Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme

The great demand for improved long-acting injectable steroid contraceptives, particularly in developing countries, and the relative lack of interest from the pharmaceutical industry to develop such products stimulated WHO to launch a synthetic and screening programme to find improved, safe and acceptable injectable preparations. More than 210 esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) have been prepared in university-based research laboratories situated mainly in developing countries, and then screened by NICHHD in animal models. The following three compounds, levonorgestrel butanoate, cyclopropylcarboxylate and cyclobutylcarboxylate, proved to be particularly long-acting when administered as microcrystalline suspensions. The overall strategy of this research and development programme is described.     

The World Health Organization's Global Strategy for the Prevention and Control of AIDS

The magnitude of the human immunodeficiency virus (HIV) pandemic and its broad impact have been seriously underestimated and underappreciated. The Special Programme on AIDS (acquired immunodeficiency syndrome) of the World Health Organization (WHO) was created on February 1, 1987, as the architect and keystone of the global AIDS plan. The Special Programme on AIDS has designed the global strategy, has raised sufficient funds to begin implementing the strategy and, for this effort, has marshalled the support of every nation in the world. AIDS affects both the developing and the industrialized worlds; therefore, every country will need a national AIDS program. This is vital not only for national interests but also because ultimately AIDS cannot be stopped in any one country unless it is stopped in all countries. National AIDS programs are being rapidly established throughout the world with the technical and financial support of WHO''s Special Programme on AIDS. At the global level, the Special Programme is responsible for strategic leadership, developing consensus, coordinating scientific research, exchanging information, assuring technical cooperation and mobilizing and coordinating resources. National AIDS committees have already been established in more than 150 countries and, by the end of 1988, the Special Programme will support every country in the world that requests collaboration.     

Current status of fertility control methods in India

Approximately 48.2% of couples of 15 to 49 years of age practice family planning methods in India. Female sterilization accounts for 34.2%, with male sterilization declining from 3·4% in 1992–93 to 1·9% in 1998–99. Use of the condom increased to 3·1% from 2·4%. There is an urgent need for research to develop new contraceptive modalities especially for men and also for women and to make existing methods more safe, affordable and acceptable. Current efforts in India to develop a male contraceptive are mainly directed towards (i) development of antispermatogenic agents to suppress sperm production, (ii) prevention of sperm maturation, (iii) prevention of sperm transport through vas deferens or rendering these sperm infertile and (iv) prevention of sperm deposition. Research work in the field of prevention of sperm transport through vas deferens has made significant advances. Styrene maleic anhydride (SMA) disturbed the electrical charge of spermatozoa leading to acrosome rupture and consequent loss in fertilizing ability of sperm. A multicentre phase-III clinical trial using SMA is continuing and it is hoped that the SMA approach would be available in the near future as an indigenously developed injectable intra-vasal male contraceptive. The safety and efficacy of available oral contraceptives were evaluated. An indigenously developed oral contraceptive ‘Centchorman’, which is a nonsteroidal, weakly estrogenic but potently antiestrogenic, was found to be safe and effective and is now being marketed in India since 1991 as a ‘once a week’ pill. Cyclofem and Mesigyna have been recommended as injectable contraceptives with proper counselling and service delivery by Indian studies. It has been recommended that these injectable contraceptives be added to the existing range of contraceptive methods available in the National Family Planning Programme. Based on the Indian studies CuT 200 was also recommended. Studies have indicated the advantage of intrauterine devices (IUD); they are long acting, relatively easily removed and fertility returns rapidly after their removal. Recent studies have recommended CuT 200 for use up to 5 years. The combination of some plant products i.e.Embelia ribes, Borax andPiper longum has been found to be safe and effective as a female contraceptive and the results of phase-I clinical trials are encouraging. Research work is going on in the country in various areas with special reference to hormonal contraceptive — a three monthly injectable contraceptive, immuno-contraceptives, antiprogestins, etc.     

DNA 测序技术领域的相关政府投入分析

DNA测序技术是遗传工程的核心技术之一,发展快速和低成本的基因测序技术成为研究焦点。美国、欧盟等发达国家和地区大力支持DNA测序技术的创新研究,并投入了大量的科研经费。在美国,国家卫生研究院(NIH)下属的国家人类基因组研究院(NHGRI)、美国能源部(DOE)以及美国科学基金委(NSF)等机构是进行DNA测序技术相关项目经费分配的主要政府部门。DNA测序作为生命科学研究的关键技术也是欧盟框架计划资助的重要内容之一,其以多个欧洲国家间合作以及产学研合作的形式开展。中国在DNA测序技术领域也开展了一些研究。     

Meeting Rural Demand: A Case for Combining Community-Based Distribution and Social Marketing of Injectable Contraceptives in Tigray,Ethiopia

Background

In Sub-Saharan Africa, policy changes have begun to pave the way for community distribution of injectable contraceptives but sustaining such efforts remains challenging. Combining social marketing with community-based distribution provides an opportunity to recover some program costs and compensate workers with proceeds from contraceptive sales. This paper proposes a model for increasing access to injectable contraceptives in rural settings by using community-based distributers as social marketing agents and incorporating financing systems to improve sustainability.

Methods

This intervention was implemented in three districts of the Central Zone of Tigray, Ethiopia and program data has been collected from November 2011 through October 2012. A total of 137 Community Based Reproductive Health Agents (CBRHAs) were trained to provide injectable contraceptives and were provided with a loan of 25 injectable contraceptives from a drug revolving fund, created with project funds. The price of a single dose credited to a CBRHA was 3 birr ($0.17) and they provide injections to women for 5 birr ($0.29), determined with willingness-to-pay data. Social marketing was used to create awareness and generate demand. Both quantitative and qualitative methods were used to examine important feasibility aspects of the intervention.

Results

Forty-four percent of CBRHAs were providing family planning methods at the time of the training and 96% believed providing injectable contraceptives would improve their services. By October 2012, 137 CBRHAs had successfully completed training and provided 2541 injections. Of total injections, 47% were provided to new users of injectable contraceptives. Approximately 31% of injections were given for free to the poorest women, including adolescents.

Conclusions

Insights gained from the first year of implementation of the model provide a framework for further expansion in Tigray, Ethiopia. Our experience highlights how program planners can tailor interventions to match family planning preferences and create more sustainable contraceptive service provision with greater impact.     

Cost effectiveness of human papilloma virus testing in cervical cancer screening: a literature review

Human papilloma virus DNA testing may improve the cost effectiveness of cervical cancer screening programs. However, the circumstances to get this improvement are not the same between countries. The objective of this paper is to evaluate the cost effectiveness of introducing human papilloma virus testing in the current screening practice both in developed and developing countries. We conducted a review of published articles since January 2000 until December 2006 related to the cost effectiveness of introducing human papilloma virus testing in cervical cancer screening programs. A total of 17 original researches and six reviews were analyzed. Human papilloma virus testing is cost effective in developed countries only if it is a complementary test to Pap test and used to determine the management of women with atypical squamus cells of undetermined significance, the interval among tests is increased more than two years and it is performed in women over 30 years. On the other hand, developing countries should establish first organized screening programs and guarantee full coverage and access to diagnosis and treatment.     

WHO's special programmes: undermining from above.

Despite the World Health Organisation''s spoken commitment to developing integrated primary health care, its most visible and successful activities are not integrated within countries; they are its disease specific intervention programmes, such as the Global Programme on AIDS and the programmes for the control of diarrhoeal and acute respiratory diseases. The 10 or so special programmes, all but one of which (the onchocerciasis control programme) are based in Geneva, have found increasing favour among donors, but critics say that they undermine WHO''s attempts to integrate its activities at country level and discourage countries from developing their own capacity.     

Oral contraceptive use and venous thromboembolism: absence of an effect of smoking.

We conducted a case-control study to test the hypothesis that women smokers who use oral contraceptives have an increased risk of developing venous thrombosis. Patients and controls were drawn from two sets of hospital patients already included in the Boston Collaborative Drug Surveillance Programme. Sixty patients with uncomplicated thromboembolism were matched with 180 controls with other diagnoses; all were premenopausal women taking oral contraceptives. Patients with conditions that might predispose to thromboembolism or be related to smoking were excluded. We found no association between smoking habits and thromboembolism. Similarly, we found no association between thromboembolism, smoking, and duration of oral contraceptive use. Thus we conclude that differences in fibrinolytic activity between smokers and non-smokers are not major factors in the aetiology of uncomplicated thromboembolism in women using oral contraceptives.     

Stability testing of vaccines: Developing Countries Vaccine Manufacturers' Network (DCVMN) perspective

Stability testing is an integral part of the vaccine manufacturing process and is crucial for the success of immunization programs. WHO (World Health Organization) has recently published guidelines on the stability testing of vaccines. These guidelines enlist scientific basis and principles for stability testing at various stages like development, pre-clinical, clinical, licensing, lot release and post-licensure monitoring. DCVMN (Developing Countries Vaccine Manufacturers' Network) is an international body of developing countries vaccine manufacturers and has viewpoints on technical and administrative issues in stability testing of vaccines. We here highlight viewpoints, possible roles and global expectations of DCVMN in the area of stability testing of vaccines.     

Making a difference: 30 years of TDR

When the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) was established in the mid-1970s, it represented an innovative institutional formula in terms of its structure and the manner in which scientists were convened from both developed and developing countries to address some of the world's most neglected parasitic diseases. A review of TDR's historical record sheds light not only on some important milestones in tropical-disease research, but also on how future challenges could be approached and hopefully surmounted.     

Perspectives of contraceptive choices for men

Apart from condoms and vasectomy, which have several limitations of their own, no other methods of contraception are available to men. Various chemical, hormonal, vas based and herbal contraceptives have been examined and few of them have reached the stage of clinical testing. Promising leads have been obtained from testosterone buciclate/undecanoate, alone or in combination with levonorgestrel butanoate or cyproterone acetate, RISUG, an injectable intravasal contraceptive and a few herbal products, particularly the seed products of Carica papaya. It is feasible that an ideal male contraceptive, that meets out all the essential criteria will be made available to the community in the near future.     

Impact of Pay for Performance on Prescribing of Long-Acting Reversible Contraception in Primary Care: An Interrupted Time Series Study

Background

The aim of this study was to evaluate the impact of Quality and Outcomes Framework (QOF), a major pay-for-performance programme in the United Kingdom, on prescribing of long-acting reversible contraceptives (LARC) in primary care.

Methods

Negative binomial interrupted time series analysis using practice level prescribing data from April 2007 to March 2012. The main outcome measure was the prescribing rate of long-acting reversible contraceptives (LARC), including hormonal and non hormonal intrauterine devices and systems (IUDs and IUSs), injectable contraceptives and hormonal implants.

Results

Prescribing rates of Long-Acting Reversible Contraception (LARC) were stable before the introduction of contraceptive targets to the QOF and increased afterwards by 4% annually (rate ratios  = 1.04, 95% CI = 1.03, 1.06). The increase in LARC prescribing was mainly driven by increases in injectables (increased by 6% annually), which was the most commonly prescribed LARC method. Of other types of LARC, the QOF indicator was associated with a step increase of 20% in implant prescribing (RR =  1.20, 95% CI =  1.09, 1.32). This change is equivalent to an additional 110 thousand women being prescribed with LARC had QOF points not been introduced.

Conclusions

Pay for performance incentives for contraceptive counselling in primary care with women seeking contraceptive advice has increased uptake of LARC methods.     

World Health Organization's programme on the prevention of blindness

The WHO Programme for the Prevention of Blindness was established in 1978, reflecting the need for action against the burden of avoidable blindness, which constitutes an increasingly serious socioeconomic problem in many countries. A vast majority of the world's blind live in developing countries, where unoperated cataract, trachoma, xerophthalmia and onchocerciasis are the main causes of visual loss. Thus, more than two-thirds of blindness encountered in such areas is either preventable or curable. The objectives of the WHO Programme for the Prevention of Blindness are to reduce the amount of avoidable blindness in developing countries, and to make essential eye care available to all. In order to achieve this, blindness prevention must form part of primary health care, which is the basic strategy of the World Health Organization to attain the overall goal of "Health for All by the Year 2000". Emphasis is placed on the establishment of national programmes for the prevention of blindness, geared to local needs and resources. This implies a need for a careful programming process, in relation to the general provision of health services.     

Invasive cervical cancer and combined oral contraceptives. WHO collaborative study of neoplasia and steroid contraceptives.

A multicentre, hospital based case-control study is being conducted under the auspices of the World Health Organisation to determine whether steroid contraceptives alter the risk of gynaecological, breast, and hepatic neoplasms. Preliminary results, largely from developing countries, on the relation between combined oral contraceptives and invasive cervical carcinoma showed a relative risk of 1.19 (95% confidence interval 0.99-1.44) in women who had ever used oral contraceptives. The risk increased with duration of use, giving a relative risk of 1.53 after five years. This finding supports a causal interpretation, but it could also be due to incomplete control for confounding sexual variables and other sources of bias.     

The Trypanosoma cruzi genome initiative

An initiative was launched in 1994 by the Special Programme for Research and Training in Tropical Diseases (TDR) of the WHO to analyse the genomes of the parasites Filaria, Schistosoma, Leishmania, Trypanosoma brucei and Trypanosoma cruzi. Five networks were established through wide publicity, holding meetings of key laboratories and developing proposals which were then reviewed by the Steering Committee of Strategic Research for financial support. The aim of the Programme was to use the platform of these networks to: (1) train scientists from tropical disease-endemic countries; (2) transfer technology and share material and expertise, thereby reducing costs and increasing efficiency; and (3) provide an information system that is accessible globally as soon as the results become available. The initial target was to produce a low-resolution genome map for each of the parasites, but it soon became evident that by using rapidly developing technologies, it might be feasible to complete DNA-sequence analysis for some of the parasites in the next decade, as discussed here by Alberto Carlos Frasch and colleagues, with particular focus on the T. cruzi genome initiative.     

Return of fertility after use of the injectable contraceptive Depo Provera: up-dated data analysis

796 Thai women who stopped using the long-acting injectable contraceptive depot medroxyprogesterone acetate (DMPA, Depo Povera), 437 women who stopped using oral contraceptives and 125 women who had an IUD removed to have a planned pregnancy, were followed up to ascertain the delay to conception after the end of contraception and to determine the proportion of women who did not conceive in the 4 years after discontinuation. The median delay to conception was 5.5 months plus the estimated duration of the effect of the last injection of DMPA, 3 months for oral contraceptives and 4.5 months after discontinuing the IUD. The proportion of women who did not conceive within 9 months after discontinuation of DMPA is similar to that of ex-IUD users, and by 3 years to that of the ex-pill sample. There is no evidence to suggest that prolonged use of DMPA increases the delay to conception. The return of fertility among never pregnant ex-users resembled that of ever pregnant ex-users. There were comparable proportons of live births among ex-DMPA users and ex-pill users and both of these showed higher proportions of live-births than ex-IUD users. There was no evidence to suggest that previous use of DMPA had any significant adverse effect on the outcome of pregnancy of the subsequent births. This study did not show any association between infertility and the previous use of DMPA or other contraceptives.     

Levonorgestrel and mifepristone in emergency contraception

Research on new technologies by the Special Programme of Research, Development and Research Training in Human Reproduction at WHO has led to the development of two new methods for emergency contraception, the levonorgestrel regimen and a low-dose mifepristone regimen. In 4 years, the levonorgestrel regimen has already been approved in some 95 countries. We review this research and present combined data from our multinational trials and combined estimates of efficacy for mifepristone and for levonorgestrel separately. Data were available for 6283 women in 10 mg mifepristone groups and 4098 women in levonorgestrel groups. One of these studies compared the two methods, namely a randomized, double-blind trial in which we also investigated a single dose of 1.5 mg of levonorgestrel. Both levonorgestrel and mifepristone are effective for emergency contraception and prevent a high percentage of pregnancies when used within a few days after coitus. Mifepristone is associated with later return of menses compared to levonorgestrel.     

A research agenda for helminth diseases of humans: health research and capacity building in disease-endemic countries for helminthiases control

Capacity building in health research generally, and helminthiasis research particularly, is pivotal to the implementation of the research and development agenda for the control and elimination of human helminthiases that has been proposed thematically in the preceding reviews of this collection. Since helminth infections affect human populations particularly in marginalised and low-income regions of the world, they belong to the group of poverty-related infectious diseases, and their alleviation through research, policy, and practice is a sine qua non condition for the achievement of the United Nations Millennium Development Goals. Current efforts supporting research capacity building specifically for the control of helminthiases have been devised and funded, almost in their entirety, by international donor agencies, major funding bodies, and academic institutions from the developed world, contributing to the creation of (not always equitable) North-South "partnerships". There is an urgent need to shift this paradigm in disease-endemic countries (DECs) by refocusing political will, and harnessing unshakeable commitment by the countries' governments, towards health research and capacity building policies to ensure long-term investment in combating and sustaining the control and eventual elimination of infectious diseases of poverty. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. This paper discusses the challenges confronting capacity building for parasitic disease research in DECs, describes current capacity building strategies with particular reference to neglected tropical diseases and human helminthiases, and outlines recommendations to redress the balance of alliances and partnerships for health research between the developed countries of the "North" and the developing countries of the "South". We argue that investing in South-South collaborative research policies and capacity is as important as their North-South counterparts and is essential for scaled-up and improved control of helminthic diseases and ultimately for regional elimination.     

Genetics and molecular basis of human peroxisome biogenesis disorders

Human peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive disorders comprised of two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. Thirteen of these genes are associated with ZSS disorders. The genetic heterogeneity among PBDs and the inability to predict from the biochemical and clinical phenotype of a patient with ZSS which of the currently known 13 PEX genes is defective, has fostered the development of different strategies to identify the causative gene defects. These include PEX cDNA transfection complementation assays followed by sequencing of the thus identified PEX genes, and a PEX gene screen in which the most frequently mutated exons of the different PEX genes are analyzed. The benefits of DNA testing for PBDs include carrier testing of relatives, early prenatal testing or preimplantation genetic diagnosis in families with a recurrence risk for ZSS disorders, and insight in genotype-phenotype correlations, which may eventually assist to improve patient management. In this review we describe the current status of genetic analysis and the molecular basis of PBDs. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.     

Availability and Use of HIV Monitoring and Early Infant Diagnosis Technologies in WHO Member States in 2011–2013: Analysis of Annual Surveys at the Facility Level

BackgroundThe Joint United Nations Programme on HIV and AIDS (UNAIDS) 90-90-90 targets have reinforced the importance of functioning laboratory services to ensure prompt diagnosis and to assess treatment efficacy. We surveyed the availability and utilization of technologies for HIV treatment monitoring and early infant diagnosis (EID) in World Health Organization (WHO) Member States.ConclusionThis is the first attempt to comprehensively gather information on HIV testing technology coverage in WHO Member States. The survey results suggest that major operational changes will need to be implemented, particularly in low- and middle-income countries, if the 90-90-90 targets are to be met.