Evolution of the AMCP Format for Formulary Submissions.

DISCLOSURES: No funding was required for this project. The authors are or have been members of the Format Executive Committee.

Pharmacoeconomics of etravirine.

HIV infection, particularly multidrug-resistant HIV, continues to be a major societal and economic challenge worldwide. Etravirine, a new (US FDA approved in 2008) non-nucleoside reverse transcriptase inhibitor, has been shown to be very effective in treating patients who have failed prior antiretroviral therapy. Clinical studies demonstrated that etravirine in combination with other antiretrovirals achieved superior levels of undetectable plasma HIV RNA and CD4 cell count increases that led to reductions in risk of death and development of AIDS-defining illnesses when compared with placebo. Etravirine was also shown to be generally well tolerated, with favorable CNS and psychiatric tolerability profiles. In addition, etravirine in combination with other antiretrovirals has been shown to improve quality of life and quality-adjusted life expectancy. Economic evaluations showed that the addition of etravirine to a regimen was associated with lower costs per person with an undetectable viral load and lower hospital-related costs compared with placebo.

The economic impact of insomnia in managed care: a clearer picture emerges.

An important question for managed care organizations is whether insomnia is associated with increased consumption of healthcare resources. Even though a large number of adults complain of insomnia, few actually receive a diagnostic code for the condition. Consequently, it has been challenging to consistently measure both direct medical costs and indirect costs attributable to insomnia. Recent data have provided a clearer picture showing that insomnia is a costly medical condition. This paper summarizes current understanding of the prevalence of insomnia and explores its impact on health-related quality of life, workplace productivity, and healthcare resource utilization.

Formularies, therapeutics, and outcomes: new opportunities.

The increasing prominence of drug therapies in health care and their rapidly rising costs have led to a dramatic escalation of interest in the use of outcomes data for therapeutics and formulary decisions. The expanded use of formulary submission dossiers, effectiveness data, health outcomes analysis, and pharmacoeconomic modeling has created an urgent need for outcomes research to investigate topics especially relevant for health plan drug therapy coverage decisions. This article examines the evolving use of outcomes data on drug formulary and other therapeutic decisions, and outlines several priority areas for outcomes research. These include research into surrogate measures of long-term health and economic outcomes, evaluations of new formulary submission programs, and research on the impact of pharmaceutical cost-sharing arrangements on health outcomes. The article also discusses the importance of evaluating patient compliance and health outcomes after implementation of a Medicare prescription drug benefit, and the need for new types of clinical trials that can respond to changing demands of pharmacy and therapeutics committees and providers

Showing outcomes and proving value brings success.

Today's pharmacoeconomics have shown how critical it is to find value in formulary drug products. For Regence BlueShield, Seattle, this means outcomes; making sure a drug truly works better than well-established alternatives, not just placebos. In 1998, Regence adopted formulary submission guidelines that have proven a solid success, and have been adopted by the Academy of Managed Care Pharmacy, Alexandria, Virginia, for evaluation nationwide.

Patients' perceived benefit from and satisfaction with asthma-related pharmacy services.

OBJECTIVE: To determine whether patients targeted to receive intervention from an asthma management program reported receiving more services and had greater perceived benefit and satisfaction with those services compared with asthma patients not targeted by the program. DESIGN: Mailed survey. SETTING: Community pharmacy. PATIENTS: 471 community-based patients receiving asthma medications from 44 intervention pharmacies and 1,164 patients from 46 usual care (control) pharmacies. MAIN OUTCOME MEASURES: Five-point agreement scale measuring asthma services received, perceived value of the services, and satisfaction. RESULTS: Usable surveys were received from 39.0% of intervention patients and 42.4% of controls. There were no statistically significant differences between groups in the frequency of provision of listed services. Approximately 60% of respondents from both groups received written materials on asthma medications and 54% received inhaler counseling; both were rated high for perceived benefit. Fewer than 20% reported being counseled about asthma triggers. Fewer than 5% reported pharmacists talking to physicians on their behalf. General satisfaction with pharmacy services was high (78.2% agree or strongly agree), but not statistically different between groups. More than 65% believed that pharmacists spend enough time counseling patients. Several comments indicated that patients did not expect or ask for information because they were unaware that services were available and/or they had already been counseled by their physician. Responses to the statement "my asthma is better controlled because of help given to me by the pharmacist" were equivocal and not different between groups. CONCLUSION: Overall, there were few differences between groups. General satisfaction with pharmacy services is high, but patients' perceived benefit and satisfaction with cognitive services is lower. Increased public awareness of pharmacists' capabilities and a more proactive approach to providing cognitive services is needed.

Incorporating clinical outcomes and economic consequences into drug formulary decisions: a practical approach.

BACKGROUND: In 1994, Regence BlueShield (Regence), a large non-staff model health plan, adopted guidelines governing the review of new and existing drug products. However, certain limitations were apparent: adequate data were not available in a timely fashion; unpublished studies and information on unapproved indications were difficult to obtain; data addressing humanistic and economic outcomes were not routinely supplied by manufacturers; and the time required by Regence staff clinical pharmacists to assemble and summarize published clinical studies for the pharmacy and therapeutics (P&T) committee was excessive. OBJECTIVE: To describe the process used by Regence to collect and review clinical, economic, and other health outcomes data as part of the plan's drug formulary adoption process. PROCESS DESCRIPTION: To address these limitations, Regence revised its process to require pharmaceutical manufacturers to submit a detailed dossier with clinical and economic data from published and unpublished studies, along with a disease-based economic model projecting the potential impact that introducing the product would have on health outcomes and economic consequences occurring across the entire Regence system. After performing independent literature reviews to ensure the accuracy and comprehensiveness of the information obtained, clinical pharmacists at Regence complete a detailed summary of each drug for the P&T committee. CONCLUSION: The new process has addressed the limitations of the previous system and, by improving the timeliness and relevance of available information, it supports Regence's goal of maintaining an evidence-based formulary.

Digitalis receptor sugar binding site characteristics: a model based upon studies of Na+, K(+)-ATPase preparations with differing digitalis sensitivities.

The structure-activity relationships of the genin moieties of digitalis glycosides are commonly elucidated by determining the inhibitory potency of a variety of genins toward the plasma membrane Na+, K(+)-ATPase; qualitatively these relationships appear to be fairly independent of the specific Na+, K(+)-ATPase preparation utilized for the analysis. To determine whether this is the case with regard to the sugar moieties of glycosides, the inhibitory effects of 12 monoglycosides of digitoxigenin toward four Na+, K(+)-ATPase preparations of different origin were measured. It was found that while recognition of the major structural determinants of sugar activity appeared to be independent of enzyme source, recognition of the minor structural determinants of activity showed some source dependence. It was also observed that the intrinsic sensitivity to sugar potentiation may be source dependent and unrelated to intrinsic sensitivity to inhibition by digitoxigenin. These observations are compatible with a model of the Na+, K(+)-ATPase sugar binding site(s) in which intrinsic sensitivity to sugar attachment as well as recognition characteristics (for sugar structural features) both determine the extent to which a sugar moiety may contribute to the activity of monoglycosides. Further, in these studies one of the Na+, K(+)-ATPase preparations employed was obtained from rat brain, a tissue known to contain a mixture of ouabain sensitive and insensitive isoforms. We have observed that the rigorous purification techniques employed appear to have selectively removed from or denatured the less ouabain sensitive alpha 1 isoform found in this enzyme preparation.

Cardiac glycosides. 7. Sugar stereochemistry and cardiac glycoside activity.

Digitoxigenin alpha-L-, beta-L-, alpha-D-, and beta-D-glucosides; alpha-L-, beta-L-, alpha-D-, and beta-D-mannosides; and alpha-L- and beta-L-rhamnosides were stereoselectively synthesized from the corresponding sugar tetrabenzyl trichloroacetimidates. The Na+,K+-ATPase receptor inhibitory activities of these glycosides (as a measure of receptor binding) were compared with those of digitoxigenin, digitoxigenin 6'-hydroxy-beta-D-digitoxoside, digitoxigenin beta-D-galactoside, and digitoxigenin beta-D-digitoxoside. The observed activities reveal that a given sugar substituent may have a role in binding of some glycoside stereoisomers, but not others. With alpha-L- and possibly beta-L-rhamnosides, the 5'-CH3 and 4'-OH appear to have a predominant role in binding to the Na+,K+-ATPase receptor. Addition of a 6'-OH to form the corresponding mannosides dramatically disrupts the effect of both the 5'-CH3 and 4'-OH in prompting receptor binding of the alpha-L isomer. However, with the beta-L isomer, some influence of 4'-OH, 3'-OH, and 2'-OH binding remains. With beta-D-glycosides, binding via the "5'-CH3 site" appears to be of little importance and addition of a 6'-OH diminishes activity only slightly. With these beta-D-glycosides, an equatorial 4'-OH, axial 3'-OH, and equatorial 2'-OH groups appear to contribute to binding.

Cardiac glycosides. 6. Gitoxigenin C16 acetates, formates, methoxycarbonates, and digitoxosides. Synthesis and Na+,K+-ATPase inhibitory activities.

A series of 17 gitoxigenin 16 beta-formates, acetates, and methoxycarbonates was synthesized, including their 3 beta-acetates, formates, and digitoxosides. A 16 beta-formate group was generally found to increase activity 30 times, a 16 beta-acetate group 9-12 times, while a 16 beta-methoxycarbonate decreased activity by two-thirds. 3 beta-Formates and acetates had little effect on activity by themselves, but sometimes reduced the activity-increasing properties of 16 beta-formates and acetates. A 3 beta-digitoxoside increases the activity of gitoxigenin by 15 times, but the effect is less if the 16 beta-group is esterified. And finally, a 16-one decreases activity dramatically. These data suggest an important role for C16 esters and possibly the presence of a separate binding site on Na+,K+-ATPase corresponding to the cardenolide C16 position.

The effect of 16 beta-substitution on the structure and activity of digitoxigenin: is there an additional binding interaction with Na+,K+-ATPase?

We have studied the basis of the effect of 16 beta-substitution on the structure and activity of digitoxigenin derivatives by examining the crystal structures of these compounds and their inhibitory activity toward the receptor for these drugs, Na+,K+-ATPase. To understand the increase in inhibitory activity of the 16 beta-ester compounds and the decrease in activity of gitoxigenin (16 beta-hydroxydigitoxigenin), both with respect to digitoxigenin, we have compared the observed conformations of gitoxigenin, gitoxigenin 16 beta-formate, and other 16 beta-esters to that of digitoxigenin. Our data do not support the possibility of hydrogen bonding between the 16 beta-hydroxyl of gitoxigenin and the lactone ring, previously suggested to account for the decreased activity of gitoxigenin vis à vis digitoxigenin, but, rather, suggest that the decreased activity may be due to an intramolecular hydrogen bond between the hydroxyls on C-14 and C-16 and an unusual D-ring conformation which combine to alter the carbonyl oxygen of the lactone ring away from the putative active position. In contrast, the 16 beta-ester moiety has a preferred conformation which may serve to fix the lactone ring in the active conformation. Thus, the increased activity of the 16 beta-esters cannot be explained by altered carbonyl oxygen position and may be related to an additional receptor binding site for the ester moiety.

The inotropic activity of digitalis genins is dependent upon C(17) side-group carbonyl oxygen position.

The inotropic potencies of four digitalis genins were studied utilizing cat left atrial strips. The genin concentration required to induce a 50% increase of isometric tension (T50) was found to closely correlate with the degree of displacement (D) of the C(17) side-group carbonyl oxygen from the position of that atom in digitoxigenin. The line of regression was: log T50 = 0.54D - 6.85, r2 = 0.98, P less than 0.008. These observations were related to recently reported cat ventricular Na+, K+ -ATPase inhibitory potencies of the same genins [expressed as 50% inhibitory (I50) concentrations]. I50 correlated strongly with T50: log I50 = 0.78 log T50 - 1.68, r2 = 0.99, P less than 0.003. Thus, the activity of digitalis genins towards their receptor in intact cardiac tissue is closely related to genin carbonyl oxygen position as well as to Na+, K+ -ATPase inhibitory activity. These results further support our earlier conclusions, based upon isolated Na+, K+ -ATPase studies, that the digitalis genin C(17) side-group carbonyl oxygen position versus activity relationship is biologically relevant and may prove to be a useful unifying structural model in the further elucidation of the mechanism of digitalis-receptor interactions.

Purification of the muscarinic acetylcholine receptor from porcine atria.

The muscarinic acetylcholine receptor from porcine atria has been purified 100,000-fold to homogeneity by solubilization in digitonin/cholate and sequential chromatography on wheat germ agglutinin-agarose, diethylaminoethylagarose, hydroxylapatite, and 3-(2'-aminobenzhydryloxy)tropane-agarose. The yield of purified receptor was 4.3% of that found in the membrane fraction, and the purified receptor bound 11.1-12.8 nmol of L-[3H]quinuclidinyl benzilate per mg of protein, corresponding to a binding component Mr of 78,400-90,000. The purified receptor preparation consisted of two polypeptides in approximately equimolar amounts when examined on silver-stained sodium dodecyl sulfate/polyacrylamide gels. The larger polypeptide (Mr 78,000 on 8% polyacrylamide gels) was specifically alkylated with [3H]propylbenzilylcholine mustard, whereas the smaller polypeptide (Mr 14,800) was not labeled. The possibility that the small polypeptide is a contaminant fortuitously appearing in equimolar amounts with the large polypeptide cannot be ruled out at this time. The purified preparation was highly stable, with no measurable change in the number of ligand binding sites or the gel pattern after 1 month's storage on ice. Scatchard analysis showed a single class of binding sites for the antagonist L-[3H]quinuclidinyl benzilate with a dissociation constant of 61 +/- 4 pM. Equilibrium titration experiments demonstrated that the antagonist L-hyoscyamine displaced L-[3H]quinuclidinyl benzilate from a single class of sites (Kd = 475 +/- 30 pM), whereas the agonist carbamoylcholine interacted at two populations of sites (53% +/- 3% high affinity, Kd = 1.1 +/- 0.3 microM; 47% +/- 3% low affinity, Kd = 67 +/- 14 microM). The ligand binding data were very similar to that for the membrane-bound receptor, suggesting that the receptor has not been altered radically during purification.

Cardiac glycosides. 1. A systematic study of digitoxigenin D-glycosides.

A series of digitoxigenin glycosides was studied: five with beta-D-sugars varying stepwise in sugar structure from beta-D-digitoxose to beta-D-galactose, including one beta-D/alpha-D pair. I50 values for these glycosides and digitoxigenin were determined with hog kidney Na+, K+-ATPase. These data suggest a major and unexpected role for 4'-OH conformation in the sugar. All the glycosides with an equatorial 4'-OH were more active than the two with the 4'-OH axial [digitoxigenin beta-D-galactoside (6) I50 = 6.45 X 10(-8) M; digitoxigenin 2'-deoxy-alpha-D-ribo-hexopyranoside (alpha-3a) I50 = 9.33 X 10(-8) M; digitoxigenin I50 = 1.17 X 10(-7) M]. Stereochemistry of the 3'-OH had much less of an activity role than that of the 4'-OH, in contrast to existing models of "sugar-site" binding.

Photoaffinity labeling of the sodium- and potassium-activated adenosinetriphosphatase with a cardiac glycoside containing the photoactive group on the C-17 side chain.

The synthesis and properties of a radiolabeled glycoside photoaffinity probe, [3H]-(3 beta,5 beta,14 beta, 20E)-24-azido-3-[(2,6-dideoxy-beta-D-ribo-hexopyranosyl) oxy]-14-hydroxy-21-norchol-20(22)-en-23-one, containing the photoactive group at the C-17 side chain of the steroid moiety are reported. The molecule binds to the sodium- and potassium-activated adenosinetriphosphatase from porcine kidney outer medulla under type II binding conditions [5 mM MgCl2, 3 mM phosphate, 2 mM ethylenediaminetetraacetic acid, 30 mM tris(hydroxymethyl)aminomethane, pH 7.2, 37 degrees C] in the dark with an equilibrium dissociation constant of (1.4 +/- 0.3) X 10(-7) M. Ultraviolet irradiation of a solution of enzyme plus 3H-labeled probe, followed by analysis of covalently incorporated radiolabel, shows ouabain-displaceable labeling exclusively of the alpha subunit of the sodium- and potassium-activated adenosinetriphosphatase. These data indicate that the binding site of the C-17 side group of cardiac glycosides is located on or near the alpha subunit of this enzyme.

Cardiac glycosides: 2. Synthesis of glucose and galactose analogs.

Five cardioactive steroid genins 1a to 5a of widely varying C17 beta-side groups were converted by modified Koenigs-Knorr reactions into the corresponding beta-D-glucosides 1c to 5c and beta-D-galactosides 1e to 5e. The genins included digitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta-card-20-(22)-enolide, 1a); (20R)-20, 22-dihydrodigitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta, 20R-cardanolde, 2a); 3 beta, 14-dihydroxy-22-methylene-5 beta, 14 beta, 20S-cardanolide (3a); methyl 3 beta, 14-dihydroxy-5 beta, 14 beta-pregn-20(E)-ene-21-carboxylate (4a); and methyl 3 beta, 14-dihydroxy-21-methylene-5 beta, 14 beta-pregnane-21-carboxylate (5a).

Interaction of (Na+,K+)-ATPases and digitalis genins. A general model for inhibitory activity.

Previous models of digitalis genin interaction with the (Na+,K+)-ATPase system (the putative receptor for such drugs) were deficient in explaining the (Na+,K+)-ATPase inhibitory activity of a number of digitalis genin analogues. With rat brain (Na+,K+)-ATPase we observed that the C-17 side chain carbonyl (C = O) oxygen distance of a given genin in relation to its position in the reference compound digitoxigenin was the primary determinant of its biological activity. With a number of genin analogues, we observed a strict correlation of this structural parameter with its binding site compatibility as well as inhibitory potency with respect to the (Na+,K+)-ATPase. In every case the correlation to inhibition data was obtained using a minimum energy conformation for the genin structure. The general applicability of that model is now proposed based on the following observations. The carbonyl oxygen position versus the biological activity relationship fully holds with (Na+,K+)-ATPase preparations from other tissues and species and also when different binding conditions are used for the enzyme genin interaction. The relationship is equally valid for the K+-p-nitrophenyl phosphatase activity. Correlations of the data obtained under these various conditions provide further support for this relationship and for the concept that altered affinities of the enzyme for a given genin under different binding conditions reflect conformational variations of a single binding site.

Is the erythrocyte sodium pump altered in human obesity?

Ouabain binding and electrolyte concentrations of erythrocytes, and Na+, K+-ATPase activity of red cell ghosts were measured in normal and obese subjects, ranging from 88-257% of their ideal body weight. All three independent measurements were virtually the same in obese and nonobese groups, and no correlations were found between these three variables and the percentage of ideal body weight. These results differ from previous reports of either increased or decreased sodium pump function and suggest that Na+, K+-ATPase does not directly influence human obesity.