How conflicts of interest hinder effective regulation of healthcare: an analysis of antimicrobial use regulation in Cambodia, Indonesia and Pakistan.

BACKGROUND: There has been insufficient attention to a fundamental force shaping healthcare policies-conflicts of interest (COI). We investigated COI, which results in the professional judgement of a policymaker or healthcare provider being compromised by a secondary interest, in relation to antimicrobial use, thereby illuminating challenges to the regulation of medicines use more broadly. Our objectives were to characterise connections between three groups-policymakers, healthcare providers and pharmaceutical companies-that can create COI, and elucidate the impacts of COI on stages of the policy process. METHODS: Using an interpretive approach, we systematically analysed qualitative data from 136 in-depth interviews and five focus group discussions in three Asian countries with dominant private healthcare sectors: Cambodia, Indonesia and Pakistan. FINDINGS: We characterised four types of connections that were pervasive between the three groups: financial, political, social and familial. These connections created strong COI that could impact all stages of the policy process by: preventing issues related to medicines sales from featuring prominently on the agenda; influencing policy formulation towards softer regulatory measures; determining resource availability for, and opposition to, policy implementation; and shaping how accurately the success of contested policies is reported. INTERPRETATION: Our multicountry study fills a gap in empirical evidence on how COI can impede effective policies to improve the quality of healthcare. It shows that COI can be pervasive, rather than sporadic, in influencing regulation of medicine use, and highlights that, in addition to financial connections, other types of connections should be examined as important drivers of COI.

Is enhancing the professionalism of healthcare providers critical to tackling antimicrobial resistance in low- and middle-income countries?

BACKGROUND: Healthcare providers' (HCPs) professionalism refers to their commitment and ability to respond to the health needs of the communities they serve and to act in the best interest of patients. Despite attention to increasing the number of HCPs in low- and middle-income countries (LMIC), the quality of professional education delivered to HCPs and their resulting professionalism has been neglected. The Global Action Plan on Antimicrobial Resistance (AMR) seeks to reduce inappropriate use of antibiotics by urging patients to access antibiotics only through qualified HCPs, on the premise that qualified HCPs will act as more responsible and competent gatekeepers of access to antibiotics than unqualified HCPs. METHODS: We investigate whether weaknesses in HCP professionalism result in boundaries between qualified HCPs and unqualified providers being blurred, and how these weaknesses impact inappropriate provision of antibiotics by HCPs in two LMIC with increasing AMR-Pakistan and Cambodia. We conducted 85 in-depth interviews with HCPs, policymakers, and pharmaceutical industry representatives. Our thematic analysis was based on a conceptual framework of four components of professionalism and focused on identifying recurring findings in both countries. RESULTS: Despite many cultural and sociodemographic differences between Cambodia and Pakistan, there was a consistent finding that the behaviour of many qualified HCPs did not reflect their professional education. Our analysis identified five areas in which strengthening HCP education could enhance professionalism and reduce the inappropriate use of antibiotics: updating curricula to better cover the need for appropriate use of antibiotics; imparting stronger communication skills to manage patient demand for medications; inculcating essential professional ethics; building skills required for effective collaboration between doctors, pharmacists, and lay HCPs; and ensuring access to (unbiased) continuing medical education. CONCLUSIONS: In light of the weaknesses in HCP professionalism identified, we conclude that global guidelines urging patients to only seek care at qualified HCPs should consider whether HCP professional education is equipping them to act in the best interest of the patient and society. Our findings suggest that improvements to HCP professional education are needed urgently and that these should focus not only on the curriculum content and learning methods, but also on the social purpose of graduates.

Invisible medicine sellers and their use of antibiotics: a qualitative study in Cambodia.

BACKGROUND: Global attention to antimicrobial resistance has increased interest in tackling the widespread inappropriate dispensing of antibiotics by informal, for-profit healthcare providers (HCPs). We provide new evidence on an understudied group of informal HCPs: invisible medicine sellers (IMS) who operate without any marked facility. We investigated factors that influence community decisions on which HCPs to purchase medicines from, focusing on reasons for using IMS, and compared different HCPs' knowledge of antibiotic use. METHODS: We conducted community focus group discussions (FGDs) in seven purposively selected villages representing high and low informal HCPs use in two peri-urban districts in Phnom Penh, Cambodia. Using information from the FGDs to identify HCPs that sell medicines, we interviewed 35 participants: 21 HCPs (including five IMS) and 14 key informants, including government HCPs and village leaders. We adopted an interpretative approach and conducted a thematic analysis. RESULTS: Community members typically knew of several formal and informal HCPs selling medicines nearby, and IMS were common, as were doctors that sell medicines covertly. Two factors were most salient in influencing the choice of HCP for medicine purchasing. The first was trust in the effectiveness of medicines provided, judged by the speed of symptomatic relief. This pushed HCPs to provide several medicines, including antibiotics, at the first consultation. The second was the convenience offered by IMS and other informal HCPs: supplying medicines when other facilities are closed, accepting delayed payments, providing incomplete courses of medication and selling human antibiotics for animal use. CONCLUSION: This first study focusing on IMS indicates that it is important, but challenging, for public health agencies to engage with them to reduce inappropriate use of antibiotics. Although public health facilities must fill some gaps that informal HCPs are currently addressing, such as access to medicines at night, reducing demand for unnecessary antibiotics is also critical.

Comparative Excito-Repellency of Three Cambodian Plant-Derived Extracts Against Two Mosquito Vector Species, Aedes aegypti and Anopheles minimus.

A study of the behavioral responses of Aedes aegypti and Anopheles minimus to 3 Cambodian plant extracts at 3 different concentrations (1%, 2.5%, and 5%) was performed using an excito-repellency test system. These 3 plants were Strophanthus scandens, Capparis micracantha, and Dioscorea hispida, selected according to traditional healer's knowledge, bibliographic studies and market surveys. Results showed that S. scandens leaves' hexane extract was the only one to exert repellency against Ae. aegypti with 23.3% of escaped mosquitoes at a concentration of 5%. Capparis micracantha was responsible for an irritant activity against An. minimus with 20.2% of escaped mosquitoes at a concentration of 2.5% and 22.8% escaping at a concentration of 5%. Dioscorea hispida showed an irritant activity on both mosquito species with 23.2% of escaped Ae. aegypti at a concentration of 5% and about 20% of escaped An. minimus at 2.5% and 5%. This is the first report on the irritant and repellent activities of S. scandens , D. hispida , and C. micracantha against mosquito species.

Ethnobotany, phytochemistry and pharmacology of Stephania rotunda Lour.

ETHNOPHARMACOLOGICAL RELEVANCE: Stephania rotunda Lour. (Menispermaceae) is an important traditional medicinal plant that is grown in Southeast Asia. The stems, leaves, and tubers have been used in the Cambodian, Lao, Indian and Vietnamese folk medicine systems for years to treat a wide range of ailments, including asthma, headache, fever, and diarrhoea. AIM OF THE REVIEW: To provide an up-to-date, comprehensive overview and analysis of the ethnobotany, phytochemistry, and pharmacology of Stephania rotunda for its potential benefits in human health, as well as to assess the scientific evidence of traditional use and provide a basis for future research directions. MATERIAL AND METHODS: Peer-reviewed articles on Stephania rotunda were acquired via an electronic search of the major scientific databases (Pubmed, Google Scholar, and ScienceDirect). Data were collected from scientific journals, theses, and books. RESULTS: The traditional uses of Stephania rotunda were recorded in countries throughout Southeast Asia (Cambodia, Vietnam, Laos, and India). Different parts of Stephania rotunda were used in traditional medicine to treat about twenty health disorders. Phytochemical analyses identified forty alkaloids. The roots primarily contain l-tetrahydropalmatine (l-THP), whereas the tubers contain cepharanthine and xylopinine. Furthermore, the chemical composition differs from one region to another and according to the harvest period. The alkaloids exhibited approximately ten different pharmacological activities. The main pharmacological activities of Stephania rotunda alkaloids are antiplasmodial, anticancer, and immunomodulatory effects. Sinomenine, cepharanthine, and l-stepholidine are the most promising components and have been tested in humans. The pharmacokinetic parameters have been studied for seven compounds, including the three most promising compounds. The toxicity has been evaluated for liriodenine, roemerine, cycleanine, l-tetrahydropalmatine, and oxostephanine. CONCLUSION: Stephania rotunda is traditionally used for the treatment of a wide range of ailments. Pharmacological investigations have validated different uses of Stephania rotunda in folk medicine. The present review highlights the three most promising compounds of Stephania rotunda, which could constitute potential leads in various medicinal fields, including malaria and cancer.

New antiplasmodial alkaloids from Stephania rotunda.

ETHNOPHARMACOLOGICAL RELEVANCE: Stephania rotunda Lour. (Menispermaceae) is a creeper growing in many countries of Asia and commonly found in the mountainous areas of Cambodia. As a folk medicine, it has been mainly used for the treatment of fever and malaria. The pharmacological activity is mostly due to alkaloids. Thus the aim of this study is to isolate new bioactive alkaloids from Stephania rotunda and to evaluate their in vitro antiplasmodial activity. MATERIALS AND METHODS: Alkaloids were isolated and identified from dichloromethane and aqueous extracts using a combination of flash chromatography, high performance liquid chromatography, mass spectrometry and nuclear magnetic resonance. The purified compounds were tested for in vitro antiplasmodial activity on chloroquine-resistant W2 strain of Plasmodium falciparum. RESULTS: A new aporphine alkaloid named vireakine (2) along with two known alkaloids stephanine (1) and pseudopalmatine (8), described for the first time in Stephania rotunda, and together five known alkaloids tetrahydropalmatine (3), xylopinine (4), roemerine (5), cepharanthine (6) and palmatine (7) were isolated and identified. The structure of the new alkaloid was established on the basis of 1D and 2D NMR experiments and mass spectrometry. The compounds were evaluated for their in vitro antiplasmodial and cytotoxic activities. All tested compounds showed significant antiplasmodial activities with IC(50) ranged from 1.2 µM to 52.3 µM with a good selectivity index for pseudopalmatine with IC(50) of 2.8 µM against W2 strain of Plasmodium falciparum and IC(50)>25 µM on K562S cells. CONCLUSIONS: This study provides evidence to support the use of Stephania rotunda for the treatment of malaria and/or fever by the healers. Alkaloids of the tuber exhibited antiplasmodial activity and particularly cepharanthine and pseudopalmatine.

HPLC analysis of Stephania rotunda extracts and correlation with antiplasmodial activity.

Stephania rotunda (Menispermaceae), a creeper commonly found in the mountainous areas of Cambodia, has been mainly used for the treatment of fever and malaria. Thus, the aim of this study is to investigate the chemical composition and antiplasmodial activity of different samples of S. rotunda and compare their antiplasmodial activity with their alkaloid content. Sixteen samples from different parts (roots, stem, and tuber) of S. rotunda were collected from four regions of Cambodia (Battambang, Pailin, Siem Reap, and Kampot). Reversed-phase HPLC was used to determine the content of three bioactive alkaloids (cepharanthine, tetrahydropalmatine, and xylopinine). These three alkaloids have been found in all samples from Battambang and Pailin (samples I-IX), whereas only tetrahydropalmatine was present in samples from Siem Reap and Kampot (samples X-XVI). The analyzed extracts were evaluated for their antiplasmodial activity on W2 strain of Plasmodium falciparum. Among them, 13 extracts were significantly active with inhibitory concentration 50 (IC(50) ) from 1.2 to 3.7 µg/mL and 2 extracts were moderately active (IC(50) = 6.1 and 10 µg/mL, respectively), whereas sample XI was not active (IC(50) = 19.6 µg/mL). A comparison between antiplasmodial activity and concentration of the three bioactive alkaloids in S. rotunda extracts has been realized.

Antiplasmodial activity of three bisbenzylisoquinoline alkaloids from the tuber of Stephania rotunda.

Three bisbenzylisoquinoline alkaloids were isolated for the first time from Stephania rotunda tuber. Their structures were elucidated by spectroscopic methods and their antiplasmodial activity was investigated in vitro on chloroquine resistant Plasmodium falciparum strain W2. These alkaloids were identified as 2-norcepharanthine (1), cepharanoline (2) and fangchinoline (3). In vitro, they displayed significant antiplasmodial activity with inhibitory concentration 50 values of 0.3, 0.2 and 0.3 µM.

Simultaneous HPLC determination of three bioactive alkaloids in the Asian medicinal plant Stephania rotunda.

A reliable high-performance liquid chromatography (HPLC) method coupled with photodiode array detection has been developed and validated for the determination of three major alkaloids: cepharanthine, tetrahydropalmatine and xylopinine in Stephania rotunda Lour. (Menispermaceae) collected in Cambodia. The chromatographic separation was carried out on a Symmetry C8 column (250 mm x 4.6 mm, 5 microm, Waters), with an isocratic solvent system of 25 mM potassium phosphate buffer (pH 3.5) - acetonitrile. UV detection was performed at 282 nm. Good linear behavior over the investigated concentration ranges was observed with values of r2 > 0.9964 for all the analytes. The method was reproducible with intra- and inter-day variations of less than 3.91%. The mean recoveries of the analytes ranged from 95.7 to 104.6%. The proposed method was linear, accurate, precise and specific. The validated method was successfully applied to quantify the three alkaloids in various parts of Stephania rotunda and in tubers collected from different Cambodian regions. The results indicated that the developed HPLC method could be used for the quality control of S. rotunda.