Health economics of rotavirus immunization in Vietnam: potentials for favorable cost-effectiveness in developing countries

Introduction

Rotavirus is the most common cause of severe diarrhoea worldwide. Vietnam is situated in the region of high rotavirus infection incidence and eligible for financial support to introduce rotavirus vaccines into the Expanded Program of Immunization (EPI) from the GAVI. This study was designed to assess the cost-effectiveness of rotavirus immunization in Vietnam, explicitly the use of Rotateq^® and to assess the affordability of implementing universal rotavirus immunization based on GAVI-subsidized vaccine price in the context of Vietnamese healthcare system for the next 5 years.

Methodology

An age-structured cohort model was developed for the 2009 birth cohort in Vietnam. Two strategies were compared: one being the current situation without vaccination, and the other being mass universal rotavirus vaccination. The time horizon of the model was 5 years with time cycles of 1 month for children less than 1 year of age and annual analysis thereafter. Outcomes included mild, moderate, severe cases and death. Multiple outcomes per rotavirus infection are possible in the model. Monte Carlo simulations were used to examine the acceptability and affordability of the rotavirus vaccination. All costs were expressed in 2009 US$.

Results

Rotavirus vaccination would not completely protect young children against rotavirus infection due to partial nature of vaccine immunity, however, would effectively reduce severe cases of rotavirus by roughly 55% during the first 5 years of life. Under GAVI-subsidized vaccine price (US$ 0.3/dose), the vaccine cost would amount to US$ 5.5 million per annum for 3-dose of the Rotateq^® vaccine. In the base-case, the incremental cost per quality-adjusted-life-year (QALY) was US$ 665 from the health system perspective, much lower than per-capita GDP of ∼US$ 1150 in 2009. Affordability results showed that at the GAVI-subsidized vaccine price, rotavirus vaccination could be affordable for Vietnamese health system.

Conclusion

Rotavirus vaccination in Vietnam would be a cost-effective health intervention. Vaccination only becomes affordable if the country receives GAVI's financial support due to the current high market vaccine price. Given the high mortality rate of under-five-year children, the results showed that rotavirus immunization is the “best hope” for prevention of rotavirus-related diarrhoeal disease in Vietnam. In the next five years, Vietnam is definitely in debt to financial support from international organizations in implementing rotavirus immunization. It is recommended that new rotavirus vaccine candidates be developed at cheaper price to speed up the introduction of rotavirus immunization in the developing world in general.     

Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation

Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.     

Progress in the research of artemisinin-related antimalarials: An update

Artemisinin, a sesquiterpene lactone endoperoxide isolated fromArtemisia annua L., and a number of its semisynthetic derivatives have shown to possess antimalarial properties. They are all eflective againstPlasmodium parasites that are resistant to the newest and commonly used antimalarial drugs. This article gives a survey of the literature dealing with artemisinin-relaled antimalarial issues that have appeared from the end of 1989 up to the beginning of 1994. A broad range of medical and pharmaceutical disciplines is covered, including phytochemical aspects like the selection of high-producing plants, analytical procedures, and plant biotechnology. Furthermore, the organic synthesis of artemisinin derivatives is discussed, as well as their mechanism of action and antimalarial activity, metabolism and pharmacokinetics, clinical studies, sideeffects and toxicology, and biological activities other than antimalarial activity.     

Eupatorium cannabinum L.

A review onEupatorium cannabinum L. is given, including botany, history and constituents. The sesquiterpene lactones are discussed in more detail, covering their biosynthesis, isolation, analysis and biological activity. Special attention is paid to the cytotoxic and antitumour activities of the sesquiterpene lactones.     

Isolation and identification of dihydroartemisinic acid from artemisia annua and its possible role in the biosynthesis of artemisinin

Dihydroartemisinic acid (2) was isolated as a natural product from Artemisia annua in a 66% yield, and its structure was confirmed by 1H and 13C NMR spectroscopy. Compound 2 could be chemically converted to artemisinin (4) under conditions that may also be present in the living plant. The results suggest that the conversion of 2 into 4 in the living plant might be a nonenzymatic conversion.     

Lignans from cell suspension cultures of Phyllanthus niruri, an Indonesian medicinal plant

Cell suspension cultures of Phyllanthus niruri were used to study the lignan profiles and biosynthesis. Suspension cultures yielded two lignans: the new cubebin dimethyl ether (1) and urinatetralin (2), a new lignan from P. niruri, but reported earlier from P. urinaria. This is the first report of cell suspension cultures of P. niruri that successfully produce lignans. Feeding 0.5 mM ferulic acid or 0.5 mM caffeic acid, being early precursors of lignan biosynthesis, resulted in an increase up to 0.7 mg g(-1) DW of 1 (control value 0.1 mg g(-1) DW) and up to 0.3 mg g(-1) DW of 2 (control value 0.2 mg g(-1) DW). Comparison of the lignan profiles of cell suspensions, callus cultures, aerial plant parts, roots, and seeds showed significant differences.     

Central nervous depressant activity of valerenic Acid in the mouse

Valerenic acid, isolated from VALERIANA OFFICINALIS L. s.l. affected the rotarod and traction performance of mice in a similar manner to that of pentobarbital which was used together with chlorpromazine and diazcpam as reference substance in both tests. A decrease of locomotility of mice was also noticed after administration of valerenic acid, in particular when this compound was administered to the same group of mice a week later than the vehicle. In addition valerenic acid was found to prolong the pentobarbital induced sleeping time. It can be concluded, that valerenic acid has aspecific central nervous depressent properties. This factor should be taken into account when considering the sedative action of Valerian preparations.     

A Non-Invasive, Low-Cost Study Design to Determine the Release Profile of Colon Drug Delivery Systems: A Feasibility Study

Purpose

Conventional bioavailability testing of dosage forms based on plasma concentration-time graphs of two products in a two-period, crossover-design, is not applicable to topical treatment of intestinal segments. We introduce an isotope dual-label approach (¹³C- and ¹⁵N₂-urea) for colon drug delivery systems that can be performed in a one-day, non-invasive study-design.

Methods

Four healthy volunteers took an uncoated or a ColoPulse-capsule containing ¹³C-urea and an uncoated capsule containing ¹⁵N₂-urea. In case of colon-release ¹³C-urea is fermented and ¹³C detected as breath ¹³CO₂. Absorbed ¹³C-urea and ¹⁵N-urea are detected in urine.

Results

C and ¹⁵N in urine released from uncoated capsules showed a ratio of 1.01?±?0.06. The ¹³C/¹⁵N-recovery ratio after intake of a ColoPulse-capsule was constant and lower >12?h post-dose (median 0.22, range 0.13?C0.48). The ¹³C/¹⁵N-ratio in a single urine sample at t ??12?h predicted the 24?h non-fermented fraction ¹³C of <26?%. Breath ¹³CO₂ indicated delayed (>3?h) release and a fermented fraction ¹³C >54?%.

Conclusions

Breath and urine ¹³C and ¹⁵N data describe the release-profile and local bioavailability of a colon delivery device. This allows non-invasive bioavailability studies for evaluation of colon-specific drug delivery systems without radioactive exposure and with increased power and strongly reduced costs.     

Applications of stable isotopes in clinical pharmacology

This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacokinetic profile or mode of action of a drug substance. Secondly, stable isotopes may be used for the assessment of drug products or drug delivery systems by determination of parameters such as the bioavailability or the release profile. Thirdly, patients may be assessed in relation to patient-specific drug treatment; this concept is often called personalized medicine. In this article, the application of stable isotope technology in the aforementioned three areas is reviewed, with emphasis on developments over the past 25 years. The applications are illustrated with examples from clinical studies in humans.