Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance

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Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria

Poor-quality antimalarial drugs lead to drug resistance and inadequate treatment, which pose an urgent threat to vulnerable populations and jeopardise progress and investments in combating malaria. Emergence of artemisinin resistance or tolerance in Plasmodium falciparum on the Thailand-Cambodia border makes protection of the effectiveness of the drug supply imperative. We reviewed published and unpublished studies reporting chemical analyses and assessments of packaging of antimalarial drugs. Of 1437 samples of drugs in five classes from seven countries in southeast Asia, 497 (35%) failed chemical analysis, 423 (46%) of 919 failed packaging analysis, and 450 (36%) of 1260 were classified as falsified. In 21 surveys of drugs from six classes from 21 countries in sub-Saharan Africa, 796 (35%) of 2297 failed chemical analysis, 28 (36%) of 77 failed packaging analysis, and 79 (20%) of 389 were classified as falsified. Data were insufficient to identify the frequency of substandard (products resulting from poor manufacturing) antimalarial drugs, and packaging analysis data were scarce. Concurrent interventions and a multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing of antimalarial drugs. Empowering of national medicine regulatory authorities to protect the global drug supply is more important than ever.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(12)70064-6.pdf

Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa

Objective: To explore the evidence available of poorquality (counterfeit and substandard) medicines in the literature. Design: Systematic review. Data sources: Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013. Eligibility criteria: Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines. Study appraisal and synthesis: Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income. Data extraction: Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines. Results: 44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (p<0.000; 95% CI 0.21 to 0.32). No individual data about the prevalence in upper middle-income countries and high-income countries were available. Limitations: Studies with strong methodology were few. The majority did not differentiate between substandard and counterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials.

https://bmjopen.bmj.com/content/bmjopen/3/8/e002923.full.pdf

Substandard and counterfeit medicines: a systematic review of the literature

Importance Substandard and falsified medicines burden health systems by diverting resources to ineffective or harmful therapies, causing medical complications and prolonging illnesses. However, the prevalence and economic impact of poor-quality medicines is unclear. Objective To conduct a systematic review and meta-analysis to assess the prevalence and estimated economic burden of substandard and falsified essential medicines in low- and middle-income countries. Data Sources Five databases (PubMed, EconLit, Global Health, Embase, and Scopus) were searched from inception until November 3, 2017. Study Selection Publications were assessed to determine whether they examined medicine quality and the prevalence and/or economic burden of substandard and falsified medicines in low- and middle-income countries. Studies with a sample size of 50 or more were included in the meta-analysis. Data Extraction and Synthesis The study is registered in PROSPERO and reported via the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Study quality was assessed using an adapted Medicine Quality Assessment Reporting Guidelines scoring metric. Multiple reviewers conducted the data extraction and quality assessment independently. Main Outcomes and Measures Prevalence and/or estimated economic impact of substandard and falsified medicines. Results Two hundred sixty-five studies that estimated the prevalence of poor-quality essential medicines in low- and middle-income countries were identified. Among 96 studies that tested 50 samples or more (67 839 total drug samples), overall prevalence of poor-quality medicines was 13.6% (95% CI, 11.0%-16.3%), with regional prevalence of 18.7% in Africa (95% CI, 12.9%-24.5%) and 13.7% in Asia (95% CI, 8.2%-19.1%). Of studies included in the meta-analysis, 19.1% (95% CI, 15.0%-23.3%) of antimalarials and 12.4% (95% CI, 7.1%-17.7%) of antibiotics were substandard or falsified. Eight approximations of the economic impact, focused primarily on market size, with poor or undisclosed methods in estimation were identified, ranging from $10 billion to $200 billion. Conclusions and Relevance Poor-quality essential medicines are a substantial and understudied problem. Methodological standards for prevalence and rigorous economic studies estimating the burden beyond market size are needed to accurately assess the scope of the issue and inform efforts to address it. Global collaborative efforts are needed to improve supply-chain management, surveillance, and regulatory capacity in low- and middle-income countries to reduce the threat of poor-quality medicines. Trial Registration PROSPERO Identifier:CRD42017080266

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Prevalence and Estimated Economic Burden of Substandard and Falsified Medicines in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

Tuberculosis (TB) is one of the most ancient diseases of mankind, with molecular evidence going back to over 17,000 years. In spite of newer modalities for diagnosis and treatment of TB, unfortunately, people are still suffering, and worldwide it is among the top 10 killer infectious diseases, second only to HIV. According to World Health Organization (WHO), TB is a worldwide pandemic. It is a leading cause of death among HIV-infected people. In India, historically speaking, fight against TB can be broadly classified into three periods: early period, before the discoveries of x-ray and chemotherapy; post-independence period, during which nationwide TB control programs were initiated and implemented; and the current period, during which the ongoing WHO-assisted TB control program is in place. Today, India's DOTS (directly observed treatment-short course) program is the fastest-expanding and the largest program in the world in terms of patients initiated on treatment; and the second largest, in terms of population coverage. Major challenges to control TB in India include poor primary health-care infrastructure in rural areas of many states; unregulated private health care leading to widespread irrational use of first-line and second-line anti-TB drugs; spreading HIV infection; lack of political will; and, above all, corrupt administration. Multidrug-resistant TB (MDR-TB) is another emerging threat to TB eradication and is a result of deficient or deteriorating TB control program. WHO with its "STOP TB" strategy has given a vision to eliminate TB as a public health problem from the face of this earth by 2050. For this review article, data available at the official websites of WHO; and from the Ministry of Health, Government of India, were consulted, and search engines PubMed(®) and Google Scholar(®) were used.

Tuberculosis: current situation, challenges and overview of its control programs in India.

There is little existing knowledge about actual quality of drugs provided by different providers in Nigeria and in many sub-Saharan African countries. Such information is important for improving malaria treatment that will help in the development and implementation of actions designed to improve the quality of treatment. The objective of the study was to determine the quality of drugs used for the treatment of malaria in a broad spectrum of public and private healthcare providers. The study was undertaken in six towns (three urban and three rural) in Anambra state, south-east Nigeria. Anti-malarials (225 samples), which included artesunate, dihydroartemisinin, sulphadoxine-pyrimethamine (SP), quinine, and chloroquine, were either purchased or collected from randomly selected providers. The quality of these drugs was assessed by laboratory analysis of the dissolution profile using published pharmacopoeial monograms and measuring the amount of active ingredient using high performance liquid chromatography (HPLC). It was found that 60 (37%) of the anti-malarials tested did not meet the United States Pharmacopoeia (USP) specifications for the amount of active ingredients, with the suspect drugs either lacking the active ingredients or containing suboptimal quantities of the active ingredients. Quinine (46%) and SP formulations (39%) were among drugs that did not satisfy the tolerance limits published in USP monograms. A total of 78% of the suspect drugs were from private facilities, mostly low-level providers, such as patent medicine dealers (vendors). This study found that there was a high prevalence of poor quality drugs. The findings provide areas for public intervention to improve the quality of malaria treatment services. There should be enforced checks and regulation of drug supply management as well as stiffer penalties for people stocking substandard and counterfeit drugs.

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Viola Okoye

Papers

Quality of anti-malarial drugs provided by public and private healthcare providers in south-east Nigeria.