The year's new drugs and biologics--2007.

This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2007, 30 new medicines--this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents--reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for 45% of the new medicines launched in 2007. Several new features were introduced last year, and have been maintained due to a high level of interest from readers: a deeper insight into the three first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an analysis of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life span of medicines; and an analysis of the market for these new medicines. We also provide a brief glimpse at selected drugs and biologics which could reach their first markets in the foreseeable future.

The year's new drugs and biologics--2006.

This annual series presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2006, 41 new medicines--this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents and, for the first time this year, an important new herbal medicine--reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for more than 20 of the new medicines launched in 2006. This year's edition of the article also includes several new features: a deeper insight into the five first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an analysis of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines; and an analysis of the market for these new medicines. New generic drug approvals are also reviewed, as well as a brief glimpse at selected drugs and biologics which could reach their first markets in the foreseeable future.

Chronicles in drug discovery.

Chronicles in Drug Discovery is a series of brief reports on timely topics in the field of drug R&D. This month's chronicles contain the following reports: Targeting DNA repair enzymes instead of viral proteins provides a great advantage in preventing the emergence of resistant mutants. A striking increase in therapeutic approaches for the treatment of IBD has been fueled by an improved understanding of the mechanisms that underlie its pathophysiology. Peptide deformylase inhibitors are under active investigation for bacterial infections and cancer treatment. Dopamine D3 receptors present an attractive target for alcoholism therapy since they are involved in the mechanisms of alcohol dependency and abuse.

Chronicles in drug discovery.

New brief reports this month include: Strategies for Duchenne Muscular Dystrophy: Various approaches are being explored to abate the dystrophic process including cellular therapies (transplanting stem cells or myogenic precursors into muscles), molecular approaches (delivering a functional or correcting the mutant dystrophin gene), such as MyoDys, Biostrophin(R) and antisense technology, and pharmacotherapeutics, which include calcium channel blockers, calpain inhibitors, phosphodiesterase inhibitors and monoclonal antibodies; Immunotherapy for Multiple Myeloma: Increasing numbers of antibodies and immunoconjugates with anticancer drugs are entering clinical development; Acute respiratory distress syndrome is among the most frequent reasons for intensive care. Current medications include antibiotics, diuretics, drugs to counteract low blood pressure caused by shock, anxiolytics and antiinflammatories, while there are eight potential drugs in active development; Pulmonary Hypertension: Drugs intervening at four signaling pathways (endothelin, prostacyclin, nitric oxide and platelet-derived growth factor), which are implicated in pulmonary hypertension, include readily available bosentan, sildenafil citrate and sitaxsentan sodium and investigational aviptadil and TBC-3711, among others.

Concentrates containing factor IX could improve haemostasis under conditions of thrombocytopenia: studies in an in vitro model.

BACKGROUND AND OBJECTIVES: We explored the effect on haemostasis of different factor IX (FIX) concentrates under thrombocytopenic conditions using an in vitro perfusion technique. MATERIALS AND METHODS: A moderate experimental thrombocytopenia (25 000-30 000 platelets/microl) was induced by means of a filtration procedure in blood anticoagulated with low-molecular-weight heparin. The effects of three different FIX concentrates - a prothrombin complex concentrate (PCC), an intermediate-purity concentrate (FIX/X), and a high-purity concentrate (HPFIX) - on platelet deposition and fibrin formation on subendothelium were assessed at two different shear rates (600/second and 1200/second). Activation of the coagulation system was monitored through assessment of prothrombin activation fragment 1 + 2 (F1 + 2). RESULTS: Fibrin deposition increased after addition of FIX concentrates, but only showed a significant increase in experiments performed after incubation of PCC at the lower shear rate (600/second) (64.25 +/- 9.61% vs. control 31.22 +/- 8.02%; P < 0.05). Addition of FIX concentrates caused a small increase in the percentage of platelet deposition and area of those aggregates. These differences reached levels of statistical significance in the presence of FIX/X and HPFIX in experiments performed at a shear rate of 600/second. F1 + 2 baseline values in anticoagulated thrombocytopenic blood were 1.15 +/- 0.13 nm and reached levels of 2.49 +/- 0.24 and 3.60 +/- 0.33 nm at shear rates of 600 and 1200/second, respectively. Increments in F1 + 2 observed after addition of different FIX concentrates always remained in the previous ranges. CONCLUSIONS: Data from the present study provide experimental support favouring the concept that FIX concentrates containing other activated factors could improve haemostasis under conditions of moderate thrombocytopenia.

Prohemorrhagic potential of dipyrone, ibuprofen, ketorolac, and aspirin: mechanisms associated with blood flow and erythrocyte deformability.

Dipyrone, ibuprofen, ketorolac, and aspirin were tested in a well-defined perfusion system (shear rates: 300/s, 800/s, and 1,800/s). Whole blood samples were treated with the drugs at analgesic doses and platelet interaction with damaged subendothelium was measured. All the drugs fully inhibited platelet cyclooxygenase, as assessed by classic aggregometry. Perfusion studies showed that there was a general tendency to reduce the percentage of large aggregates (thrombus; %T), to increase the percentage of adhered platelets (adhesion; %A), and to reduce the height of thrombi with respect to control. Aspirin significantly increased %A and reduced %T at all shear rates tested, whereas dipyrone had the same effect at 800/s, and ketorolac and ibuprofen at 1,800/s. In addition, aspirin significantly reduced erythrocyte deformability with respect to the other drugs. In conclusion, under our experimental conditions, aspirin showed the most remarkable effects on platelet function, closely followed by dipyrone. The effects of ketorolac were moderate, whereas ibuprofen had a minor impact on platelet function.

Effect of anticoagulants on activation of polymorphonuclear leukocytes induced by shear stress.

We analyzed how actin polymerization, CD11b expression and homotypic aggregation could be used as markers to study leukocyte activation. Leukocytes were obtained from blood anticoagulated with: citrate, unfractioned heparin (UH) and low molecular weight heparin (LMWH). Flow cytometry was used to study actin polymerization and expression of CD11b after leukocyte exposure to shear stress. Leukocyte aggregation was microscopically assessed. Shear increased both actin polymerization and expression of CD11b in citrated blood (100.1±7.1 vs. 85.8±8.5 p< 0.05 and 53.5±3.5 vs. 20.7±5.1; p< 0.005 respectively). These parameters remained unmodified in UH samples. Using both anticoagulants together, we observed increase in CD11b expression induced by shear stress (59.3±2.1 vs. 25.1±11.0; p< 0,05). LMWH samples showed higher basal levels of actin polymerization and CD11b expression than citrated samples (237±40.8, vs. 85.8±8.5 p< 0.05 and 47.8±2.6, vs. 20.7±5.1; p< 0.005) but no changes induced by shear were observed. When LMWH was used in combination with citrate we observed a decrease in basal activation and significant modifications in CD11b expression induced by shear stress (80.0±4.1 vs. 50.4±2.7). Leukocyte aggregation was modified by UH at basal levels and by LMWH after shear stress. These results indicate that exposure to shear stress results in leukocyte activation. The choice of anticoagulant is a crucial factor in studies of leukocyte function.

Comparison of the effects of human erythrocyte ghosts and intact erythrocytes on platelet interactions with subendothelium in flowing blood.

We investigated whether ghosts behaved similarly to intact erythrocytes to maintain regular primary hemostasis under flow conditions. To this end we performed perfusion experiments with whole blood in which erythrocytes were replaced by pink ghosts, and platelet interaction with the subendothelial surface of a damaged vessel was morphometrically evaluated. The same objective was sought by means of studies with a platelet function analyzer (PFA-100(TM) instrument). Perfusions performed with control blood reconstituted with intact erythrocytes gave rise to 0.4+/-0.2% contact but not spread platelets, 10.8+/-3.4% adhering and spread platelets, 16.3+/-4.6% platelets in thrombi, with 27.5+/-7.4% of the surface covered. Even though the average diameter of the ghosts was smaller than that of intact erythrocytes (5.3 microm vs. 7.7 microm), the values obtained in perfusions performed with ghosts were similar to those of the erythrocyte controls. Studies performed with the PFA-100(TM) analyzer were consistent with those observed in perfusion studies. The viscosity of control blood was compared with that of blood reconstituted with ghosts. At shear rates lower than 450 s(-1), the viscosity of the ghost samples was higher than that of the controls, but the difference progressively decreased as shear rate increased up to 750 s(-1) (3.61+/-0.15 and 3.71+/-0.17 cP, respectively). In conclusion, the results of our study showed that ghosts behaved similarly to intact erythrocytes in maintaining a normal platelet interaction with digested subendothelium, under conditions of moderate shear rate and constant hematocrit (40%). The rheological activity of ghosts, bodies that are metabolically less active, was sufficient for them to satisfactorily act as substitutes for intact erythrocytes in our system.

Infusible platelet membranes improve hemostasis in thrombocytopenic blood: experimental studies under flow conditions.

BACKGROUND: The potential hemostatic effect of infusible platelet membranes (IPM; Cyplex, Cypress Bioscience) prepared from outdated human platelets is investigated. STUDY DESIGN AND METHODS: Increasing concentrations of IPM were added to blood samples anticoagulated with low-molecular-weight heparin, in which platelets and WBC counts had been experimentally reduced by a filtration procedure. Thrombocytopenic blood with IPM was circulated in a perfusion chamber at various shear rates (300, 600, and 1200/sec(-1)), and platelet and fibrin deposition on the surface of a damaged vessel was measured. Prothrombin fragments 1 and 2 (F1+2) levels were also monitored. RESULTS: Under conditions of severe thrombocytopenia (<6000 platelets/microL) IPM did not increase platelet deposition. However, a dose-dependent increase in fibrin deposition was observed with concentrations of IPM ranging from 0.5 to 2 mg per kg in perfusions at 300 and 600 per sec(-1) (p<0.05 vs. thrombocytopenic blood). Experimental studies performed under conditions of moderate thrombocytopenia and higher shear rates (25, 000-30,000 platelets/microL; at 600 and 1200/sec(-1)) showed that IPM concentrations equivalent to 0.5 or 1 mg per kg improved fibrin deposition (33.5 +/- 9.5% and 37.7 +/- 12.8%, respectively, vs. 22.7 +/- 5.2% in controls) and also promoted a moderate increase in platelet deposition, with a concomitant significant increase in the size of platelet aggregates (p<0.05). Exposure of thrombocytopenic blood to a damaged vessel resulted in an increase of F1+2 levels from 0.8 +/- 0.15 to 1.7 +/- 0.22 nM at 300 per sec(-1) and 1.94 +/- 0.46 nM at 600 per sec(-1). Postperfusion levels of F1+2 after the addition of IPM were always similar to levels in untreated controls. CONCLUSION: IPM promotes local procoagulant activity at sites of vascular damage under conditions of severe and moderate thrombocytopenia. IPM also appears to facilitate platelet cohesive functions under conditions of moderate thrombocytopenia.

Bringing decision support to nurse managers.

Modern hospital nursing management requires timely and accurate information to allow nurse managers to adjust resources to patient requirements. We report an experience using production theory to provide the framework for the development of Decision Support Objects: graphic displays of nursing hours budgeted, scheduled, and worked within institution-specific control limits. Every month, nurse managers follow an analytic algorithm to understand nursing resources and trends on their units. Exception reporting closes the accountability loop. The essentials of education for nurse managers include skill training in the use of the decision-support tools and supportive lecture/seminars for understanding the managerial implications of using them.

Antiplatelet effects of sodium nitroprusside in flowing human blood: studies under normoxic and hypoxic conditions.

We explored the ability of sodium nitroprusside to modify adhesive and cohesive function of platelets in flowing blood, under normoxic and hypoxic conditions. Aliquots of both untreated and sodium nitroprusside-treated blood were prepared for studies of: (1) platelet aggregation in plasma; (2) erythrocyte deformability; (3) platelet interaction with damaged subendothelium, by using a well-defined perfusion system; and (4) blood gasometry in the perfused samples. Results showed that sodium nitroprusside-treated blood always showed a totally inhibited arachidonic acid-induced platelet aggregation in plasma, as well as significantly increased erythrocyte deformability (0.44+/-0.09 up to 0.66+/-0.05; p<0.05). However, treatment with sodium nitroprusside did not modify the pattern of platelet interaction with subendothelium (percentage of contact, adhesion, thrombus, and covered surface) with respect to untreated blood, under any of the shear rates used (300, 800, and 1800 seconds(-1)), although it significantly reduced the height of thrombi (9.8+/-0.4 vs. 8.3+/-0.4 microm; p<0.05). Hypoxic conditions did not have a noticeable effect in modifying antiplatelet effects of sodium nitroprusside. Additionally, the presence of sodium nitroprusside impaired the normal oxygenation of the blood during perfusion. pO2 in control untreated samples rose from 40.3+/-5.0 mm Hg perfusions to 100.4+/-12.5 mm Hg but remained at 66.3+/-6.3 mm Hg in sodium nitroprusside-treated blood (p<0.05). Our results did not show a significant effect of sodium nitroprusside in the modulation of platelet interaction with subendothelium. The marginal reduction in the thrombi height could be related to rheological interference of increased erythrocyte deformability.

Assessment of potential thrombogenicity of coagulation factor IX concentrates in an in vitro model of human thrombogenesis.

We have investigated the potential use of perfusion techniques in the evaluation of the thrombogenic profile of factor IX concentrates. Blood from healthy donors was anticoagulated with low molecular weight heparin and incubated with one of the following: (a) diluent (DIL); (b) a prothrombin complex concentrate (PCC); (c) an intermediate-purity concentrate (FIX/X); or (d) a high-purity concentrate (HPFIX). The thrombogenic potential was assessed as: (1) fibrin formation on subendothelium (Baumgartner's perfusion) and (2) prothrombin activation fragment 1+2 (F1+2, nM) determination. The percentage of fibrin deposition on the subendothelium was only significantly increased after incubation with PCC (62.0+/-3.6% vs. DIL 35.0+/-6.1%;p<0.05). None of the FIX concentrates modified platelet interaction versus control blood (DIL: 26.7+/-2.1%). F1+2 baseline values in anticoagulated blood were 0.6+/-0.1 nM. Preperfusion levels of F1+2 reached values of 4.4+/-0.1 nM for PCC and 5.4+/-0.1 nM for FIX/X. After perfusion, F1+2 values were 2.7+/-0.2 nM for DIL, 5.6+/-0.1 nM for PCC and FIX/X, and 3.3+/-0.2 nM for HPFIX. While measurement of F1+2 was influenced by residual contaminants present in the concentrates, the morphometric evaluation of fibrin deposition on perfused vascular surfaces could be more closely related to the net thrombogenic profile of each FIX preparation.

Impaired antiplatelet effects of aspirin associated with hypoxia and ATP release from erythrocytes. Studies in a system with flowing human blood.

BACKGROUND: We have explored how hypoxic conditions may affect the antiplatelet effects of aspirin. MATERIALS AND METHODS: For this purpose, a perfusion system containing a damaged vessel segment was modified in order to induce hypoxia (low Po2) in flowing blood. Blood samples were incubated with 50 mumol L-1 aspirin and divided into two aliquots, one being perfused under standard conditions (normoxic) and the other under hypoxic conditions. The interaction of platelets with the subendothelium was morphometrically evaluated. RESULTS: In studies with untreated blood under normoxic conditions, platelet interaction with the subendothelium was 0.3 +/- 0.1% of contact, 5.3 +/- 1.6% of adhesion, 24.3 +/- 3.3% of thrombus and 29.9 +/- 2.7% of total covered surface. Aspirin-treated blood perfused under normoxic conditions showed a marked decrease in thrombus with a concomitant increase in both platelet adhesion and covered surface percentages. However, when aspirin-treated blood was perfused under hypoxic conditions, platelet interaction was not significantly different from that observed in untreated blood. Hypoxia induced a 10-fold increase in ATP release from erythrocytes in the perfusates. If apyrase was added to the perfusates, ATP release was prevented and aspirin effects were evident again. CONCLUSION: Our results suggest that, under hypoxic conditions, the presence of aspirin would not help to inhibit further platelet activation.

Preparations of synthetic phospholipids promote procoagulant activity on damaged vessels: studies under flow conditions.

BACKGROUND: The possibility of developing synthetic platelet substitutes that could promote hemostasis with prolonged shelf-life and increased safety is an appealing one. STUDY DESIGN AND METHODS: Preparations containing synthetic phospholipids were incorporated into blood samples (1.15 mg/mL) in which platelets and white cell counts had been experimentally reduced by a filtration procedure. Vesicles containing phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), or combinations of PC and PE and of PC and PS were tested in this system. Blood was recirculated (10 min; shear rate, 250/sec) through a perfusion chamber containing vascular segments. The ability of the various phospholipid preparations to promote fibrin formation on the damaged subendothelium was evaluated morphometrically and expressed as the percentage of fibrin coverage. Generation of thrombin in the system was monitored through the measurement of prothrombin fragments 1 and 2. RESULTS: Vesicles containing PC, PI, PE:PC (1:1), or PS:PC (1:3) increased fibrin deposition on the subendothelium (64.5 +/- 9.8%, 32.7 +/- 6.3%, 58.3 +/- 6.5%, and 46.6 +/- 15.2%, respectively; p < 0.01 vs. 11.5 +/- 1.2% in thrombocytopenic blood). Vesicles containing PE, PS, or PS:PC (3:1) did not show procoagulant effect. CONCLUSION: Synthetic phospholipid preparations promote a local procoagulant activity at sites of vascular damage when they are incorporated into thrombocytopenic blood maintained under flow conditions.

Platelet-leukocyte activation during hemodialysis detected with a monoclonal antibody to leukocyte integrin CD11b.

Platelet activation is commonly monitored with a battery of monoclonal antibodies against different platelet epitopes with controversial results. The transient expression of platelet markers and their role mediating interactions with other cells could easily explain these discrepancies. The present study has evaluated whether the analysis of a leukocyte activation antigen (CD11b) could provide more reliable results than detection of platelet activation markers. Cytometric techniques with specific monoclonal antibodies were used to compare the reliability of platelet and leukocyte markers to detect activation. Modifications in the presence of platelet glycoproteins GPIb (CD42b), GPIIIa (CD41) and GPIV (CD36), expression of specific platelet markers (P-selectin (CD62P) and lysosomal protein (CD63)) and leukocyte integrin (CD11b) were assessed during hemodialysis. Platelet antigens remained in uremic patients at levels similar or slightly above those detected in a group of healthy subjects. Modifications of platelet antigens during hemodialysis produced inconclusive results. However, numbers of leukocytes expressing CD11b increased progressively during hemodialysis (17.2 +/- 5.1% at 15 min and 21.3 +/- 6.6% at 2 h, p < 0.05, vs. baseline 6.9 +/- 0.2%). The hemodialysis procedure caused an increased formation of leukocyte-platelet aggregates. Detection of leukocyte CD11b may be a useful marker of overall cellular activation during the hemodialysis procedure.

Using hospital data systems to find target populations: new tools for clinical nurse specialists.

A newly appointed diabetes clinical nurse specialist/nurse practitioner at Yale-New Haven Hospital was charged with redesigning the diabetes nursing role. For help, she turned to a special information management service within the Nursing and Operational Finance departments. This article describes the project that used an integrated financial and clinical information system to locate and characterize adult patients with diabetes mellitus. Patients with principal and secondary diagnoses of diabetes were identified by ICD-9-CM codes and tracked across inpatient and outpatient services. These data were used to identify opportunities for case management and for managing the costs related to diabetes care. The data also supported proposals made by the clinical nurse specialist/nurse practitioner to management to allocate clinical resources for the care of patients with diabetes. When the clinical wisdom of advanced practice nurses is joined with nursing information management expertise and technology, opportunities for understanding and advancing nursing's work are revealed.