Treatment and prevention of malaria in pregnancy: opportunities and challenges

Control of malaria in pregnancy through prevention or treatment may save lives of mothers and babies. Selection of drugs for treatment of infected pregnant women, or for prevention in exposed populations is problematic owing to resistance to established drugs and lack of pregnancy-specific safety and pharmacological data for new drugs. Encouragingly, a number of new drugs and combinations of drugs hold promise for effective treatment, but adequate data on their safety in pregnancy is currently lacking. Our principal challenges are to decide which drugs to develop for use in malaria treatment and prevention in pregnancy and to develop mechanisms to rapidly and comprehensively evaluate their safety. Prevention of pregnancy malaria by vaccination may also become possible, but targets must be closely defined, and strategies developed to test candidates against meaningful end points.     

Antimalarial drug toxicity: a review

Antimalarial drug toxicity is viewed differently depending upon whether the clinical indication is for malaria treatment or prophylaxis. In the treatment of Plasmodium falciparum malaria, which has a high mortality if untreated, a greater risk of adverse reactions to antimalarial drugs is inevitable. As chloroquine resistance has become widespread, alternative agents may be used in treatment regimens, however, the toxicity of these antimalarial agents should be considered. Quinine is the mainstay for treating severe malaria due to its rare cardiovascular or CNS toxicity, but its hypoglycemic effect may be problematic. Mefloquine can cause dose-related serious neuropsychiatric toxicity and pyrimethamine-dapsone is associated with agranulocytosis, especially if the recommended dose is exceeded. Pyrimethamine-sulfadoxine and amodiaquine are associated with a relatively high incidence of potentially fatal reactions, and are no longer recommended for prophylaxis. Atovaquone/proguanil is an antimalarial combination with good efficacy and tolerability as prophylaxis and for treatment. The artemisinin derivatives have remarkable efficacy and an excellent safety record. Prescribing in pregnancy is a particular problem for clinicians because the risk-benefit ratio is often very unclear.     

Prevention and control of malaria in pregnancy – new threats,new opportunities?

Introduction: Over 100 million women and their babies are at risk of malaria in pregnancy each year. Malaria prevention in pregnancy relies on long-lasting insecticidal nets (LLINs), and, in Africa, intermittent preventive treatment in pregnancy (IPTp). Increasing resistance of malaria parasites to sulfadoxine-pyrimethamine, the only drug endorsed for IPTp, and increasing mosquito resistance to pyrethroids used in LLINs, threaten the efficacy of these proven strategies, while operational challenges restrict their implementation in areas of great need.

Areas Covered: This review summarizes strategies for malaria prevention in pregnancy (both currently used and those undergoing preclinical and clinical evaluation), primarily drawing on publications and study protocols from the last decade. Challenges associated with each strategy are discussed, including the particular problem of HIV and malaria in pregnancy, and areas of further research are highlighted.

Expert Commentary: Alternative drugs for IPTp are needed. Dihydroartemisinin-piperaquine is particularly promising, but requires further evaluation, and might contribute to artemisinin resistance. Intermittent screening and treatment in pregnancy (ISTp) is an alternative to IPTp that could reduce unnecessary antenatal drug exposure and resistance risk, but it is not recommended with current, insensitive screening tests. Optimal strategies for areas of low or declining malaria transmission remain to be determined.     

In Vitro and In Vivo Antimalarial Efficacies of Optimized Tetracyclines

With increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potent in vitro activity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of cultured Plasmodium falciparum with a 50% inhibitory concentration (IC₅₀) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC₅₀ at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence of in vitro phototoxicity. In a murine Plasmodium berghei model, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.     

Recognition and management of falciparum malaria

Falciparum malaria is a serious parasitic infection that, if left untreated, can give rise to a range of life‐threatening complications. Prompt recognition depends on a high index of suspicion and a detailed history identifying possible malaria risk factors. Symptoms and signs, apart from periodic fever in some cases, are typically non‐specific. Even in cases of severe falciparum malaria with vital organ involvement, the differential diagnosis can be broad. The gold standard diagnostic test is blood film microscopy but antigen detection tests have become available as an alternative. Other laboratory tests can, together with the history and examination findings, help confirm the diagnosis and provide data relating to the nature and severity of complications. Management of malaria involves prompt administration of effective antimalarial drugs and prevention or amelioration of complications such as coma (cerebral malaria), renal failure and acidosis. Oral treatment is usually given to patients with uncomplicated malaria while therapy should be administered parenterally in severe cases. Conventional drugs such as quinine are still useful but the artemisinin derivatives are rapidly acting antimalarial drugs that are increasingly used as first‐line therapy in tropical countries. Most adjunctive therapies assessed specifically for their effectiveness against complications have proved disappointing but some (such as prophylactic phenobarbitone and exchange transfusion) can complement generic management protocols that remain the cornerstone of intensive care for the severely ill patient with malaria.     

Treatment of Murine Cerebral Malaria by Artemisone in Combination with Conventional Antimalarial Drugs: Antiplasmodial Effects and Immune Responses

The decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications of Plasmodium falciparum resistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to kill P. falciparum in a high-throughput in vitro assay and to protect mice against lethal cerebral malaria caused by Plasmodium berghei ANKA when used alone or in combination with established antimalarial drugs. Artemisone effects against P. falciparum in vitro were synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cells in vitro were much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given individually mostly protected mice against cerebral malaria caused by P. berghei ANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma of P. berghei-infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.     

Medication use in the treatment of migraine during pregnancy and lactation

Migraine is very common in women of reproductive age. With peak prevalence of migraine occurring during childbearing years, many women with migraine may knowingly or unknowingly use medication during pregnancy. Although migraine tends to improve during pregnancy, many women may still experience moderate to severe disabling headache and need pharmacologic treatment for the pain, nausea, and vomiting. This article explores the physiologic changes occurring during pregnancy that can affect pharmacokinetic properties of drugs and their metabolism. Acute and preventive treatment of migraine during pregnancy and lactation is discussed, with an emphasis on safety to the fetus and nursing infant. Safety and recommended use of medication during pregnancy may be different when use is considered during breastfeeding. A goal of treatment is to balance potential risk of treatment to the fetus and nursing infant with significant relief and return to normal function of the mother.     

Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria

The combination of fosmidomycin and clindamycin (F/C) is effective in adults and older children for the treatment of malaria and could be an important alternative to existing artemisinin-based combinations (ACTs) if proven to work in younger children. We conducted an open-label clinical trial to assess the efficacy, safety, and tolerability of F/C for the treatment of uncomplicated P. falciparum malaria in Mozambican children <3 years of age. Aqueous solutions of the drugs were given for 3 days, and the children were followed up for 28 days. The primary outcome was the PCR-corrected adequate clinical and parasitological response at day 28. Secondary outcomes included day 7 and 28 uncorrected cure rates and fever (FCT) and parasite (PCT) clearance times. Fifty-two children were recruited, but only 37 patients were evaluable for the primary outcome. Day 7 cure rates were high (94.6%; 35/37), but the day 28 PCR-corrected cure rate was 45.9% (17/37). The FCT was short (median, 12 h), but the PCT was longer (median, 72 h) than in previous studies. Tolerability was good, and most common adverse events were related to the recurrence of malaria. The poor efficacy observed for the F/C combination may be a consequence of the new formulations used, differential bioavailability in younger children, naturally occurring variations in parasite sensitivity to the drugs, or an insufficient enhancement of their effects by naturally acquired immunity in young children. Additional studies should be conducted to respond to the many uncertainties arising from this trial, which should not discourage further evaluation of this promising combination.     

Pregnancy and thrombophilia

The physiological changes that occur during pregnancy create a hypercoagulable milieu. This hypercoagulable state is thought to be protective, especially at the time of labor, preventing excessive hemorrhage. The presence of hereditary or acquired causes of thrombophilia during pregnancy tilts the balance in favor of unwanted venous thromboembolism and adverse pregnancy outcomes due to vascular uteroplacental insufficiency. These adverse pregnancy outcomes include recurrent pregnancy losses, intrauterine fetal death, intrauterine growth retardation, preeclampsia and placental abruption. Much of the current data with regards to the association of the different thrombophilias and pregnancy-related complications are based on retrospectively designed studies. This lack of randomization, in-homogeneity of patient populations, varying case definitions, selection biases and inadequately matched control populations, have given rise to conflicting data with regard to screening for, and treatment of, pregnant women with suspected thrombophilias. The limited data that we have support the use of anticoagulant drugs for the prevention of pregnancy-related complications in the setting of thrombophilia. Heparin and low-molecular-weight heparins are the anticoagulant drugs of choice as they do not cross the placental barrier and, hence, do not cause fetal anticoagulation or teratogenicity. Warfarin can be used from the 12th week of gestation onwards but is preferably reserved for the postpartum period.     

Pregnancy and thrombophilia

The physiological changes that occur during pregnancy create a hypercoagulable milieu. This hypercoagulable state is thought to be protective, especially at the time of labor, preventing excessive hemorrhage. The presence of hereditary or acquired causes of thrombophilia during pregnancy tilts the balance in favor of unwanted venous thromboembolism and adverse pregnancy outcomes due to vascular uteroplacental insufficiency. These adverse pregnancy outcomes include recurrent pregnancy losses, intrauterine fetal death, intrauterine growth retardation, preeclampsia and placental abruption. Much of the current data with regards to the association of the different thrombophilias and pregnancy-related complications are based on retrospectively designed studies. This lack of randomization, in-homogeneity of patient populations, varying case definitions, selection biases and inadequately matched control populations, have given rise to conflicting data with regard to screening for, and treatment of, pregnant women with suspected thrombophilias. The limited data that we have support the use of anticoagulant drugs for the prevention of pregnancy-related complications in the setting of thrombophilia. Heparin and low-molecular-weight heparins are the anticoagulant drugs of choice as they do not cross the placental barrier and, hence, do not cause fetal anticoagulation or teratogenicity. Warfarin can be used from the 12th week of gestation onwards but is preferably reserved for the postpartum period.     

Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria

Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.     

Standby emergency treatment of malaria in travelers: experience to date and new developments

The concept of 'standby emergency treatment' (SBET) describes the strategy where travelers carry an emergency malaria treatment for self-administration when no medical attention is available or for use under medical supervision after a confirmed malaria diagnosis, and raises many issues for discussion. International guidelines vary on the topic, and there is controversy regarding the appropriate niche for this imperfect strategy. There are situations when SBET can supplement chemoprophylaxis with mosquito bite prevention and for some travelers, particularly those visiting minimal malaria risk areas, carriage of SBET and concomitant anti-mosquito bite measures can constitute the main antimalaria strategy. A strong argument in support of equipping travelers with a quality effective antimalarial treatment as part of their travel medical kit is the global proliferation of counterfeit antimalarials, a situation that is increasing in Africa but is especially prevalent in Asia where more than 50% of artemisinin products are fake. New developments such as improved rapid malaria tests and their wider distribution together with the availability of effective, well-tolerated malaria treatments, such as atovaquone/proguanil, artemether/lumefantrine and a new artemisinin combination dihydroartemisin/piperaquine, which is licensed in Europe for uncomplicated malaria, suggest that it is time to revisit and re-evaluate this strategy for travelers.     

News on antithrombotic therapy and pregnancy

Objectives. State of the art of antithrombotics and their use recommendations during pregnancy. Methods. A review Results. Aspirin and heparins remain the safest molecules during pregnancy, and oral anticoagulants are still used for mechanical valves. Heparinoids are the methods of choice in case of heparin-induced thrombopenia but other molecules could find their place: fondaparinux at first and possibly the direct thrombin inhibitors. Thrombolysis may be used in case of life-threatening incident. At present, the new oral forms can not be used during pregnancy Conclusions. During pregnancy, all antithrombotics, except the oral forms, can be used, but the low molecular weight heparins replacing the unfractionated ones in the treatment and prevention of venous thromboembolism remain the treatment of choice.     

The glory of guidelines and the twilight of reality: controversies and challenges in the prevention and treatment of HIV in children

Since the discovery of HIV 30 years ago, we have learned much about HIV in children and adolescents. Dramatic declines have occurred in mother-to-child transmission of HIV in resource-rich countries. Resource-poor countries struggle with improving prevention of mother-to-child transmission due to the lack of universal antiretroviral treatment for pregnant and nursing mothers. In children infected with HIV, pharmacokinetic, safety and efficacy data have been determined for many of the older drugs. Data are lacking for the newer, safer and more effective currently available drugs, resulting in the pediatric guidelines lagging behind adult recommendations. Although guidelines for prevention and treatment are helpful, the way they are created causes them to lag behind new scientific evidence, and in some situations they will be confusing or only based on expert opinion. Improving prevention of HIV infection in adolescents and young adults and in treating those who become HIV infected is crucially important. The next 10 years hold tremendous opportunities for improvements in prevention and treatment of HIV in children, adolescents and young adults.     

Synthesis of artemiside and its effects in combination with conventional drugs against severe murine malaria

This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.     

Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs

Malaria and tuberculosis (TB) are two major global diseases mostly affecting the developing countries. Their treatment is often complex because of the drugs used, multidrug resistance, drug interactions and logistic problems such as drug availability and access. Patients are treated for TB for a minimum of 6 months and may concomitantly develop and be treated for malaria, especially during the rainy season. Rifampicin, a standard component of combination regimens for treating TB, is a potent inducer of hepatic cytochrome and other metabolic enzymes and is able to influence the pharmacokinetics of many drugs. Rifabutin, another rifamycin used less frequently than rifampicin, can also interact with drugs metabolized through the hepatic cytochromes. The mechanisms of any interaction of rifamycins with drugs used in malaria are not well defined. To complicate matters, acute malaria also plays a role in the pharmacokinetics and pharmacodynamics of drugs (i.e. quinine). The aim of this paper is to review known and potential drug-drug interactions between rifampicin, rifabutin and antimalarial drugs.     

Therapy of vector-borne protozoan infections in nonendemic settings

Vector-borne protozoan infections are responsible for a wide variety of illnesses (mainly malaria, trypanosomiasis and leishmaniasis) affecting tropical and subtropical areas, but increasingly diagnosed in nonendemic settings. This article summarizes the therapeutic developments for these conditions during the past decade and focuses specifically on treatment recommendations for returning travelers and migrants. The treatment of malaria has known the most spectacular improvements. Progress in the management of leishmaniasis and trypanosomiasis has also been substantial and includes introduction of new drugs into clinical practice, combinations of existing drugs, or new laboratory tools for treatment monitoring as well as extension of treatment indications to new groups of patients. Serious gaps still exist in terms of effectiveness and tolerance. Since the research pipeline is very limited for the coming 5–10 years, optimized combinations of existing drugs need to be urgently explored.     

Antipsychotic drugs and pregnant or breastfeeding women: the issues for mental health nurses

Antipsychotic drugs and pregnant or breastfeeding women: the issues for mental health nurses Mental illness can affect up to 10% of pregnant women, and women with a pre-existing psychiatric condition are more likely to experience a relapse of symptoms during pregnancy. Antipsychotic drugs are an important part of the treatment of psychotic illnesses; however, their safety with pregnant or breastfeeding women has not been fully established. Given that these drugs will be ordered for pregnant or breastfeeding women diagnosed with a psychosis or with a pre-existing psychiatric condition, it is imperative that mental health nurses and others administering the drugs, or caring for those taking the drugs, be aware of their consequences. A review of the available evidence, albeit at times contradictory, is presented along with a discussion of the implications for mental health nurses. Recommendations for consideration when administering or counselling women regarding the use of antipsychotic drugs in pregnancy or when breastfeeding, are also included.     

Therapy of vector-borne protozoan infections in nonendemic settings

Vector-borne protozoan infections are responsible for a wide variety of illnesses (mainly malaria, trypanosomiasis and leishmaniasis) affecting tropical and subtropical areas, but increasingly diagnosed in nonendemic settings. This article summarizes the therapeutic developments for these conditions during the past decade and focuses specifically on treatment recommendations for returning travelers and migrants. The treatment of malaria has known the most spectacular improvements. Progress in the management of leishmaniasis and trypanosomiasis has also been substantial and includes introduction of new drugs into clinical practice, combinations of existing drugs, or new laboratory tools for treatment monitoring as well as extension of treatment indications to new groups of patients. Serious gaps still exist in terms of effectiveness and tolerance. Since the research pipeline is very limited for the coming 5-10 years, optimized combinations of existing drugs need to be urgently explored.