Malaria medicines to address drug resistance and support malaria elimination efforts

Introduction: Antimalarial drugs are essential weapons to fight malaria and have been used effectively since the 17^th century. However, P.falciparum resistance has been reported to almost all available antimalarial drugs, including artemisinin derivatives, raising concerns that this could jeopardize malaria elimination.

Areas covered: In this article, we present a historical perspective of antimalarial drug resistance, review current evidence of resistance to available antimalarial drugs and discuss possible mitigating strategies to address this challenge.

Expert commentary: The historical approach to drug resistance has been to change the national treatment policy to an alternative treatment. However, alternatives to artemisinin-based combination treatment are currently extremely limited. Innovative approaches utilizing available schizonticidal drugs such as triple combination therapies or multiple first line treatments could delay the emergence and spread of drug resistance. Transmission blocking drugs like primaquine may play a key role if given to a substantial proportion of malaria infected persons. Deploying antimalarial medicines in mass drug administration or mass screening and treatment campaigns could also contribute to containment efforts by eliminating resistant parasites in some settings. Ultimately, response to drug resistance should also include further investment in the development of new antimalarial drugs.     

Pharmacotherapy for the prevention of malaria in pregnant women: currently available drugs and challenges

ABSTRACT

Introduction: Malaria in pregnancy continues to be a significant public health burden globally, with over 100 million women at risk each year. Sulfadoxine-pyrimethamine (SP) is the only antimalarial recommended for intermittent preventive therapy in pregnancy (IPTp) but increasing parasite resistance threatens its viability. There are few other available antimalarial therapies that currently have sufficient evidence of tolerability, safety, and efficacy to replace SP.

Areas covered: Novel antimalarial combinations are under investigation for potential use as chemoprophylaxis and in IPTp regimens. The present review summarizes currently available therapies, emerging candidate combination therapies, and the potential challenges to integrating these into mainstream policy.

Expert opinion: Alternative drugs or combination therapies to SP for IPTp are desperately required. Dihydroartemisinin-piperaquine and azithromycin-based combinations are showing great promise as potential candidates for IPTp but pharmacokinetic data suggest that dose modification may be required to ensure adequate prophylactic efficacy. If a suitable candidate regimen is not identified in the near future, the success of chemopreventive strategies such as IPTp may be in jeopardy.     

Antimalarial drugs: current status and new developments

Malaria continues to be a major threat in the developing world, with > 1 million clinical episodes and 3000 deaths every day. In the last century, malaria claimed between 150 and 300 million lives, accounting for 2 – 5% of all deaths. Currently ~ 40% of the world population resides in areas of active malaria transmission. The disease symptoms are most severe in young children and pregnant women. A total of 90% of the disease-associated mortality occurs in Subsaharan Africa, despite the fact that malaria is indigenous to most tropical regions. A licensed vaccine for malaria has not become a reality and antimalarial drugs are the only available method of treatment. Although chloroquine, the first synthetically developed antimalarial, proved to be an almost magical cure for > 30 years, the emergence and spread of chloroquine-resistant parasites has made it virtually ineffective in most parts of the world. Currently, artemisinin, a plant-derived antimalarial, is the only available drug that is globally effective against the parasite. Although several new drugs have been introduced in the past 30 years, widespread or isolated cases of resistance indicate that their window of effectiveness will be limited. Thus, there is an urgent need to develop new therapeutics and regimens for malaria control. This article presents an overview of the currently available antimalarial chemotherapy options and the efforts being undertaken to develop new drugs based on both the recent technological advances and modifications to the old remedies, and on combination therapies.     

抗肿瘤药物说明书166份妊娠及哺乳期妇女用药标注情况分析

目的 了解常用抗肿瘤药物说明书中妊娠及哺乳期妇女用药的标注情况,为规范药品说明书的标注提供参考.方法 2019年1—2月收集江苏省五家三甲医院抗肿瘤药物的药品说明书,2019年3—9月对其中关于妊娠及哺乳期妇女用药信息的标注情况进行调查分析.结果 共收集166份抗肿瘤药物说明书,按来源分为国产药(84份)、进口药(82...     

Chloroquine pharmacokinetics in pregnant and nonpregnant women with vivax malaria

Purpose  We compared the pharmacokinetics of chloroquine in pregnant and nonpregnant women treated for Plasmodium vivax malaria. Methods  Twelve pregnant women and 15 nonpregnant women of child-bearing age with acute P. vivax malaria were treated with 25 mg chloroquine base/kg over 3 days on the northwestern border of Thailand. Blood concentrations of chloroquine and desethylchloroquine were measured using hydrophilic interaction liquid chromatography coupled with fluorescence detection. Twenty-five women completed the pharmacokinetic study. Results  Although increasing gestational age was associated with reduced chloroquine , there was no significant difference overall in the pharmacokinetics of chloroquine between pregnant and nonpregnant women. Fever was associated with lower chloroquine values. Desethylchloroquine area under the curve (AUC) values were not significantly affected by pregnancy. Conclusions  Pregnancy did not significantly affect blood concentrations of chloroquine or its metabolite, desethylchloroquine, in women with P. vivax malaria.     

Investigational drugs in early development for treating dengue infection

Introduction: Dengue has emerged as the most significant arboviral disease of the current century. A drug for dengue is an urgent unmet need. As conventional drug discovery efforts have not produced any promising clinical candidates, there is a shift toward re-positioning pre-existing drugs for dengue to fast-track dengue drug development.

Areas covered: This article provides an update on the current status of recently completed and ongoing dengue drug trials. All dengue drug trials described in this article were identified from a list of >230 trials that were returned upon searching the World Health Organization’s International Clinical Trials Registry Platform web portal using the search term ‘dengue’ on December 31^st, 2015.

Expert opinion: None of the handful of drugs tested so far has yielded encouraging results. Early trial experience has served to emphasize the challenge of drug testing in the short therapeutic time window available, the need for tools to predict ‘high-risk’ patients early on and the limitations of the existing pre-clinical model systems. Significant investment of efforts and resources is a must before the availability of a safe, effective and inexpensive dengue drug becomes a reality. Currently, supportive fluid therapy remains the only option available for dengue treatment.     

Patterns of alcohol intake of pregnant and lactating women in Perth, Australia

Introduction and Aims. Australian alcohol consumption data for women during the period of pregnancy and lactation is limited. The purpose of this paper is to provide current alcohol consumption data for pregnant and lactating women in Perth, Western Australia (WA). Data were collected from 587 women between mid-September 2002 and mid-July 2003. Design and Methods. Women from two public hospitals with maternity wards in the Perth metropolitan area completed a self-administered baseline questionnaire while in hospital or shortly after discharge. All women, regardless of their chosen infant feeding method, were followed-up by telephone interview at 4, 10, 16, 22, 32, 40 and 52 weeks postpartum. Data were analysed to determine alcohol use patterns of the women during the period of pregnancy and lactation and results were compared to national guidelines for alcohol consumption. Results. Approximately 32% of women stopped drinking alcohol during pregnancy. A remaining 35% of pregnant women consumed alcohol during pregnancy, with 82.2% of these women consuming up to two standard drinks per week. At 4, 6 and 12 months postpartum, 46.7%, 47.4% and 42.3% of breastfeeding women were consuming alcohol, respectively. Discussion and Conclusions. The majority of breastfeeding women consumed up to two standard drinks per week, which is within levels recommended by national authorities. There is, however, a small proportion of women consuming alcohol at levels above national recommendations for pregnancy and lactation. The development of 'safe' alcohol intake practices, within national recommendations, during the postnatal period would remove any potential health risks to the infant from alcohol exposure at this vulnerable growth stage. [Giglia RC, Binns CW. Patterns of alcohol intake of pregnant and lactating women in Perth, Australia. Drug Alcohol Rev 2007;26:493 - 500]     

The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria

Objective To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil.Methods Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily.Results The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313±33 ml/h/kg and 1109±43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0±1.3 l/kg and 22.9±1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria.Conclusion Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.     

孕妇及乳妇安全合理用药科普干预研究

目的：帮助孕妇及乳妇解答日常用药中存在的疑难问题,做好孕妇及乳妇安全合理用药的科普宣传教育工作,以期促进孕妇及乳妇安全合理用药工作开展。方法：组织从事妇幼保健工作的临床药师和药师,设计活动策划方案与发放编写材料、在微信公众号上传科普文章、举办公益科普讲座、发放调查问卷并评估科普活动效果。 结果：科普活动效果调查显示,接受多种形式科普宣教与未进行科普宣的用药观点和用药行为比较,科普宣教效果优于未进行科普宣教,P<0.001,表明孕妇及乳妇在科普干预后,用药观点和用药行为上发生较大变化。结论：采用上述丰富多彩的科普教育宣传活动,能使孕妇及乳妇更好地掌握孕妇及乳妇安全合理用药科普知识,有助于树立良好用药观点,养成良好用药行为,且可向亲朋好友宣传推广,学以致用。     

孕妇及乳妇安全合理用药科普干预研究

为帮助孕妇及乳妇解答日常用药中存在的疑难问题,对其开展用药科普宣教,包括编写发放科普材料、在微信公众号上发布科普文章、举办科普讲座.调查问卷并评估科普活动效果显示,孕、乳妇在科普宣教后,用药观点和用药行为上发生了积极变化.     

Analysis of the Antimalarial Sesquiterpene Artemisinin in Artemisia annua by High-Performance Liquid Chromatography (HPLC) with Postcolumn Derivatization and Ultraviolet Detection

Pharmaceutical Research -     

Antimalarial drugs - what is in use and what is in the pipeline

Malaria continues to be a potentially fatal threat to almost half of the world's population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.     

Darunavir for use in pregnant women with HIV

Introduction: Combination antiretroviral therapy is recommended during pregnancy to decrease the rate of HIV transmission to the baby and reduce morbidity in the mother. More than 50% of women are prescribed a protease inhibitor-based regimen during pregnancy. Darunavir was recently reclassified as a first-line protease inhibitor for use in pregnancy in the US Department of Health and Human Services Perinatal Guidelines.

Areas covered: This is a brief review of the use of protease inhibitor therapy during pregnancy, and a discussion of darunavir’s utility in this area. Clinical pharmacology and trial data are reviewed, and the safety, efficacy and dosing of darunavir during pregnancy is discussed.

Expert commentary: Darunavir has become an important option in the management of HIV during pregnancy. Both once-daily dosing and twice-daily dosing regimens have shown efficacy in clinical studies. Although a significant reduction in total (protein bound and unbound) plasma concentrations of darunavir has been noted during pregnancy, antiviral activity appears to be maintained with standard dosing. This is likely due to diminished changes in unbound drug concentrations. Preterm delivery and low birth weight have been noted for pregnancies of women on darunavir-containg regimens, but a causal relationship has not yet been demonstrated.     

Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women

Aim

Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy.

Methods

Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp® software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (C_max) and oral clearances (CL/F).

Results

PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%).

Conclusions

Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.     

孕妇甲状腺球蛋白水平检测在碘缺乏病预防中的价值研究

目的 :探讨孕妇甲状腺球蛋白 (TG)水平和促甲状腺素 (TSH)水平之间的关系。方法 :应用免疫放射分析(IRMA)法检测了 10 0例碘缺乏地区孕妇的 TG和 TSH水平 ,并选择 10 0例非缺碘地区孕妇作为对照。结果 :研究组孕妇 TG均值为 17.6 ng/ m L± 4.6 7ng/ m L,对照组为 14.45 ng/ m L± 4.43ng/ m L(P<0 .0 5 )。研究组孕妇 TSH均值为 5 .36 m U / L± 2 .2 0 m U / L ,对照组为 4.6 9m U / L± 1.34 m U / L (P<0 .0 5 )。两组孕妇 TG水平和其 TSH水平呈显著正相关。结论 :孕妇的 TG水平可作为妊娠期预防碘缺乏的监测指标     

抗甲状腺药物对妊娠合并甲状腺功能亢进患者的疗效及对胎儿的影响分析

目的:探讨抗甲状腺药物对妊娠合并甲状腺功能亢进患者的治疗效果及对胎儿的影响。方法:选取2009年5月—2014年5月收治的妊娠合并甲状腺功能亢进患者96例,随机分成对照组和观察组,每组48例。对照组患者不接受抗甲状腺药物治疗,观察组接受抗甲状腺药物治疗。对两组患者甲状腺功能、孕妇并发症以及新生儿平均体重和1 min Apgar评分进行分析比较。结果:观察组患者的游离三碘甲状腺原氨酸(FT3)、游离甲状腺激素(FT4)以及血清促甲状腺激素(TSH)水平均显著低于对照组;观察组并发症发生率显著低于对照组,差异均有统计学意义(P<0.05)。结论:抗甲状腺药物可以显著改善妊娠合并甲状腺功能亢进患者的甲状腺功能,并可增加胎儿体重,提高Apgar评分。     

Upcoming drugs for the treatment of preeclampsia in pregnant women

Preeclampsia is a pregnancy-specific multisystem disorder, complicating 2 – 8% of pregnancies, and represents a leading cause of maternal and perinatal morbidity and mortality. Recent investigations have elucidated the understanding of its underlying pathogenic mechanisms. However, despite these advances, therapeutic approaches are still severely limited. Ongoing lines of research indicate some potential novel therapeutic options, targeting the etiopathogenic pathways and, thus, offering hope for effective pharmacologic interventions to be available in the near future. In this editorial, we will give an updated overview of Preeclampsia pathogenesis and promising emerging therapeutic options.