Rosiglitazone causes endothelial dysfunction in humans.

OBJECTIVES: We explored the impact of rosiglitazone on endothelial function in normal volunteers and its interaction with glyceryl trinitrate (GTN)-induced abnormalities in endothelial function. We hypothesized that rosiglitazone would have a neutral effect on endothelial function in normal volunteers and would favorably modify endothelial dysfunction induced by GTN. METHODS: In this double-blind, randomized, placebo-controlled study, 44 participants were randomized to placebo, rosiglitazone (4 mg twice daily), transdermal GTN (0.6 mg/h), or both GTN and rosiglitazone. After 7 days of treatment, participants underwent measures of forearm blood flow during brachial artery infusion of acetylcholine (Ach). Serum glucose concentrations and insulin sensitivity were assessed. RESULTS: Unexpectedly, rosiglitazone-treated participants experienced blunted responses to endothelium-dependent responses to Ach (P < .05 vs placebo). Sustained GTN administration caused similar abnormalities in endothelial function (P < .05 vs placebo) and rosiglitazone + GTN (P < .05 vs placebo; P = ns vs rosiglitazone). Interestingly, co-infusion of the antioxidant vitamin C improved endothelial responses in those randomized to rosiglitazone and GTN alone (P = not significant [ns] compared with placebo), but it did not improve endothelial function in those treated with rosiglitazone + GTN. Neither rosiglitazone nor GTN treatment modified the measures of glucose metabolism. CONCLUSIONS: Unexpectedly, therapy with rosiglitazone caused abnormalities in endothelial function in normal volunteers. These findings have important implications with respect to drug development and surveillance.

Indian vaccine innovation: the case of Shantha Biotechnics.

BACKGROUND: Although the World Health Organization had recommended that every child be vaccinated for Hepatitis B by the early 1980s, large multinational pharmaceutical companies held monopolies on the recombinant Hepatitis B vaccine. At a price as high as USD$23 a dose, most Indians families could not afford vaccination. Shantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need domestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than $1/dose. Further expansion enabled low-cost mass vaccination globally through organizations such as UNICEF. In 2009, Shantha sold over 120 million doses of vaccines. The company was recently acquired by Sanofi-Aventis at a valuation of USD$784 million. METHODS: The case study and grounded research method was used to illustrate how the globalization of healthcare R&D is enabling private sector companies such as Shantha to address access to essential medicines. Sources including interviews, literature analysis, and on-site observations were combined to conduct a robust examination of Shantha's evolution as a major provider of vaccines for global health indications. RESULTS: Shantha's ability to become a significant global vaccine manufacturer and achieve international valuation and market success appears to have been made possible by focusing first on the local health needs of India. How Shantha achieved this balance can be understood in terms of a framework of four guiding principles. First, Shantha identified a therapeutic area (Hepatitis B) in which cost efficiencies could be achieved for reaching the poor. Second, Shantha persistently sought investments and partnerships from non-traditional and international sources including the Foreign Ministry of Oman and Pfizer. Third, Shantha focused on innovation and quality - investing in innovation from the outset yielded the crucial process innovation that allowed Shantha to make an affordable vaccine. Fourth, Shantha constructed its own cGMP facility, which established credibility for vaccine prequalification by the World Health Organization and generated interest from large pharmaceutical companies in its contract research services. These two sources of revenue allowed Shantha to continue to invest in health innovation relevant to the developing world. CONCLUSIONS: The Shantha case study underscores the important role the private sector can play in global health and access to medicines. Home-grown companies in the developing world are becoming a source of low-cost, locally relevant healthcare R&D for therapeutics such as vaccines. Such companies may be compelled by market forces to focus on products relevant to diseases endemic in their country. Sanofi-Aventis' acquisition of Shantha reveals that even large pharmaceutical companies based in the developed world have recognized the importance of meeting the health needs of the developing world. Collectively, these processes suggest an ability to tap into private sector investments for global health innovation, and illustrate the globalization of healthcare R&D to the developing world.

Systematic review and meta-analysis of the effect of warming local anesthetics on injection pain.

STUDY OBJECTIVE: Local anesthetics are the main class of analgesics used for pain management during laceration repair and other minor surgeries; however, they are administered by injection, which is painful. Warming local anesthetics has been proposed as a cost-free intervention that reduces injection pain. A systematic review of the effectiveness of this technique has not yet been undertaken. We determine the effectiveness of warming local anesthetics to reduce pain in adults and children undergoing local anesthetic infiltration into intradermal or subcutaneous tissue. METHODS: We used published articles from MEDLINE (1950 to June 2010), EMBASE (1980 to June 2010), CINAHL (1982 to June 2010), the Cochrane Library (second quarter 2010), International Pharmaceutical Abstracts (1970 to June 2010), and ProQuest Dissertations and Theses database (1938 to June 2010). We included studies with randomized or pseudorandomized designs and healthy subjects or patients receiving subcutaneous or intradermal injection of local anesthetics that were warmed (body temperature) or not (room temperature). Studies of regional anesthesia and intraarticular, spinal, or periorbital administration of local anesthetics were excluded. Data were extracted onto predesigned forms and verified by 2 reviewers. Quality was assessed with the Cochrane risk of bias tool. The primary outcome was self-reported pain as assessed by a visual analog or numeric rating scale. Data were combined with mean differences with 95% confidence intervals (CIs) by using a random-effects model. RESULTS: Twenty-nine studies were retrieved for close examination and 19 studies met inclusion criteria. A total of 18 studies with 831 patients could be included in a meta-analysis. Seventeen studies had an unclear risk of bias and 1 had a high risk of bias. A mean difference of -11 mm (95% CI -14 to -7 mm) on a 100-mm scale was found in favor of warming local anesthetics. Subgroup analysis of 8 studies investigating the effect of warming on buffered local anesthetics yielded similar results: -7 mm (95% CI -12 to -3 mm). CONCLUSION: Warming local anesthetics leads to less pain during injection and therefore should be done before administration.

The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan.

BACKGROUND: Developing novel drugs from traditional medicinal knowledge can serve as a means to improve public health. Yet countries in sub-Saharan Africa face barriers in translating traditional medicinal knowledge into commercially viable health products. Barriers in moving along the road towards making a new drug available include insufficient manufacturing capacity; knowledge sharing between scientists and medical healers; regulatory hurdles; quality control issues; pricing and distribution; and lack of financing. The case study method was used to illustrate efforts to overcome these barriers during the development in Nigeria of Niprisan - a novel drug for the treatment of sickle cell anemia, a chronic blood disorder with few effective therapies. DISCUSSION: Building on the knowledge of a traditional medicine practitioner, Nigeria's National Institute for Pharmaceutical Research and Development (NIPRD) developed the traditional herbal medicine Niprisan. The commercialization of Niprisan reached a number of commercial milestones, including regulatory approval in Nigeria; securing US-based commercial partner XeChem; demonstrating clinical efficacy and safety; being awarded orphan drug status by the US Food and Drug Administration; and striking important relationships with domestic and international groups. Despite these successes, however, XeChem did not achieve mainstream success for Niprisan in Nigeria or in the United States. A number of reasons, including inconsistent funding and manufacturing and management challenges, have been put forth to explain Niprisan's commercial demise. As of this writing, NIPRD is considering options for another commercial partner to take the drug forward. SUMMARY: Evidence from the Niprisan experience suggests that establishing benefit-sharing agreements, fostering partnerships with established research institutions, improving standardization and quality control, ensuring financial and managerial due diligence, and recruiting entrepreneurial leaders capable of holding dual scientific and business responsibilities should be incorporated into future drug development initiatives based on traditional medicines. Country-level supporting policies and conditions are also important. With more experience and support, and an improved environment for innovation, developing new drugs from traditional medicines may be an attractive approach to addressing diseases in sub-Saharan Africa and other regions.

The impact of rosiglitazone on nitric oxide bioavailability and endothelial function.

Clinical studies have demonstrated that rosiglitazone can improve vascular function in patients with diabetes mellitus. It remains unclear whether this effect depends on a direct improvement in endothelial function or whether it is mediated by the drug's effect on glycemic control. Yet, rosiglitazone has been linked to serious cardiovascular events. A number of studies recently investigated whether rosiglitazone affects endothelial function in healthy volunteers and patients with cardiovascular disease. Controversial observations have been reported; the observation that rosiglitazone might in certain cases impair endothelial function may suggest a mechanistic explanation for the observation of increased cardiovascular events in patients treated with rosiglitazone who have underlying cardiovascular disease. These studies are summarized and discussed in the present paper.