NADPH oxidase 2 (NOX2): a key target of oxidative stress-mediated platelet activation and thrombosis

Oxidative stress represents an imbalance between the production of reactive oxygen species (ROS) and the cellular antioxidant system. Increased levels of oxidative stress contribute to the development of atherosclerosis that eventually leads to thrombosis; a principle cause of heart attacks and strokes. Thrombosis is a consequence of platelet activation and aggregate formation within the circulation. Platelet ROS are mostly generated by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NOX2 is an isoform from NADPH oxidase expressed in platelets and an important regulator of platelet activation‐associated thrombosis. The present article aims to highlight the relative contribution of NOX2 as a key target of different platelet activation pathways and antiplatelet treatment

The Impact of Reference Pricing of Cardiovascular Drugs on Health Care Costs and Health Outcomes: Evidence from British Columbia--Volume III: ACE and CCB Literature Review

(see SEDAP 70 for abstract)reference pricing,prescription drugs,ACE inhibitors,calcium channel blockers,nitrates,pharmaceutical cost control,seniors,user fees

The Impact of Differential Cost Sharing of Non-Steroidal Anti-Inflammatory Agents on the Use and Costs of Analgesic Drugs

OBJECTIVE: To estimate the effect of differential cost sharing (DCS) schemes for non-steroidal anti-inflammatory drugs (NSAIDs) on drug subsidy program and beneficiary expenditures. DATA SOURCES/STUDY SETTING: Monthly aggregate claims data from Pharmacare, the public drug subsidy program for seniors in British Columbia, Canada over the period 1989-11 to 2001-06. STUDY DESIGN: DCS limits insurance reimbursement of a group of therapeutically similar drugs to the cost of the lowest priced drugs, with beneficiaries responsible for costs above the reimbursement limit. Pharmacare introduced two different forms of DCS, generic substitution (GS) and reference pricing (RP), in April 1994 and November 1995, respectively, to the NSAIDs. Under GS, generic and brand versions of the same NSAID are considered interchangeable, whereas under RP different NSAIDs are. We extrapolated average reimbursement per day of NSAID therapy over the months before GS and RP to estimate what expenditures would have been without the policies. These counterfactual predictions were compared to actual values to estimate the impact of the policies; the estimated impacts on reimbursement rates were multiplied by the post-policy volume of NSAIDS dispensed, which appeared unaffected by the policies, to estimate expenditure changes. DATA COLLECTION: The cleaned NSAID claims data, obtained from Pharmacare’s databases, were aggregated by month and by their reimbursement status under the GS and RP policies. PRINCIPAL FINDINGS: After RP, program expenditures declined by $22.7 million, or$4 million annually, cutting expenditure by half. Most savings accrued from the substitution of low cost NSAIDs for more costly alternatives. About 20% of savings represented expenditures by seniors who elected to pay for partially-reimbursed drugs. GS produced one quarter the savings of RP. CONCLUSIONS: RP of NSAIDs achieved its goal of reducing drug expenditures and was more effective than GS. The effects of RP on patient health and associated health care costs remain to be investigated.Reference pricing; generic substitution; prescription drugs; drug cost containment; NSAIDs.

The platelet-surface thiol isomerase enzyme ERp57 modulates platelet function

Background: Thiol isomerases are a family of endoplasmic reticulum enzymes which orchestrate redox-based modifications of protein disulphide bonds. Previous studies have identified important roles for the thiol isomerases PDI and ERp5 in the regulation of normal platelet function. Objectives: Recently, we demonstrated the presence of a further five thiol isomerases at the platelet surface. In this report we aim to report the role of one of these enzymes - ERp57 in the regulation of platelet function. Methods/Results: Using enzyme activity function blocking antibodies, we demonstrate a role for ERp57 in platelet aggregation, dense granule secretion, fibrinogen binding, calcium mobilisation and thrombus formation under arterial conditions. In addition to the effects of ERp57 on isolated platelets, we observe the presence of ERp57 in the developing thrombus in vivo. Furthermore the inhibition of ERp57 function was found to reduce laser-injury induced arterial thrombus formation in a murine model of thrombosis. Conclusions: These data suggest that ERp57 is important for normal platelet function and opens up the possibility that the regulation of platelet function by a range of cell surface thiol isomerases may represent a broad paradigm for the regulation of haemostasis and thrombosis

The Impact of Reference Pricing of Cardiovascular Drugs on Health Care Costs and Health Outcomes: Evidence from British Columbia -- Volume I: Summary

Objective: We estimate the effects of Reference Pricing, a drug cost control policy introduced by the BC Ministry of Health Pharmacare program in 1995, on its program expenditures for seniors, out of pocket costs paid by its senior beneficiaries, indicators of beneficiary health status and attendant Ministry of Health expenditures on physicians and hospitals services. Rationale: Reference pricing (RP) limits the reimbursement of a group of drugs with similar therapeutic effect but different active ingredients to a fixed "reference price". The setting of the reference price varies by jurisdiction but typically is based on an average of the lowest cost "reference standard" drugs within the group. Critics of RP contend that the partially subsidized and fully subsidized (reference standard) drugs are not therapeutically interchangeable, and therefore patient health will be compromised and use of other non-pharmacologic health services may increase as a result, thus partially or wholly offsetting any potential cost savings from the policy. Findings: The application of RP to 3 groups of cardiac drugs produced annualized savings to Pharmacare of about $7.7 million, or 3.6$213.7 million that Pharmacare spent on drugs for seniors (not including dispensing fees) in 1997. The additional costs for physician consultations were modest, around $500,000 in the subsample of seniors we studied, from the introduction of the RP plans to March 1998, although the costs could be greater, perhaps up to twice this amount, if we accounted for all seniors exposed to the RP over the same period. We found no effects of RP on mortality, or premature admission to a longterm care facility. Seniors using the nitrate drugs for angina that were no longer fully subsidized when RP was introduced faced a higher probability in the short run of using medicines to deal with acute exacerbations of angina and in the longer run having bypass surgery or other revascularization procedures. No long run effects of morbidity were observed for the application of RP to two different types of anti-hypertensive medications, although there was a short run increase in the rate of revascularizations among those taking 1 type of anti-hypertensive: the ACE inhibitors. The results of these morbidity models should be seen as tentative, until these results can be replicated using alternative estimation strategies. Conclusions: The introduction of RP can indeed reduce Ministry of Health drug expenditures. The effects of RP on patient morbidity remain to be fully investigated before definitive policy recommendations can be offered.reference pricing,prescription drugs,ACE inhibitors,calcium channel blockers,nitrates,pharmaceutical cost control,seniors,user fees

The Impact of Reference Pricing of Cardiovascular Drugs on Health Care Costs and Health Outcomes: Evidence from British Columbia -- Volume II: Technical Report

(see QSEP 369 for abstract)reference pricing,prescription drugs,ACE inhibitors,calcium channel blockers,nitrates,pharmaceutical cost control,seniors,user fees

The Impact of Reference Pricing of Cardiovascular Drugs on Health Care Costs and Health Outcomes: Evidence from British Columbia--Volume I: Summary

Objective: We estimate the effects of Reference Pricing, a drug cost control policy introduced by the BC Ministry of Health Pharmacare program in 1995, on its program expenditures for seniors, out of pocket costs paid by its senior beneficiaries, indicators of beneficiary health status and attendant Ministry of Health expenditures on physicians and hospitals services. Rationale: Reference pricing (RP) limits the reimbursement of a group of drugs with similar therapeutic effect but different active ingredients to a fixed "reference price". The setting of the reference price varies by jurisdiction but typically is based on an average of the lowest cost "reference standard" drugs within the group. Critics of RP contend that the partially subsidized and fully subsidized (reference standard) drugs are not therapeutically interchangeable, and therefore patient health will be compromised and use of other non-pharmacologic health services may increase as a result, thus partially or wholly offsetting any potential cost savings from the policy. Findings: The application of RP to 3 groups of cardiac drugs produced annualized savings to Pharmacare of about $7.7 million, or 3.6$213.7 million that Pharmacare spent on drugs for seniors (not including dispensing fees) in 1997. The additional costs for physician consultations were modest, around $500,000 in the subsample of seniors we studied, from the introduction of the RP plans to March 1998, although the costs could be greater, perhaps up to twice this amount, if we accounted for all seniors exposed to the RP over the same period. We found no effects of RP on mortality, or premature admission to a longterm care facility. Seniors using the nitrate drugs for angina that were no longer fully subsidized when RP was introduced faced a higher probability in the short run of using medicines to deal with acute exacerbations of angina and in the longer run having bypass surgery or other revascularization procedures. No long run effects of morbidity were observed for the application of RP to two different types of anti-hypertensive medications, although there was a short run increase in the rate of revascularizations among those taking 1 type of anti-hypertensive: the ACE inhibitors. The results of these morbidity models should be seen as tentative, until these results can be replicated using alternative estimation strategies. Conclusions: The introduction of RP can indeed reduce Ministry of Health drug expenditures. The effects of RP on patient morbidity remain to be fully investigated before definitive policy recommendations can be offered.reference pricing,prescription drugs,ACE inhibitors,calcium channel blockers,nitrates,pharmaceutical cost control,seniors,user fees

Difference in prevalence of common mental disorder as measured using four questionnaire delivery methods among young people in rural Zimbabwe.

BACKGROUND: Previous studies have suggested that interviewer-administered questionnaires can under-estimate the prevalence of depression and suicidal ideation when compared with self-administered ones. We report here on differences in prevalence of reporting mental health between four questionnaire delivery modes (QDM). METHODS: Mental health was assessed using the Shona Symptom Questionnaire (SSQ), a locally validated 14-item indigenous measure for common mental affective disorders. A representative sample of 1495 rural Zimbabwean adolescents (median age 18) was randomly allocated to one of four questionnaire delivery modes: self-administered questionnaire (SAQ), SAQ with audio (AASI), interviewer-administered questionnaire (IAQ), and audio computer-assisted survey instrument (ACASI). RESULTS: Prevalence of common affective disorders varied between QDM (52.3%, 48.6%, 41.5%, and 63.6% for SAQ, AASI, IAQ, and ACASI respectively (P<0.001)). Fewer participants failed to complete SSQ using IAQ and ACASI than other methods (1.6% vs. 12.3%; P<0.001). Qualitative data suggested that respondents found it difficult answering questions honestly in front of an interviewer. LIMITATIONS: Direction of accuracy cannot be ascertained due to lack of objective or clinical assessments of affective disorders. CONCLUSIONS: Estimates of prevalence of psychosomatic symptoms and suicidal ideation varied according to mode of interview. As each mode's direction of accuracy remains unresolved evaluations of interventions continue to be hampered

The Impact of Reference Pricing of Cardiovascular Drugs on Health Care Costs and Health Outcomes: Evidence from British Columbia--Volume II: Technical Report

(see SEDAP 70 for abstract)reference pricing,prescription drugs,ACE inhibitors,calcium channel blockers,nitrates,pharmaceutical cost control,seniors,user fees

OX133, a monoclonal antibody recognizing protein-bound N-ethylmaleimide for the identification of reduced disulfide bonds in proteins

In vivo, enzymatic reduction of some protein disulfide bonds, allosteric disulfide bonds, provides an important level of structural and functional regulation. The free cysteine residues generated can be labeled by maleimide reagents, including biotin derivatives, allowing the reduced protein to be detected or purified. During the screening of monoclonal antibodies for those specific for the reduced forms of proteins, we isolated OX133, a unique antibody that recognizes polypeptide resident, N-ethylmaleimide (NEM)-modified cysteine residues in a sequence-independent manner. OX133 offers an alternative to biotin-maleimide reagents for labeling reduced/alkylated antigens and capturing reduced/alkylated proteins with the advantage that NEM-modified proteins are more easily detected in mass spectrometry, and may be more easily recovered than is the case following capture with biotin based reagents