Flasch: provider-owned plan focuses on quality, growth, and new technology.

H. Michael Flasch, FHFMA, is vice president of claims/administrative services and support for Detroit, Michigan-based Health Alliance Plan (HAP), a subsidiary of Henry Ford Health System (HFHS), which also comprises a dozen owned or affiliated hospitals, 25 medical centers, and numerous other health services. His responsibilities at HAP encompass benefits coordination, configuration of information services, and the claims function. He also has played a key role in HAP's acquisition and integration of an HMO, SelectCare, in March 2001. Flasch joined HFHS in 1984 as associate controller and senior director of patient financial services. He served as vice president of managed care for HFHS and COO of Alliance Health and Life Insurance Company for HAP from 1995 until 2000, when he assumed his current position. Before Joining HFHS, Flasch worked for Hospital Corporation of America in Nashville, Tennessee, and other hospitals in Cincinnati.

2-in-1 shampoo technology: state-of-the-art shampoo and conditioner in one.

Consumers have expressed a need for cleaning and conditioning in one step. Conventional shampoo technology using anionic surfactants and cationic conditioners results in charge interaction and complexing of the ingredients. Neither shampoo nor conditioners achieves the desired result. The successful solution was to incorporate charge neutral dimethicone conditioning ingredients, suspended as microfine droplets within complex crystal lattices, into anionic surfactant shampoo technology. The same solution has also been applied to amphoteric surfactant systems. This provides complete cleaning, and hair conditioning fully equal to separate conditioners without the problems of sebum interactions and conditioner build-up. This was achieved by keeping the dimethicone in suspension throughout the shampoo process. During rinsing, excess water breaks the crystalline lattice and allows deposition of the dimethicone droplets onto the hair. Full cleaning and conditioning are, therefore, achieved in one application. Dimethicone build-up is not encountered as subsequent washes first remove soil and previously deposited dimethicone. Neither do neutral dimethicones show any reactions with sebum. The development of effective 2-in-1 technology has had a major impact on shampoo technology and consumer habits and practices. This has significantly changed the way consumers care for their hair.

[Incidence of side effects in digitalis therapy]. / Häufigkeit von Nebenwirkungen bei Digitalis-Therapie.

In a literature research program concerning side effects during digitalis therapy 75 publications had been evaluated. Comparing 15 drug monitoring studies with different types of drugs, cytostatics, antibiotics and analgetics most frequently led to side effects. Digitalis glycosides ranged on the place 3-9. Adverse reactions rates up to 20% had been observed in hospitalized patients. The average of all data, however, was near 10%. Because of their generally low-risk rate of intoxication ambulant patients--with 96-97% glycoside prescriptions the dominant part of digitalis recipients--evidently had a lower incidence of adverse reactions. In this group of patients the rate of side effects ranged about 3% for digoxin and digitoxin, respectively. Comparative clinical studies with digoxin and digitoxin showed no signs of differences in the rate of adverse reactions between these two digitalis glycosides.

[Penetration kinetics of fluocortolone from a new base for ointment and creme (author's transl)]. / Penetrationskinetik von Fluocortolon aus einer neuen Salben- und Cremegrundlage.

The penetration of fluocortolone from topically administered Syracort ointment and creme was investigated in guinea pigs. Two fluocortolone standards were tested as reference preparations (ointment and creme). 1. Fluocortolone liberation from the ointments and Syracort Creme within 24 h varied between 55% and 62% of the administered dose. The reference creme gave lower drug liberation values (39%). 2. The penetration profile of fluocortolone changed gradually. Non-absorbed portions and the concentrations in the upper layers of the stratum corneum decreased during inunction up to 24 h. Within the same time concentrations in the deeper layers of the skin increased. 3. The two ointments showed comparably good penetration properties, whereas Syracort creme gave flux values higher than those obtained from the reference creme. 4. 24 h after removal of the non-absorbed portion of the ointments a further persistence of the drug could be observed within the skin: 14.3% to 18.5% after additional 6 days. The mean renal elimination rate was found to be 3 days, a total amount between 28% to 30% of the dose was excreted via urine and feaces. Consequently, fluocortolone can be considered a fast penetrating topical which is accumulated especially in the layers of the epidermis and cutis.

Pharmacokinetics of dihydrodigitoxin in the cat. A comparison with digitoxin.

Pharmacokinetics of digitoxin (DGT) and its derivative hydrogenated at the unsaturated lactone ring have been studied using the 3H-labelled compounds in cats. Blood level data could be described by an open three compartment body model. The biological half-lives of dihydrodigitoxin (DH-DGT) and DGT are rather similar (0.12, 0.48, 20.4 h, and 0.11, 0.43, 31.8 h, respectively), whereas the volume of distribution of DH-DGT is about 1/10 from that of DGT (0.241 versus 2.581). Especially in myocardial tissue a significantly lower DH-DGT concentration was measured, indicating the loss of affinity to cardenolide binding sites by hydrogenation. Dihydrodigitoxinic acid was detected as the main metabolite of DH-DGT.

Correlation between inhibition of (Na+, K+)-membrane-ATPase and positive inotropic activity of cardenolides in isolated papillary muscles of guinea pig.

Concentrations of 17 cardenolides, cardenolide glucuronides and sulfates producing half-maximal inhibition of (Na+, K+)-membrane-ATPase from different organs and animal species were determined in vitro. In addition the concentrations that increased the contractility of guinea pig isolated papillary muscles to a particular level were investigated. Comparisons between ATPase-inhibiting and positive inotropic cardiac activities showed extensive parallelism: the correlation coefficients after log/log transformation were between 0.92 and 0.97. The same close correlations are found if dissociation constants of cardenolide receptor complexes and concentrations causing 86Rb-uptake inhibition in human erythrocytes are examined. The concentrations necessary for inhibition of (Na+, K+)-membrane-ATPase of the guinea pig heart and the concentrations required to achieve a defined positive inotropic effect in guinea pig papillary muscle showed a log/log correlation coefficient of 0.97 (P less than 0.001). In both tests the potencies covered more than three orders of magnitude. The results support Repke's hypothesis on the digitalis receptor.

Comparison of the pharmacokinetics of digoxin and dihydrodigoxin in cats in single-dose studies.

Pharmacokinetics of 3H-dihydrodigoxin and 3H-digoxin after single intravenous and intraduodenal administration in cats are compared. Data could be described by an open two compartment body model. The beta half-life in plasma of dihydrodigoxin after initial rapid distribution is 4.6h compared to 10.4 h after digoxin administration. The volume of tissue distribution of dihydrodigoxin is 7 times smaller than that of digoxin (0.311 versus 2.051). The "specific uptake" of dihydrodigoxin into myocardium and some other tissues is very low. Over 5.5h the cumulative biliary and urinary elimination of dihydrodigoxin is definitely higher (45.7% versus 14.4%). An unexpected peak in TLC plates after dihydrodigoxin administration in blood, bile and urine was identified to be the sodium salt of the opened lactone structure: dihydrodigoxin acid.

[Enhanced bioavailability of digoxin from silica matrix formulations (author's transl)]. / Erhöhte Bioverfügbarkeit von Digoxin aus Kieselsäure-Matrix-Zubereitungen.

The bioavailability of digoxin from 3 silica matrix formulations was assessed in single-dose crossover studies in 12 healthy human volunteers: digoxin/silica matrix tablets (I, Digacin), digoxin/silica matrix in capsule form (II) and digoxin/silica matrix dragées, protected against gastrict juice by film coating (III). Urinary glycoside excretion for 6 days after 0.5 mg doses were measured by radioimmunoasay. Referring to an intravenous injection the bioavailability of digoxin from Digacin tablets is 82%, from the encapsulated matrix 69%, and from the dragées 54%. In comparison with corresponding results from other investigators Digacin tablets havet the same high bioavailability as digoxin solutions. In vitro liberations of digoxin from the silica matrix formulations (94% in 90 s) is significantly better than from conventional tablets produces from a digoxin-lactose trituration (61% in 90 s).

[Partition coefficients and Rm-values of cardenolides (author's transl)]. / Verteilungskoeffizienten und Rm-Werte von Cardenoliden.

Partition coefficients (P) of 48 cardenolides were determined in octanol/water. Furthermore Rm-values of most of these substances were measured in different thin-layer chromatography systems (TLC) and related to P. Regression analysis revealed that the best linear fit of the data was obtained when Rm-values from reversed-phase TLC on octanol impregnated silica-gel layer as stationary phase and methanol/water as mobile phase were correlated with log P (r = 0.91). A better correlation between these two sets of data was obtained by restricting the calculations to groups of cardenolides with similar structural features (r = 0.96-0.98). The present results are showing that Rm-values from reversed-phase TLC--a rapid and reproducible method with many advantages over the tedious measurement of P--can be used to predict P.

[Lipophilicity and enteral absorption of cardenolides (author's transl)]. / Lipophilie und enterale Resorption bei Cardenoliden.

Intestinal absorption of 15 cardenolides has been examined in cats. The 3H-labelled substances were injected intraluminally into ligated duodenal loops of anaesthetized animals. 3H-Concentrations were followed in the portal circulation and in the bile. 1 h after drug administration the duodenal sac was removed, and the residual in the lumen then was washed out and assayed radiochemically. The decrease of radioactivity during 1 h was calculated as extent of absorption (QR). Cardenolide absorption was compared with the corresponding in vitro parameters of lipophilicity like octanol/water partition coefficients and Rm values from reversed phase thin-layer chromatography. The Spearman rank sum correlation test revealed coefficients of 0.95 to 0.97. The result lends support to the use of the easily available Rm values as a good tool to predict intestinal absorption of various cardenolides.

[Synthesis and characterization of some cardenolide glucuronides and sulphates (author's transl)]. / Darstellung und Eigenschaften einiger Glukuronide und Sulfate von Cardenoliden und Cardenolid-glykosiden

Cardenolide glucuronides are synthesized in the following way: firstly cardenolide glucosides are prepared by the reaction with acetobromglucose; secondly the hydroxymethyl group of the glucose moiety is oxydized in presence of a platinum catalyst to the carboxyl group of the final glucuronic acid. Glucuronides of the following cardenolides are prepared and described: digoxin, digoxigenin, digitoxin, digitoxigenin-monodigitoxoside, digitoxigenin, and 3-epi-digitoxigenin. Sulphates of digoxigenin, digitoxigenin, and 3-epi-digitoxigenin are prepared by direct reaction of these cardenolides with chlorosulphonic acid in pyridine. The assumed structure of some conjugates has been confirmed by n.m.r. spectroscopy. A high water solubility (6.7-65.1 g/l), a minute chloroform solubility (0.0002-0.0005 g/l), and a low octanol/polar nature of these compounds. Inotropic or toxic cardiac activities of the conjugates are examined on isolated guinea pig papillary muscles and by the Hatcher method on cats. Conjugates with at least one digitoxose show cardioactivities comparable to digoxin or digitoxin. In contrast to that the conjugated genins indicate decreased activities which are at least one-tenth of the potency of the unconjugated glycosides.

[Affinity of polar digoxin and digitoxin metabolites for digoxin and digitoxin antibodies]. / Affinität von polaren Digoxin- und Digitoxin-Metaboliten zu Digoxin- und Digitoxin-Antiköpern

The affinities of some polar and non-polar digoxin and digitoxin metabolites to the related antibodies are largely dependent on the structure of their genin parts. Metabolites with unchanged genins show high cross reactivities towards their related antibodies when compared to the original immunogenic cardenolides. Towards the digoxin antibody the following cross reactivities were found: digoxin-16'-glucuronide 50%, digoxigenin 89.5%, and digoxigenin-3-glucuronide 85%. Values of the same order of magnitude were found with the corresponding digitoxin metabolites and the digitoxin antibody. In contrast, there is a marked decrease in cross reactivity caused by only minor changes in the genin part. With the digitoxin antibody the following cross reactivities are found: digoxin (i.e. 12-OH-digitoxin) 9.1%, 3-epi-digitoxigenin 5.6% and 3-epi-digitoxigenin-3-sulphate 1%. Bcause 12-hydroxylation has been reported to be one of several possible ways of digitoxin metabolisation in man, from a theoretical point of view erroneous results in the clinical digitoxin estimation by radioimmuno-assay are possible. In the case of all of the other metabolites the alterations in positive inotropic activity and cross reactivity run largely parallel.

[Fate of orally administered beta-acetyldigoxin in man (author's transl)]. / Resorptionsverhalten von oral appliziertem beta-Acetyldiogoxin beim menschen

After oral administration of 3H-beta-acetyldigoxin to four patients aspirates of gastric and duodenal contents were obtained with intestinal tubes. Concentration of label in the aspirates was measured. Radiochromatographic analysis of the aspirates showed that 90% of the beta-acetyldigoxin was unchanged during the period it was in the stomach. In the duodenum a small part of the administered dose was transformed to 3H-alpha-acetyldigoxin. When given 3H-beta acetyl-digoxin intraduodenally to three subjects in the portal vein blood 93% of the labelled compunds was 3H-digoxin. According to these data the absorption of beta-acetyldigoxin can be described as follows: After oral ingestion beta-acetyl-digoxin rapidly passes the stomach with a half-life of 10 min. Most of the glycoside is absorbed unchanged in the duodenum. On passage through the intestinal wall the acetyl group is removed and digoxin is the active drug reaching the heart.

[Concentration of cardiac glycosides in the heart and brain (author's transl)]. / Konzentration von Herzglykosiden im Myokard und im Gehirn

In cats the concentration of cardio-active glycosides in the heart and brain were investigated with trititum-labelled substances. Steady-state conditions were achieved by repeated i.v. injections of ouabain, digoxin, beta-methyldigoxin, digitoxin, and oleandrin over 5 days. 5 h after the last application glycoside concentrations were measured in plasma, urine, heart, cerebrum and cerebellum. Furthermore the metabolic pattern in these compartments was determined. 1. The glycoside concentration in the heart per g wet weight ranges only from 0.93 (oleandrin) to 1.88% (ouabain) of the daily administered dose per kg. 2. The concentrations in the brain show much higher differences between the diverse glycosides: ouabain with a concentration of 0.02%/g wet weight in the cerebrum shows the lowest and oleandrin with 1.60% the highest value. 3. By calculating the mean relative weights for the hearts (3.9 g/kg) and the brains (11.1 g/kg) 3.7% of the daily administered ouabain activity were found in the whole heart and only 0.18% in the whole brain. In contrast to these data the content of heart and brain after giving the more lipophilic oleandrin was 3.6% and 17.7% (!), respectively. 4. Under steady-state conditions the glycosides ouabain, digoxin, beta-methyldigoxin and digitoxin in heart and brain are mainly unchanged whereas oleandrin is transformed at a higher rate to polar metabolites.

[Bioavailability of beta-acetyldigoxin and digoxin (author's transl)]. / Die biologische Verfügbarkeit von beta-Acetyldigoxin und Digoxin

Five beta-acetyldigoxin and two digoxin preparations were given orally to eleven healthy volunteers. In a single dose crossover study bioavailability of the oral preparations was compared to an intravenous injection of digoxin as a standard for complete bioavailability. A mean bioavailability of 82% (sx = 1.8) was found for beta-acetyldigoxin tablets (Novodigal¿), PETN/beta-acetyldigoxin tablets (Nitro-Novodigal¿), oxyfedrin/beta-acetyldigoxin tablets (ildamen¿-Novodigal¿) and beta-acetyldigoxin liquid. Analysis of variance shows no differences in absorption for the five tested beta-acetyldigoxin preparations. Beta-Acetyldigoxin administered orally in an alcoholic solution is nearly completely absorbed (94%) whereas a corresponding digoxin solution is available to a significantly lesser content (79.2%). Comparable differences in absorption were found for beta-acetyldigoxin tablets (81%) and digoxin tablets (Digacin¿) (63.5%).