Performance status of health care facilities changes with risk adjustment of HbA1c.

OBJECTIVE: To develop a risk adjustment method for HbA1c, based solely on administrative data and to determine the extent to which risk-adjusted HbA1c changes the identification of high- or low-performing medical facilities. RESEARCH DESIGN AND METHODS: Through use of pharmacy records, 204,472 diabetic patients were identified for federal fiscal year 1996 (FY96). Complete information (HbA1c levels, demographic data, inpatient records, outpatient pharmacy utilization records) was available on 38,173 predominantly male patients from 48 Veterans Health Administration (VHA) medical facilities. Hierarchical mixed-effects models were used to estimate risk-adjusted unique facility-level HbA1c. RESULTS: Predicted HbA1c demonstrated expected patterns for major factors known to influence glycemic control. Poorer glycemic control was seen in minorities and patients with greater disease severity, longer duration of disease (using treatment type or presence of amputation as surrogates), and more extensive comorbidity (measured by an adapted Charlson index). Better glycemic control was seen in Caucasians, older diabetic patients, and patients with higher outpatient utilization. The number of performance outliers was reduced as a result of risk adjustment. For mean HbA1c levels, 7 facilities that were initially identified as statistically significant outliers were no longer outliers after risk adjustment. For high-risk HbA1c (>9.5%) rates, 12 facilities that were initially identified as statistically significant outliers were no longer outliers after risk adjustment. CONCLUSIONS: Risk adjustment using only administrative data resulted in substantial changes in identification of high or low performers compared with non-risk-adjusted HbA1c. Although our findings are exploratory, risk adjustment using administrative data may be a necessary and achievable step in quality assessment of diabetes care measured by rates of high-risk HbA1c (>9.5%).

Diabetes prevalence and hospital and pharmacy use in the Veterans Health Administration (1994). Use of an ambulatory care pharmacy-derived database.

OBJECTIVE: To develop a diabetes registry from an outpatient pharmacy database to systematically analyze the prevalence of diabetes, patterns of glycemic medication and glucose monitoring, pharmacy costs, and hospital use related to diabetes care in the Veterans Health Administration (VHA) in fiscal year (FY) 1994. RESEARCH DESIGN AND METHODS: Veterans with diabetes were identified using a software program that extracted the social security number (SSN) of patients receiving insulin, sulfonylurea agents, or glucose-monitoring supplies. The cumulative FY94 cost for a drug was calculated by multiplying the units dispensed times the unit cost for each fill, using the actual drug cost that was in effect at the time of dispensing. Admission data were obtained by crossmatching the SSN registry with the VHA Austin Mainframe Patient Treatment Files to retrieve associated diagnosis-related groups (DRG), Physicians' Current Procedural Terminology (CPT), and International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes. RESULTS: From among 1,180,260 unique patients, 139,646 veterans with diabetes receiving insulin, oral agents, or glucose-monitoring strips were identified, accounting for a prevalence of 11.83% from 62 Veterans Administration medical centers. There were 63,078 individuals (52%) who received oral agents, of whom 26.3% also received blood glucose-monitoring supplies; 46,664 individuals (39%) received insulin, of whom 53.2% received blood glucose-monitoring supplies; and 9,440 individuals (8%) received both oral agents and insulin during FY94, with 64.4% receiving blood glucose-monitoring supplies. Only 1,482 (1.2%) individuals received monitoring supplies alone, and 129 patients (0.1%) were provided with an insulin pump. Using an adjusted data set, 12% of veterans accounted for 24% of all outpatient pharmacy costs, with an average expenditure of $622 for veterans with diabetes compared with $276 for veterans without diabetes. There was $454 (73%) for non-diabetes-specific prescriptions and $168 (27%) for prescriptions related to glycemic control. Of pharmacy expenditures for glycemic control, $101 (60.1%) was attributed to insulin, oral agents, and supplies, while $67 (39.9%) was attributable to glucose monitoring. Veterans with diabetes were admitted 1.6 times as frequently as veterans without diabetes. CONCLUSIONS: This study demonstrates the feasibility of using a pharmacy-based electronic diabetes database in a payor system that can track both claims and individual classes of medication based on a unique identifier number. While the prevalence of diabetes in the VHA is high relative to other health care systems and the general population, patterns of medication usage, pharmacy costs, and relative admission frequency are comparable to results from the private sector.

N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.

Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.

Transport rate limited catalysis on macroscopic surfaces: the activation of factor X in a continuous flow enzyme reactor.

Blood coagulation is initiated on cells which present a macroscopic surface to the flowing blood stream. We have used a continuous flow enzyme reactor to model this system and to investigate the effects of shear rate and mass transport on the activation of factor X by the complex of the transmembrane protein, tissue factor, and the serine protease, factor VIIa. This initial step of blood coagulation was found to be half-maximal at very low enzyme densities (0.03-0.06%) on the wall of the capillaries. In agreement with hydrodynamic theory, the apparent Km in the flow reactor was correlated with the cube root of the wall shear rate. These data indicate that at high tissue factor densities (> 0.6%) the activation of 150 nM factor X is controlled by the flux of X toward the surface, which is controlled by wall shear rate and substrate concentration. The appearance of the product, Xa, in the effluent was delayed to 8-12 min, which was caused by high-affinity binding of Xa to the phospholipid. This delay was considerably shortened by embedding tissue factor into PC or by coating the PS/PC surface with the phospholipid binding protein, annexin V. At low tissue factor densities, annexin V inhibited X activation by 45%, while no inhibition was observed at high densities. We demonstrate that when the reaction is limited by substrate flux, addition of further enzyme does not increase reaction rates. This contrasts with classical three-dimensional catalysis in which the initial velocity is ordinarily linear with the enzyme concentration.

2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists.

Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

Structure-affinity relationships of 12-sulfonyl derivatives of 5,8,8a,9,10,11,12,12a,13,13a-decahydro-6H-isoquino[2,1-g][1 ,6] naphthyridines at alpha-adrenoceptors.

Analogues of the potent alpha 2-adrenoceptor antagonist (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a- decahydro-3-methoxy-12-(methylsulfonyl)- 6H-isoquino[2,1-g][1,6]naphthyridine (1b) were prepared and evaluated for alpha 1- and alpha 2-adrenoceptor affinity. Affinity for alpha 2-adrenoceptors was assessed by displacement of [3H]yohimbine from rat cerebral cortical membranes and although 1b and close structural analogues demonstrated high affinity, none were selective for the alpha 2A or alpha 2B subtypes reputedly present in this tissue. All of the high affinity alpha 2-adrenoceptor ligands were, however, selective with respect to [3H]prazosin (alpha 1) binding. Affinity for [3H]yohimbine-labeled alpha 2-adrenoceptors was found to be highly dependent on the stereochemistry of the tetracyclic system. The 8a beta,12a alpha,13a alpha diastereomer of 1 (56) had moderate affinity for alpha 2-adrenoceptors while the 8a beta,12a beta,13a alpha diastereomer (55) had very low affinity. The affinity and selectivity of these agents for alpha 2-adrenoceptors was found to correspond to that observed for several isomeric yohimbine analogues which have similar relative and absolute stereochemistries. Deviation from the structure of 1 by opening the B ring, changing the position of the sulfonamide nitrogen, or changing the attachment of the D ring led to a dramatic decrease in alpha 2-adrenoceptor affinity. High binding affinity was found to correlate with functional antagonism in the guinea pig ileum. The reversal of clonidine-induced mydriasis in the rat was used to assess bioavailability and indicated that 1b was a potent alpha 2-adrenoceptor antagonist in vivo.

Hemophilia as a defect of the tissue factor pathway of blood coagulation: effect of factors VIII and IX on factor X activation in a continuous-flow reactor.

The effect of factors VIII and IX on the ability of the tissue factor-factor VIIa complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIIa, VIII, IX, and X flowing at a shear rate of 57, 300, or 1130 sec-1. Factor Xa in the effluent was determined by chromogenic assay. The flux of factor Xa (moles formed per unit surface area per unit time) was strongly dependent on wall shear rate, increasing about 3-fold as wall shear rate increased from 57 to 1130 sec-1. The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2- to 3-fold increase. The direct activation of factor X by tissue factor-factor VIIa could be virtually eliminated by the lipoprotein-associated coagulation inhibitor; however, when factors VIII and IX were present at their approximate plasma concentrations, factor Xa production rates were enhanced 15- to 20-fold. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia.

Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes.

Affinities of drugs for 21 indolealkylamine derivatives, some with putative hallucinogenic activity, were determined at 5-HT1A, 5-HT2A and 5-HT2B recognition sites, using radioligand competition studies. Nearly all of the derivatives displayed greatest potency for the 5-HT2A receptor, labelled by [125I]R-(-)DOI in the cortex of the rat. Most derivatives displayed 2-10 times lower affinity at the HT2B receptor labelled by [3H]ketanserin in bovine cortex. Derivatives lacking ring substituents displayed lower affinities for all of the recognition sites, compared to derivatives substituted in the 4- or 5-position of the indole ring. The 4-hydroxylated derivatives displayed 25-380-fold selectivity for the 5-HT2A site, vs the 5-HT1A site, while the 5-substituted derivatives displayed approximately equal potency at the 5-HT1A and 5-HT2A sites. Affinity of all the compounds at the 5-HT2B site was greater than 300 nM. The 6-substituted derivatives displayed greater than micromolar affinities for all of the 5-HT recognition sites examined. The size of the N,N-dialkyl substituent was a secondary determinant of affinity, with groups larger than N,N-diisopropyl resulting in a marked reduction in affinity at both the 5-HT2A and 5-HT1A recognition sites. This study demonstrated that hallucinogenic 4-hydroxy-indolealkylamines, like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT2A recognition site, labelled by [125I]R-(-)DOI. This provides further evidence indicating that this recently described subtype of the 5-HT2 receptor may partially mediate the action of hallucinogenic agents.

In vitro study of the aromatic hydroxylation of 1-methyltetrahydro-beta-carboline (methtryptoline) in rat.

The incubation of 1-methyltetrahydro-beta-carboline (1-MeTHBC) with hepatocytes isolated from 3-methylcholanthrene-treated rats led to formation of the 5-, 6- and 7-hydroxylated products. The hydroxylating activity was associated with the microsomal fraction as indicated by testing different subcellular fractions. The highest activity for hydroxylating 1-MeTHBC was found in liver which was about ten times as active as lung. Only a trace amount of hydroxylating activity was present in brain and kidney tissue. Analysis using chiral gas chromatography revealed an unequal abundance of enantiomers in all three products. The formation of the 5-, 6- and 7-hydroxylated products was confirmed in vivo by analysis of 24 h urine samples after intraperitoneal administration of 1-MeTHBC to 3-methylcholanthrene-treated rats.

Antihypertensive 1-acyl-4-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethylamino]pip eridines.

Several 1-acyl-4-[2-(1,4-benzodioxan-2-yl)-2-hydroxy-ethylamino]piperidine s were prepared and a number of the compounds showed antihypertensive activity in the spontaneously hypertensive rat (SHR). This activity was specific for the (2S, 2R) enantiomers. General pharmacological evaluation and ligand binding data on selected compounds indicated a moderate degree of alpha 1- and beta-antagonistic activity. The alpha 1 antagonism was probably not of sufficient magnitude to explain the blood pressure lowering activity in the SHR.

6-Hydroxymethtryptoline is naturally occurring in mammalian urine: identification by combined chiral capillary gas chromatography and high resolution mass spectrometry.

The tricyclic indole derivative 6-hydroxymethtryptoline (7-hydroxy-1-methyltetrahydro-beta-carboline) was identified as a normal constituent of human and cat urine. The identification was based on the correct retention time on a chiral capillary gas chromatographic column and on selected ion monitoring of the molecular ion with the mass spectrometer set at high resolving power (RP 10,000). The quantitation utilized a 13C-labeled analog as internal standard and demonstrated levels of 135 +/- 35 and 174 +/- 42 (pmol ml-1, mean +/- SEM) for the S(-) and R(+) enantiomers, respectively, in human urine. In cat urine, the levels were 203 +/- 55 and 108 +/- 44 (pmol ml-1, mean +/- SEM) for the S(-) and R(+) enantiomers, respectively. In human urine, the compound occurred predominantly in a conjugated form while in cat urine the free compound predominated. It was concluded that 6-hydroxymethtryptoline is naturally occurring in mammalian urine and that it most likely constitutes a metabolite of endogenous methtryptoline (1-methyltetrahydro-beta-carboline).

Rapid hydroxylation of methtryptoline (1-methyltetrahydro-beta-carboline) in rat: identification of metabolites by chiral gas chromatography-mass spectrometry.

Racemic methtryptoline (1-methyltetrahydro-beta-carboline) and 5-hydroxymethtryptoline-9-carboxylic acid (6-hydroxy-1-methyltetrahydro-beta-carboline-1-carboxylic acid) were administered intraperitoneally to rats and the components of their urine was subsequently investigated by chiral gas chromatography-mass spectrometry. Methtryptoline rapidly became hydroxylated in the 5- and 6-position and excreted in urine. There was about a ninefold predominance of the S(-) enantiomer over the other in the 5-hydroxylated species, while the 6-hydroxylation produced a small excess of the R(+) enantiomer. About 75% of the injected dose of methtryptoline was recovered in the urine as 5- and 6-hydroxylated compounds during the first 24 h period, demonstrating that hydroxylation represents the major metabolic pathway. Treatment with 6-hydroxymethtryptoline-9-carboxylic acid led to a fivefold increase in the urinary excretion of 5-hydroxymethtryptoline during the first 24 h period with a predominance of the S(-)-enantiomer, indicating a much smaller conversion rate than from methtryptoline. It was concluded that hydroxylation of methtryptoline is a likely pathway for the natural formation of 5-hydroxymethtryptoline.

Antihypertensive aminotetralins related to labetalol and medroxalol.

A series of compounds was prepared in which the 1-methyl-3-phenylpropylamino moieties of the antihypertensive agents labetalol and medroxalol were replaced by 2-aminotetralins. Compounds containing a 6-methoxy and 6,7-methylenedioxy group in the aminotetralin were at least as active as labetalol in lowering the blood pressure of the spontaneously hypertensive rat (SHR). As determined by ligand binding, these compounds were comparable to labetalol as alpha 1-antagonists but were substantially weaker beta 1-antagonists.

Tissue factor accelerates the activation of coagulation factor VII: the role of a bifunctional coagulation cofactor.

One way in which coagulation may be initiated is via the tissue factor pathway in which a non-proteolytic enzyme activator, tissue factor, complexes with a plasma protein, factor VII. Factor VII is the zymogen of a serine protease, factor VIIa. While factor VII-tissue factor has coagulant activity, upon conversion to factor VIIa the activity increases about 120-fold. We now show that tissue factor markedly accelerates the conversion of factor VII to factor VIIa. Thus, this essential coagulation cofactor is clearly bifunctional.

Psychotomimetic N-methyl-N-isopropyltryptamines. Effects of variation of aromatic oxygen substituents.

Eight N-methyl-N-isopropyltryptamines (MIPTs) possessing various aromatic oxygen substituents were prepared, characterized, and evaluated for hallucinogenic activity in man. In at least two instances (the Ar H and the Ar 5-OCH3, 1 and 4) the unsymmetrical nitrogen substitution led to a substantial increase in potency as well as oral activity when compared to the symmetrical dimethyl homologues. Qualitatively, 4-hydroxy-N-methyl-N-isopropyltryptamine (2) was the most interesting in overall effect, producing a classic hallucinogenic profile. The 5-methoxy congener 4 resulted in a state characterized by heightened conceptual stimulation lacking in visual phenomena. Other members of the series exhibited diminished effects.

Syntheses and hypotensive properties of substituted 2-aminotetralins.

The synthesis and activity in the spontaneously hypertensive rat of several 4-(1,2,3,4-tetrahydronaphthyl-2-amino)-1-(4-fluorophenyl)-1-but anones is reported. Maximal antihypertensive activity was associated with 5,6-dimethoxy substitution in the aminotetralin moiety.

Antihypertensive 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones.

Forty-one 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones were prepared for antihypertensive screening in the spontaneously hypertensive rat (SHR). For the 9-(2-indol-3-ylethyl) series, the parent compound, 9-(2-indol-3-ylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (21), was the most potent antihypertensive agent. Substitution of lower alkyl groups on the spirolactam ring gave compounds close in activity to 21, while substitution with large alkyl or aryl groups led to a significant decrease in activity. Ring-opened analogues of 21 that contained the same functionality were markedly less active. Several 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones substituted at the 9 position with 1,4-benzodioxan-2-ylmethyl, 1,4-benzodioxan-2-ylhydroxyethyl, and 2-phenylethyl groups also demonstrated significant activity. Compound 21 was chosen for a detailed pharmacological evaluation. Its antihypertensive activity appears to be predominantly due to peripheral alpha 1-adrenoceptor blockade.

Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones.

A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.