BACKGROUND:There have been isolated reports of Aloe vera hepatotoxicity, usually manifested by transient liver function test abnormalities. While the European Food Safety Authority has recommended that whole leaf products containing the rind of the Aloe vera plant should not be used for human oral consumption, those Aloe vera gels made of the treated plant pulp alone are considered safe for daily consumption, provided recommended quantities are not exceeded. We aimed to assess hepatic function in healthy volunteers consuming the purified plant pulp Aloe vera gel over a 60 day period.METHODS:35 healthy volunteers consumed the maximum recommended daily dose of 2 oz (57 mL) of Aloe vera gel twice daily for a total of 60 days. The participants attended an initial baseline visit where biochemical measurements of hepatic synthetic function were obtained, and each volunteer underwent hepatic ultrasound with elastography, superb microvascular imaging and image quantification. Further visits were undertaken at days 30 and 60 to undergo the same biochemical and imaging measurements of liver function to monitor if there were any changes in the parameters measured.RESULTS:Seven volunteers failed to complete the study, citing unspecified gastrointestinal upset and/or an inability to tolerate the taste of the Aloe vera gel. None of these individuals had disturbance of biochemical or imaging parameters of hepatic function. Of the remaining 27 healthy volunteers, none had a change in either biochemical indices of liver function, or of ultrasound markers of hepatic blood flow or liver tissue elasticity after 60 days of Aloe vera gel consumption. However, there was a non-significant reduction in serum homocysteine levels as the only detectable change in the cohort.CONCLUSIONS:Despite reports of potential hepatotoxicity with some Aloe vera products, in this healthy cohort, extended consumption of purified plant-pulp Aloe vera gel did not have any detectable effects on hepatic function, blood flow or tissue elasticity.

This chapter examines general approaches and utility of in vivo/in vitro correlations and associations. In vitro tests must be validated by an in vivo correlation/association to be a meaningful quality control tool and to be useful as a surrogate marker for in vivo performance. Science and regulatory issues relative to in vivo/in vitro correlations have been topics of several national and international conferences and publications. For immediate-release products, useful correlations may sometimes be developed for several dosage forms, i.e., a correlation or association is applicable irrespective of formulation differences. Two general relationships can be defined between in vitro dissolution and in vivo bioavailability as follows: in vivo/in vitro correlations; and in vivo/in vitro associations. The in vivo parameters essential for correlation and/or association with in vitro data are obtained from bioavailability and/or bioequivalence studies in humans. In vitro parameters for correlation and/or association with in vivo performance parameters are obtained from in vitro dissolution test procedures that yield dissolution profiles.

Background and Aims: Gut microbial changes associated with Middle Eastern compared to Western diet can benefit cirrhosis by reducing hospitalizations.The interaction of gutderived and other metabolites across these dietary & ethnic differences is unclear.We aimed to define metabolomic changes associated with Western & Middle-Eastern diet in healthy & cirrhotic subjects.Method: Compensated(Comp) & decompensated (Decomp) cirrhotic outpts and healthy controls (ctrls) were enrolled.A dietary history, cirrhosis severity were obtained with stool for microbiota (16srRNA diversity) and plasma for metabolomics (NMR spectroscopy) were obtained.Comparisons were made between cohorts based on liver disease/stage & within the country-based cohort.These were correlated with microbial diversity & diet.Q 2 >0.4 indicates good separation.Results: 296 age-balanced subjects (157 USA [8 ctrls,59 comp,50 decomp]; 139 Turkey [46 ctrls,50 comp,43 decomp] were included.Cirrhotics between cohorts had similar MELD scores (11 vs 12) metabolic syndrome & diabetes (p=0.42).Diet: All of the USA cohort consumed a high-fat Western diet.Coffee intake was higher in US subjects, while tea, fermented milk and chocolate intake were higher in the Turkish group (all p<0.05).Microbiota: We found a significantly higher diversity in Turkish cohort than USA group regardless of cirrhosis; diversity similar in Turkish group between controls & cirrhotics (p=0.16),but altered within the US-cohort being lowest in decomp pts (p<0.001).Metabolomics: Between countries: There were differences between controls, comp & decomp pts of US vs Turkey (Figure, Q2 0.62, 0.41 & 0.60 respectively) due to a higher lactate and lipid differences in Turkey compared to US. CH2 and CH3 lipids were higher in earlier stages but lower in decomp in Turkey compared to US (Figure).Within countries: there were differences in plasma metabolites within the Turkish cohort, despite similar microbial diversity, which was greatest between ctrls vs cirrhosis (Q2 ctrlcomp 0.44, ctrl-decomp 0.70 & comp-decomp 0.26).Within the US group, the difference was greatest between ctrl-decomp (Q2 0.58) rather than ctrl-comp (Q2 0.21) & compdecomp (Q2 0.28).Phosphocholine & CH2 lipids were lowest in decomp followed by comp & ctrls regardless of country, suggesting systemic lipid derangement related to cell regeneration.Conclusion: Plasma metabolomics showed systemic differences in circulating lipid metabolites in Turkish vs US cirrhosis and healthy cohort related to the dietary changes.These could modulate the potential benefits of the Middle Eastern diet in cirrhosis Su1087

The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeial Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration.

In this report, we emphasize the importance of public monographs with reference materials, coupled with careful process and change control and attention to GMPs, as a means of advancing access to good quality, safe, and effective medicines, with emphasis on available and incoming biologic medicines. With adequate control of articles covered by a monograph, these public standards can form the basis for a global public quality platform that covers reference products, non-interchangeable reference products, biosimilars, and interchangeable biosimilars. Working collaboratively with all stakeholders, new approaches allow these public standards to emerge nationally and globally in a timely way. Yet, there are increasing limitations in the availability of public standards for biologic medicines, which may reverse many decades of progress. Solutions are considered in this report.

Principles of dissolution science have been applied to allow waiver of in vivo bioequivalence studies for oral immediate release solid dosage forms, providing certain stipulations are met. This approach reduces regulatory burden without sacrificing product quality and performance requirements that assure continuing equivalence. These principles are broadly applicable to other dosage forms and routes of administration. In this article, we postulate a further opportunity, which relies on a determination of “optimal performance” for nonsolution orally administered drug products. The determination can be applied to certain highly soluble and rapidly dissolving drug products without further study, paving the way possibly for even further reductions in regulatory burden.

This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.

In the 5-year cycle that characterizes a continuous improvement of the US Pharmacopeial (USP) Convention, the Council of the Convention's Section on Global Public Health worked with USP's staff to assess USP's international contributions to date and to consider opportunities for expanding activities that help to ensure good healthcare around the globe.1 This article reviews USP's process and product standards that are used worldwide to ensure the quality of medicines and dietary supplements and to help mitigate the burden of counterfeit and substandard ingredients and products. The article also reviews USP's international programs during the past 5-year cycle, along with continuing and planned international activities.

On 1 March 2010, the US Pharmacopeial Convention released into commerce Lot P1I300 of its Prednisone Tablets Reference Standard for use in periodic performance verification testing (PVT) of dissolution Apparatus 1 and 2. This report presents the collaborative study data, development of the acceptance limits, and results from supporting work for this Lot.

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This article continues USP's public dialogs about applications of modern measurement science (metrology) to public or private specifications (monographs) of food and drug articles. An objective of the discussion is to promote understanding of traceability and uncertainty of measurement results. Adoption of modern metrologic principles helps ensure that a measurement of one or more property values (attributes) of a food or drug article are acceptable without regard to when (time), where (space), or how (technology) the measurement was conducted. The approach is applicable to both in-process and end-product measurements and facilitates and supports understanding of manufacturing and measurement variability relative to acceptance criteria. Application of modern metrologic principles to measurement of food and drug articles expands opportunities to ensure availability of good quality food and drugs in national and international markets.