REIMPORTATION OF U.S. PHARMACEUTICALS: POLITICAL, ECONOMIC, AND LEGAL PERSPECTIVES

The high cost of prescription drugs in the United States is a problem that has engendered much political attention. One proposed solution to the prescription drug problem is to permit reimportation of U.S.-made drug products, allowing Americans to take advantage of products sold at lower prices abroad. In 2000, the United States passed such a measure known as the Medicine Equity and Drug Safety Act (“MEDSAâ€), which, if implemented, would have overturned a decade-long bad on the reimportation of pharmaceuticals without the consent of the manufacturer. Though supported by many consumer advocates and politicians, MEDSA would have had tenuous affect on drug prices and posed unnecessary risks to consumer safety. Reimportation’s theoretic results of eliminating geographic price discrimination would have detrimental results for society as a whole by reducing the incentive for drug manufacturers to innovate. Furthermore, a global pricing system for pharmaceuticals may create severe consumer losses, especially in developing counties. Lastly, reimportation of patented goods may be subject to legal challenge under current construction of the exhaustion of rights principle. Rather than considering reimportation, the government should implement a policy that provides lower-cost drugs to those who need them the most, the uninsured elderly. A policy of price discounts for uninsured elderly would improve the prescription drug situation without threatening the incentives for pharmaceutical innovation, and would lead to greater social benefits overall

Assessing the Quality of Regulatory Impact Analyses

This study provides the most comprehensive evaluation of the quality of recent economic analyses that agencies conduct before finalizing major regulations. We construct a new dataset that includes analyses of forty-eight major health, safety, and environmental regulations from mid-1996 to mid-1999. This dataset provides detailed information on a variety of issues, including an agency's treatment of benefits, costs, net benefits, discounting, and uncertainty. We use this dataset to assess the quality of recent economic analyses and to determine the extent to which they are consistent with President Clinton's Executive Order 12866 and the benefit-cost guidelines issued by the Office of Management and Budget (OMB). We find that economic analyses prepared by regulatory agencies typically do not provide enough information to make decisions that will maximize the efficiency or effectiveness of a rule. Agencies quantified net benefits for only 29 percent of the rules. Agencies failed to discuss alternatives in 27 percent of the rules and quantified costs and benefits of alternatives in only 31 percent of the rules. Our findings strongly suggest that agencies generally failed to comply with the executive order and adhere to the OMB guidelines. We offer specific suggestions for improving the quality of analysis and the transparency of the regulatory process, including writing clear executive summaries, making analyses available on the Internet, providing more careful consideration of alternatives to a regulation, and estimating net benefits of a regulation when data on costs and benefits are provided.

Assessing Regulatory Impact Analyses: The Failure of Agencies to Comply With Executive Order 12,866

None.Environment, Health and Safety, Regulatory Reform

Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: Correlations with fetal growth

We previously described significant changes in GH-binding protein (GHBP) in pathological human pregnancy. There was a substantial elevation of GHBP in cases of noninsulin-dependent diabetes mellitus and a reduction in insulin-dependent diabetes mellitus. GHBP has the potential to modulate the proportion of free placental GH (PGH) and hence the impact on the maternal GH/insulin-like growth factor I (IGF-I) axis, fetal growth, and maternal glycemic status. The present study was undertaken to investigate the relationship among glycemia, GHBP, and PGH during pregnancy and to assess the impact of GHBP on the concentration of free PGH. We have extended the analysis of specimens to include measurements of GHBP, PGH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFSP-2, and IGFBP-3 and have related these to maternal characteristics, fetal growth, and glycemia. The simultaneous measurement of GHBP and PGH has for the first time allowed calculation of the free component of PGH and correlation of the free component to indexes of fetal growth and other endocrine markers. PGH, free PGH, IGF-I, and IGF-II were substantially decreased in IUGR at 28-30 weeks gestation (K28) and 36-38 weeks gestation (K36). The mean concentration (+/-SEM) of total PGH increased significantly from K28 to K36 (30.0 +/- 2.2 to 50.7 +/- 6.2 ng/mL; n = 40), as did the concentration of free PGH (23.4 +/- 2.3 to 43.7 +/- 6.0 ng/mL; n = 38). The mean percentage of free PGH was significantly less in IUGR than in normal subjects (67% vs. 79%; P < 0.01). Macrosomia was associated with an increase in these parameters that did not reach statistical significance. Multiple regression analysis revealed that PGH/IGF-I and IGFBP-5 account for 40% of the variance in birth weight. IGFBP-3 showed a significant correlation with IGF-I, IGF-II, and free and total PGK at K28 and K36. Noninsulin-dependent diabetes mellitus patients had a lower mean percentage of free PGH (65%; P < 0.01), and insulin-dependent diabetics had a higher mean percentage of free PGH (87%; P < 0.01) than normal subjects. Mean postprandial glucose at K28 correlated positively with PGH and free PGH (consistent with the hyperglycemic action of GH). GHBP correlated negatively with both postprandial and fasting glucose. Although GHBP correlated negatively with PGH (r = -0.52; P <.001), free PGH and total PGH correlated very closely (r = 0.98). The results are consistent with an inhibitory function for GHBP in vivo and support a critical role for placental GH and IGF-I in driving normal fetal growth

Technologies for removing pharmaceuticals and personal care products (PPCPs) from aqueous solutions: Recent advances, performances, challenges and recommendations for improvements

In recent years, the removal of pharmaceutical and personal care products (PPCPs) from aqueous solutions has been gaining a lot of attention from researchers throughout the world. This is particularly due to the concern about their potential hazards and toxicities, as they are classified as emerging contaminants. Thus, there is an increasing need to investigate removal technologies for PPCPs at a deeper and more holistic level. This review aims to provide the latest developments in removal technologies for PPCPs. It first succinctly describes the types, characteristics, and hazards of PPCPs on the environment and human health. It then comprehensively covers a wide range of technologies for removing PPCPs from aqueous solutions, comprising the adsorption process (using carbon-based adsorbents, plant biomasses, clay and clay minerals, silica-based adsorbents, zeolite-based adsorbents, polymers and resins, and hybrid adsorbents), advanced oxidation processes (AOPs) (photocatalysis, Fenton or photo-Fenton or electro-Fenton, ozonation, ultrasonication, electrochemical oxidation, persulfate oxidation), membrane separation processes (ultrafiltration, nanofiltration, reverse osmosis), biodegradation processes (bacteria, fungi, and algae), and hybrid treatment (adsorption-AOP, AOP-membrane, membrane-biodegradation, and others). According to the specific experimental conditions, the reported removal efficiencies for adsorption, AOPs, membrane processes, biodegradation processes and hybrid treatment were 40–100%, 40–100%, 3–100%, 14–100% and 5–100%, respectively. This review paper also highlights the challenges in this field of research, particularly incomplete removal of certain PPCPs, high costs of some treatment technologies and generally insufficient understanding on the removal kinetics and mechanisms of PPCPs. This review offers recommendations for future works to further advance the technical performances to eventually realize the wider application of these technologies at the industrial scale

The problem of obesity among adolescents in Hong Kong: a comparison using various diagnostic criteria

<p>Abstract</p> <p>Background</p> <p>Obesity is now a global epidemic. In this study, we aimed to assess the rates of obesity using several major diagnostic criteria in Chinese school adolescents in Hong Kong.</p> <p>Methods</p> <p>This is a cross-sectional study. Using a computer-generated coding system, we randomly selected schools from different geographical regions in Hong Kong to obtain a representative sample. Subjects aged 11–18 years of age were randomly selected from different class of the schools. Their rates of obesity according to four different international and local criteria were compared [International Obesity Task Force (IOTF) 2000 criterion; the Group of China Obesity Task Force (COTF) 2004 criterion; Centers for Disease Control and Prevention (CDC) 2000 Growth Charts and the Hong Kong Growth Survey (HKGS) charts in 1993].</p> <p>Results</p> <p>Of the 2098 adolescents [982 (46.8%) boys and 1116 (53.2%) girls], the mean age (± SD) was 15.1 ± 1.8 years (range: 11–18 years; median: 15.0 years). The crude rates of obesity were similar based on IOTF, COTF or CDC criteria (boys: 3.9–6.0%, girls: 1.8–3.7%), however, the rate increased to 11–27% if the HKGS charts were used. Obesity rate varied markedly according to age. It decreased from 8–10% among those aged 12–13 years to 2–4% among those aged 17–18 years.</p> <p>Conclusion</p> <p>The prevalence of obesity in Hong Kong adolescents using various diagnostic criteria were similar except for the 1993 HKGS criteria, which gave an exceeding high figure. Using the IOTF, COTF or CDC criteria, the adolescent obesity in Hong Kong varied from 1.8% to 6.0%.</p

Apolipoprotein M Gene (APOM) Polymorphism Modifies Metabolic and Disease Traits in Type 2 Diabetes

This study aimed at substantiating the associations of the apolipoproein M gene (APOM) with type 2 diabetes (T2D) as well as with metabolic traits in Hong Kong Chinese. In addition, APOM gene function was further characterized to elucidate its activity in cholesterol metabolism. Seventeen APOM SNPs documented in the NCBI database were genotyped. Five SNPs were confirmed in our study cohort of 1234 T2D and 606 control participants. Three of the five SNPs rs707921(C+1871A), rs707922(G+1837T) and rs805264(G+203A) were in linkage disequilibrium (LD). We chose rs707922 to tag this LD region for down stream association analyses and characterized the function of this SNP at molecular level. No association between APOM and T2D susceptibility was detected in our Hong Kong Chinese cohort. Interestingly, the C allele of rs805297 was significantly associated with T2D duration of longer than 10 years (OR = 1.245, p = 0.015). The rs707922 TT genotype was significantly associated with elevated plasma total- and LDL- cholesterol levels (p = 0.006 and p = 0.009, respectively) in T2D patients. Molecular analyses of rs707922 lead to the discoveries of a novel transcript APOM5 as well as the cryptic nature of exon 5 of the gene. Ectopic expression of APOM5 transcript confirmed rs707922 allele-dependent activity of the transcript in modifying cholesterol homeostasis in vitro. In conclusion, the results here did not support APOM as a T2D susceptibility gene in Hong Kong Chinese. However, in T2D patients, a subset of APOM SNPs was associated with disease duration and metabolic traits. Further molecular analysis proved the functional activity of rs707922 in APOM expression and in regulation of cellular cholesterol content

APOE Genotype-Function Relationship: Evidence of −491 A/T Promoter Polymorphism Modifying Transcription Control but Not Type 2 Diabetes Risk

BACKGROUND: The apolipoprotein E gene (APOE) coding polymorphism modifies the risks of Alzheimer's disease, type 2 diabetes, and coronary heart disease. Aside from the coding variants, single nucleotide polymorphism (SNP) of the APOE promoter has also been shown to modify the risk of Alzheimer's disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigate the genotype-function relationship of APOE promoter polymorphism at molecular level and at physiological level: i.e., in transcription control of the gene and in the risk of type 2 diabetes. In molecular studies, the effect of the APOE -491A/T (rs449647) polymorphism on gene transcription was accessed by dual-luciferase reporter gene assays. The -491 A to T substitution decreased the activity (p<0.05) of the cloned APOE promoter (-1017 to +406). Using the -501 to -481 nucleotide sequence of the APOE promoter as a 'bait' to screen the human brain cDNA library by yeast one-hybrid system yielded ATF4, an endoplasmic reticulum stress response gene, as one of the interacting factors. Electrophoretic-mobility-shift assays (EMSA) and chromatin immuno-precipitation (ChIP) analyses further substantiated the physical interaction between ATF4 and the APOE promoter. Over-expression of ATF4 stimulated APOE expression whereas siRNA against ATF4 suppressed the expression of the gene. However, interaction between APOE promoter and ATF4 was not -491A/T-specific. At physiological level, the genotype-function relationship of APOE promoter polymorphism was studied in type 2 diabetes. In 630 cases and 595 controls, three APOE promoter SNPs -491A/T, -219G/T (rs405509), and +113G/C (rs440446) were genotyped and tested for association with type 2 diabetes in Hong Kong Chinese. No SNP or haplotype association with type 2 diabetes was detected. CONCLUSIONS/SIGNIFICANCE: At molecular level, polymorphism -491A/T and ATF4 elicit independent control of APOE gene expression. At physiological level, no genotype-risk association was detected between the studied APOE promoter SNPs and type 2 diabetes in Hong Kong Chinese

Common Polymorphisms in MTNR1B, G6PC2 and GCK Are Associated with Increased Fasting Plasma Glucose and Impaired Beta-Cell Function in Chinese Subjects

BACKGROUND: Previous studies identified melatonin receptor 1B (MTNR1B), islet-specific glucose 6 phosphatase catalytic subunit-related protein (G6PC2), glucokinase (GCK) and glucokinase regulatory protein (GCKR) as candidate genes for type 2 diabetes (T2D) acting through elevated fasting plasma glucose (FPG). We examined the associations of the reported common variants of these genes with T2D and glucose homeostasis in three independent Chinese cohorts. METHODOLOGY/PRINCIPAL FINDINGS: Five single nucleotide polymorphisms (SNPs), MTNR1B rs10830963, G6PC2 rs16856187 and rs478333, GCK rs1799884 and GCKR rs780094, were genotyped in 1644 controls (583 adults and 1061 adolescents) and 1342 T2D patients. The G-allele of MTNR1B rs10830963 and the C-alleles of both G6PC2 rs16856187 and rs478333 were associated with higher FPG (0.0034<P<6.6x10(-5)) in healthy controls. In addition to our previous report for association with FPG, the A-allele of GCK rs1799884 was also associated with reduced homeostasis model assessment of beta-cell function (HOMA-B) (P=0.0015). Together with GCKR rs780094, the risk alleles of these SNPs exhibited dosage effect in their associations with increased FPG (P=2.9x10(-9)) and reduced HOMA-B (P=1.1x10(-3)). Meta-analyses strongly supported additive effects of MTNR1B rs10830963 and G6PC2 rs16856187 on FPG. CONCLUSIONS/SIGNIFICANCE: Common variants of MTNR1B, G6PC2 and GCK are associated with elevated FPG and impaired insulin secretion, both individually and jointly, suggesting that these risk alleles may precipitate or perpetuate hyperglycemia in predisposed individuals

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder