic Press
[Not Available].
The Discovery of the Unconscious by Henri F. Ellenberger has become a common topic in the historiography of (dynamic) psychiatry. But many users of this term have still the opinion that Sigmund Freud was the unique discoverer. In reality there was a scientific context at the fin de siècle, which corresponded intensively with Freud's original concepts and formed their implications (e.g. Darwinism, Neurophysiology). Besides well-documented synchronic analogies Freud implanted diachronic traditions within his psychoanalytic theory. Especially, his main work The Interpretation of Dreams implied Greek mythology as well as natural philosophy of romanticism. Freuds special concepts like 'transfer' and 'resistance' have to be analysed as historical metaphors.
Pharmacokinetics of N4-octadecyl-1-beta-D-arabinofuranosylcytosine in plasma and whole blood after intravenous and oral administration to mice.
N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) is a new cytotoxic derivative of cytosine arabinoside with improved cytotoxic activity and stability against deamination. Its pharmacokinetics were studied in mice. The drug was administered intravenously and orally to ICR mice to assess its pharmacokinetic parameters in plasma and whole blood. The lipophilic drug was administered in small unilamellar liposomes 100-400 nm in diameter. The concentrations of NOAC in plasma and erythrocytes were determined by high-performance liquid chromatography (HPLC). When given orally a rather low amount of the delivered NOAC was absorbed as the unchanged drug, resulting in a bioavailability of 1.1% from the plasma and 12.9% from whole blood. As shown elsewhere, the amount of drug absorbed is sufficient to provide excellent cytotoxic activity in the L1210 leukemia and in human xenograft models after oral administration. The mean residence time of NOAC after intravenous administration was 3.5 h in plasma and 6 h in whole blood giving NOAC a terminal half-life in blood substantially longer than that of cytosine arabinoside. After oral administration the mean residence time was 18 h in plasma and whole blood. In summary, NOAC has a prolonged half-life after intravenous administration compared with cytosine arabinoside. The distribution of NOAC in blood is highly dependent on its mode of administration.
Plasma von Willebrand factor in thoroughbreds in response to high-intensity treadmill exercise.
OBJECTIVE: To determine whether plasma von Willebrand factor (vWf) concentration changes in horses during and after treadmill exercise. ANIMALS: 5 mature, fit Thoroughbreds. PROCEDURE: A blood sampling catheter was placed in the right jugular vein. A warm-up period was followed by a 3-minute rest period. Horses were galloped at racing pace until fatigued (about 2 minutes). Blood samples were collected prior to warm-up, during the postwarm-up rest period, 1 minute into the run, at cessation of the run, and 5 to 120 minutes after cessation of the run. vWf activity was measured by ELISA and corrected for plasma volume changes (measured by changes in plasma albumin concentration). Platelet-poor plasma from 10 clinically normal, resting horses was pooled, assigned a value of 100 U/dl, and served as a control for all assays. RESULTS: vWf activity began increasing 1 minute after horses reached full speed. At 5 minutes after cessation of exercise, vWf values had increased by mean of 92% (P < 0.05) from baseline. vWf activity returned baseline by 15 minutes after exercise, and remained there until 90 minutes after exercise, when it began to increase. CONCLUSION AND CLINICAL RELEVANCE: The spontaneous decrease in vWf values after completion of exercise was unexpected because vWf has a long half-life in circulation. This unexpected finding is compatible with increased vWf consumption and suggests that microvascular trauma may occur in horses during strenuous exercise.
Interactions with human blood in vitro and pharmacokinetic properties in mice of liposomal N4-octadecyl-1-beta-D-arabinofuranosylcytosine, a new anticancer drug.
The interactions of N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC), a lipophilic derivative of 1-beta-D-arabinofuranosylcytosine (ara-C), were studied in vitro with human blood components. Binding of NOAC incorporated into liposomes to erythrocytes (Ec) was saturated at 63 nmol/10(9) Ec and binding analysis resulted in a weak affinity of 3 x 10(3) liters/mol and 4 x 10(7) binding sites per Ec. The Ec partition coefficient D(Ec) was approximately 4, which demonstrates the high accumulation of NOAC in Ec membranes. The calculated fraction f(b) of drug bound to plasma proteins was 30%. Analysis of serum protein binding of NOAC was done by density gradient ultracentrifugation and agarose gel electrophoresis. Liposomal NOAC was distributed to low-density lipoproteins (LDL) at 36%, to high-density lipoproteins at 21%, to albumin and other proteins at 12% and to very-low-density lipoproteins at 5%. Comparable results were obtained for the analog N4-hexadecyl-1-beta-D-arabinofuranosylcytosine and when the drugs were dissolved in dimethyl sulfoxide. The biodistribution of liposomal NOAC in ICR mice after intravenous application revealed a biphasic blood concentration versus time curve with a distribution half-life t1/2alpha of 23 min and an elimination half-life t1/2beta of 7 h. The drug was distributed mainly into the liver with an organ load of 69% and with an elimination half-life of 8 h. The strong affinity of NOAC to LDL might be exploited for the enhanced uptake of the drug in tumor cells expressing high numbers of LDL receptor molecules.
Lipophilic 1-beta-D-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model.
The N4-alkylcytosine arabinoside derivative N4-octadecyl-AraC (AraC-Ocd, NOAC) and the (1-octadecylglycero-3-phospho)-AraC (Ocd-GroP-AraC, OPA) conjugate are new lipophilic derivatives of the cytostatic drug 1-beta-D-arabinofuranosylcytosine (AraC) that produce high antileukemic effects in the L1210 murine leukemia model when administered orally or parenterally as liposomal formulations. Between 83% and 100% of the treated animals were cured after five consecutive daily oral drug applications with a total dose of 1 mmol/kg AraC-Ocd or Ocd-GroP-AraC. Corresponding results were obtained after parenteral therapy on days 2 and 6 after tumor inoculation with five- to ten-fold lower concentrations of these two compounds. A comparable cytotoxic activity was found with the orally active AraC-5'-(n-stearyl phosphate). However, because of its strong hemolytic toxicity this derivative cannot be used for parenteral therapy. Another AraC conjugate, which was modified with two long-chain hydrocarbons, the (1-octadecylglycero-3-phospho)-N4-hexadecyl-AraC was, probably because of poor oral bioavailability, only active when applied parenterally. The new lipophilic AraC derivatives AraC-Ocd and Ocd-GroP-AraC are compounds with a high potential for the oral treatment of leukemias and possibly also of solid tumors.
Oral antitumour activity in murine L1210 leukaemia and pharmacological properties of liposome formulations of N4-alkyl derivatives of 1-beta-D-arabinofuranosylcytosine.
The oral cytostatic activity in L1210 mouse leukaemia of the two new N4-alkyl derivatives of 1-beta-D-arabinofuranosylcytosine (AraC), N4-hexadecyl- and N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NH-AraC, NO-AraC) was investigated. In contrast to AraC, both derivatives were highly cytostatic after oral application as liposome formulations. With treatment schedules of five consecutive dosages or with two applications on days 1 and 4 after intravenous tumour cell inoculation with a total dose of 470-1000 mg/kg NH-AraC or NO-AraC, 70%-100% of the treated animals were cured. The lethal dose in healthy ICR mice after a single intraperitoneal application, corresponding to the LD50, was 524 mg/kg for NO-AraC, whereas NH-AraC proved to be less toxic. The haematological toxicity remained moderate for both drugs with a mild leucopenia and a drop in platelet counts, which recovered 4-6 days after treatment. The erythrocytes were not affected and haemolytic toxicities were absent. As non-haematological toxicities, at high drug concentrations, a pronounced atrophy of the rapidly dividing epithelia of the small intestines and of the white pulp of the spleen were observed. The blood levels of NH-AraC given orally reached values comparable to those after parenteral application of a four-times lower dose of NH-AraC, suggesting a moderate bioavailability. Thus, these two lipophilic derivatives of AraC are compounds with a potential for the oral treatment of malignant diseases.
Synthesis and structure-activity studies in vivo of liposomal phospholipid-N4-palmitoyl- and N4-hexadecyl-1-beta-D-arabinofuranosylcytosine conjugates.
N4-Hexadecyl-1-beta-D-arabinofuranosylcytosine (hxd4araC), a new cytostatic derivative of the antileukemic drug 1-beta-D-arabinofuranosylcytosine (araC), was linked in gram-scale syntheses to phospholipids containing differently substituted glycerol residues. All phospholipid-araC conjugates which were condensed via a phosphotriester linkage were shown to be ineffective in the in vivo treatment of L1210 murine leukemia. The transformation of the triesters into phosphodiester-linked conjugates by cleavage of the 2-chlorophenyl protecting group resulted in conjugates which were highly active against L1210 leukemia. These conjugates form stable liposomes with matrix lipids which exert antileukemic effects depending on the number and characteristics of the lipophilic residues of the conjugates. By treatment of L1210 leukemic mice with 100 mumol/kg body wt as total dose given by i.p. injection on days 2 and 6 after tumor inoculation with liposomal hxd4araC or 1-O-octadecyl-rac-glycero-3-phosphoryl-(3-->5')-1- beta-D-arabino-furanosylcytosine (Ocd1GroP-araC) the fraction of 60-day survivors was 100%. Corresponding curative effects were observed after treatment with 200 mumol/kg of 1,2-O-dipalmitoyl-rac-glycero-3-phosphoryl-(3-->5')-N4-palmitoyl-1-beta- D-arabinofuranosylcytosine (Pam1pam2GroP-pam4araC); 1,2-O-dioctadecyl-rac-glycero-3-phosphoryl- (3-->5')-N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (Ocd1ocd2GroP-pam4araC) or 1-O-octadecyl-rac-glycero-3-phosphoryl-(3-->5')-hxd4araC (Ocd1GroP-hxd4araC). Four other conjugates with differently combined palmitoyl-, octadecyl- and hexadecyl residues were significantly less active or inactive. A distinct relationship between the chemical structures and the antileukemic activity of the nine investigated compounds was not found.
Sensitive high-performance liquid chromatographic method for the determination of N4-hexadecyl- and N4-octadecyl-1-beta-D-arabinofuranosylcytosine in plasma and erythrocytes.
N4-Hexadecyl- and N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NHAC, NOAC) are two new cytostatic derivatives of cytosine arabinoside (ara-C) with improved cytostatic activity and stability against deamination. A high-performance liquid chromatography (HPLC) method was developed for the specific determination of NHAC and NOAC in plasma and erythrocytes, after solid-phase extraction using UV detection at 275 mm. Because of the strong binding of the drugs to proteins and membranes, the samples have to be pretreated with urea (plasma) or butanol and ultrasonication (erythrocytes). The calibration curves are linear for both drugs (r > 0.999) in the concentration ranges 20-2100 micrograms/l for plasma and 40-4200 micrograms/l for erythrocytes, respectively. The within-day and between-day precision studies showed a good reproducibility, with coefficients of variation below 8.5%. The recoveries of the lipophilic ara-C derivatives are greater than 66%. The method described can be applied to pharmacokinetic studies with NHAC and NOAC.
Hydrophilic-lipophilic balance, solubility parameter, and oil-water partition coefficient as universal parameters of nonionic surfactants.
The following three parameters describing the balance between the hydrophilicity of the polar moieties and the lipophilicity of the hydrocarbon moieties of nonionic surfactants are tabulated and examined: hydrophilic-lipophilic balance (HLB), oil-water partition coefficient (KWO), and a solubility parameter (delta O) modified to take into account hydrogen bonding between water and the ether and hydroxyl groups of the surfactants. The purpose of the study is to ascertain whether these parameters are universal properties applicable to different categories of nonionic surfactants. Included were the following five nonionic surfactant categories or homologous series, comprising a total of 51 surfactants for which KWO values are available: octoxynols, nonoxynols, polyoxyethylated linear alcohols and dodecylamines, and sorbitan monoesters. The HLB of each homologous surfactant series gave a nearly linear correlation with log KWO. However, the five lines were spread far apart rather than falling on a single master curve. Therefore, the HLB is not a universal property, because it is based exclusively on the weight-percent of polyoxyethylene or polyol in the surfactant molecule while disregarding its molecular weight, the chemical nature of its hydrophilic and lipophilic moieties, and the structural features of the latter. These characteristics are taken into account when computing delta O. The correlation between the 51 experimental log KWO values and their calculated delta O is linear, with a regression coefficient of 0.902. Moreover, it is possible to estimate the KWO value of a nonionic surfactant (which is difficult to determine experimentally) from its delta O value (which is readily calculated) within a 95% confidence limit. Our conclusion, subject to continuing reappraisal as additional KWO values become available, is that delta O is a universal property applicable to all categories of nonionic surfactants.
Cellular pharmacology of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine in the human leukemic cell lines K-562 and U-937.
The mechanisms of cytotoxicity, cellular drug uptake, intracellular drug distribution, cellular pharmacokinetics, formation of arabinofuranosylcytosine triphosphate (ara-CTP), and DNA incorporation of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC), a new lipophilic derivative of arabinofuranosylcytosine (ara-C) formulated in small unilamellar liposomes, were determined in vitro in the human leukemic cell lines K-562 and U-937. Furthermore, the induction of erythroid differentiation by NHAC was tested in K-562 cells. The cytotoxicity of NHAC in both cell lines was not influenced by the deoxycytidine (dCyd) concentration or the presence of the nucleoside-transport-blocking agent dipyridamole as demonstrated in coincubations with dCyd and/or dipyridamole, whereas in contrast, the cytotoxicity of ara-C was decreased additively by both drugs. As compared with ara-C, the uptake of NHAC displayed up to 16- and 5-fold increases in K-562 and U-937 cells, respectively, depending on the drug concentration. Studies of the drug distribution and pharmacokinetics of NHAC revealed a depot effect for NHAC in the cell membranes, resulting in half-lives 2.6 and 1.4 times longer than those of ara-C in the two cell lines. The ara-CTP concentrations derived from NHAC were 150- and 75-fold lower at a drug concentration of 1 microM in K-562 and U-937 cells, respectively. The DNA incorporation of the drugs observed after incubation with 2 microM NHAC was 60- and 30-fold lower as compared with that seen at 2 microM ara-C in the two cell lines. Furthermore, NHAC was capable of inducing irreversible erythroid differentiation to a maximum of only 22% of K-562 cells, whereas ara-C induced differentiation at a drug concentration 100-fold lower in 50% of the cells. These results indicate a mechanism of cytotoxicity for NHAC that is independent of the nucleoside transport mechanism and the phosphorylation pathway and suggest that the mechanisms of action of NHAC are significantly different from those of ara-C. Therefore, NHAC might be used for the treatment of ara-C-resistant malignancies.
Vascular access for haemodialysis--role of the urologist.
Twelve years urological experience at the Klinikum Potsdam with subcutaneous arteriovenous anastomosis as a vascular access for chronic haemodialysis is described. More than 774 access operations have been performed, 344 of them on 255 patients in the last 3 years. The side-to-end anastomosis between radial artery and cephalic vein in the lower arm has proved to be the method of choice. In 187 of the 255 patients (73%) the first operation was successful. Of the other 68, more than 157 operations were necessary for successful vascular access in 55 patients. To summarize, in 242 out of 255 patients (95%) a functioning vascular access was achieved after 1.4 operations per patient. In only 13 patients was it necessary to implant a heterologous vascular graft. In our opinion, the urologist should contribute to the success of treatment for end-stage-renal-disease.
Cellular pharmacology of a liposomal preparation of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine, a lipophilic derivative of 1-beta-D-arabinofuranosylcytosine.
The in vitro deamination, cytotoxicity, cellular drug uptake, distribution and cellular pharmacology in HL-60 cells of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC), a lipophilic derivative of arabinofuranosylcytosine (ara-C), were studied. Compared with ara-C, NHAC in liposomal formulations was highly resistant to deamination, resulting in levels of formation of arabinofuranosyluracil 42 and ten times lower in plasma and liver microsomes respectively. The cytotoxicity of NHAC was independent of both the nucleoside transporter mechanism and the deoxycytidine (dCyd) kinase activity as demonstrated by co-incubating NHAC with dipyridamole and/or dCyd. In ara C-resistant HL-60 cells NHAC was still cytotoxic, requiring drug concentration only 1.6 times higher than sensitive cells. Uptake of NHAC was six times higher and was not inhibited by dipyridamole. The pharmacokinetics of NHAC revealed that its intracellular half-life is 4.8 times longer than that of ara-C. Ara-CTP formation and incorporation into DNA was up to 25-50 times lower than that of ara-C and contributed only marginally to the cytotoxic effects of NHAC. These results indicate that, because of the significantly increased stability, the transporter-independent uptake and the dCyd-kinase-independent cytotoxicity, NHAC might be active in ara-C-resistant cells.
Cell cycle-dependent cytotoxicity and induction of apoptosis by liposomal N4-hexadecyl-1-beta-D-arabinofuranosylcytosine.
The clonogenic growth inhibition, the cell cycle dependence of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) cytotoxicity and the capability to induce apoptosis in ara-C-sensitive and -resistant HL-60 cells were investigated and compared with arabinofuranosylcytosine (ara-C). In the clonogenic assay with sensitive HL-60 cells, ara-C was slightly more effective than a liposomal preparation of NHAC, whereas in the resistant cells, NHAC revealed its potency to overcome ara-C resistance, resulting in a 23-fold lower 50% inhibitory concentration compared with ara-C. Cell cycle dependent cytotoxicity and induction of apoptosis were studied by flow cytometry, using the bromodeoxyuridine-propidium iodide and terminal transferase method respectively. In contrast to ara-C, NHAC exerted no phase-specific toxicity at low concentrations (< 40 microM). At higher concentrations the S-phase-specific toxicity increased, probably resulting from ara-C formed from NHAC. NHAC induced apoptosis at higher drug concentrations than ara-C, however apoptosis appeared not to be limited to the S-phase cells. Apoptosis occurred in both cell lines within 2-4 h after drug exposure. These results give further evidence that NHAC exerts its cytotoxicity by different mechanisms of action than ara-C and might therefore be active in ara-C-resistant tumours.
Pharmacokinetic properties and interactions with blood components of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) incorporated into liposomes.
N4-Hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) is a new lipophilic derivative of 1-beta-D-arabinofuranosylcytosine (ara-C) with strong antitumour activity. The interactions of NHAC incorporated into small unilamellar liposomes of different compositions with blood components were evaluated. In comparison with ara-C, NHAC is highly protected against deamination to inactive arabinofuranosyluracil (ara-U) in human plasma, resulting in only 2% conversion into ara-U after 4 h incubation at 37 degrees C, whereas from ara-C more than 80% was deaminated. In in-vitro incubations with human blood, it was found that NHAC was transferred from the liposomes at about 47% efficiency to plasma proteins, particularly to albumin and to the high and low density lipoproteins. The remaining part of NHAC was bound to erythrocytes (50%) and to leucocytes (3%). The addition of poly(ethylene) glycol-modified phospholipids to the liposomes (PEG liposomes), which were composed of soy phosphatidylcholine and cholesterol (plain liposomes), did not significantly prevent the fast transfer of NHAC from the liposomes to the blood components. Pharmacokinetic studies in mice revealed that NHAC had biphasic kinetics in blood with a t1/2 alpha of 16 min and a t1/2 beta of 3.8 h when the drug was formulated in plain liposomes and a t1/2 alpha of 15 min and a t1/2 beta of 9.67 h in PEG liposomes, respectively. NHAC was predominantly distributed in the liver with 29% of the injected dose found after 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Interaction of anionic compounds with gelatin. II: Effect on some physicochemical properties of gelatin.
The interaction of gelatin with four monosulfonated or monocarboxylated azo dyes was investigated by measuring the surface tension and intrinsic viscosity of gelatin solutions containing the dyes at different concentrations, the rigidity and melting point of their gels, and the moisture regain of their films. The dyes, which were used as models for anionic drugs, differed in the size of their aromatic hydrocarbon moieties. Surface tension measurements showed that the gelatin did not affect the critical micelle concentration of the free dyes and that the bound dyes increased the surface activity of the gelatin. The dyes reduced the intrinsic viscosity of gelatin by as much as 2/3. They also lowered the rigidity and the melting point of dilute gelatin gels and reduced the moisture regain of dry gelatin films. These changes became more pronounced with increasing dye concentrations. The effectiveness of the dyes in producing these changes increased with the size of their hydrocarbon moieties because, as had been shown in a previous study, increasingly larger hydrocarbon moieties increased the binding of the dyes to gelatin. At the pH of the measurements, which was 1.9 units below the isoelectric point of the gelatin, the gelatin was a cationic polyelectrolyte. Binding of the dye anions by ion pairing, hydrogen bonds, and other secondary valence forces rendered the gelatin less ionic and less hydrophilic, which accounts for the present observations.
Interaction of anionic compounds with gelatin. I: Binding studies.
Even though gelatin is the most widely used polymeric excipient in pharmaceutical products, scant attention has been paid to its interaction with small organic molecules. The present work deals with the interaction of gelatin and four monosulfonated or monocarboxylated azo dyes having hydrocarbon moieties of different sizes. These dyes were used as models for anionic drugs, which make up a significant percentage of all new drugs. Most binding studies used ultrafiltration to separate free from bound dye, followed by spectrophotometric dye assays. One binding study was based on the shift in pH when a dye was added to gelatin solutions. All binding isotherms consisted of two linear segments. The initial segments, which start at the origin, represent the partitioning of the dyes between the dissolved gelatin and the aqueous buffer solution. They changed abruptly to horizontal plateaus, which represent the binding limit. Increases in pH from 5.00 to 7.00 reduced the binding of the sulfonated dyes but increased the binding of the carboxylated dye. At pH > or = 7.00, where even the carboxylic acid groups are fully ionized, the carboxylated dye and its sulfonated analog were bound to gelatin to the same extent. The binding of all dyes decreased with increasing temperature (i.e., the standard enthalpy of binding was negative), with a change of the solvent medium from water to 0.15 M ammonium acetate, and with decreasing size of the hydrocarbon moieties of the dyes. The binding of the dyes to gelatin was always reversible and the standard entropy change associated with it was negative.(ABSTRACT TRUNCATED AT 250 WORDS)