Clinical pharmacokinetics of quinine and its relationship with treatment outcomes in children, pregnant women, and elderly patients, with uncomplicated and complicated malaria: a systematic review.

BACKGROUND: Standard dosage regimens of quinine formulated for adult patients with uncomplicated and complicated malaria have been applied for clinical uses in children, pregnant women, and elderly. Since these populations have anatomical and physiological differences from adults, dosage regimens formulated for adults may not be appropriate. The study aimed to (i) review existing information on the pharmacokinetics of quinine in children, pregnant women, and elderly populations, (ii) identify factors that influence quinine pharmacokinetics, and (iii) analyse the relationship between the pharmacokinetics and treatment outcomes (therapeutic and safety) of various dosage regimens of quinine. METHODS: Web of Sciences, Cochrane Library, Scopus, and PubMed were the databases applied in this systematic search for relevant research articles published up to October 2020 using the predefined search terms. The retrieved articles were initially screened by titles and abstracts to exclude any irrelevant articles and were further evaluated based on full-texts, applying the predefined eligibility criteria. Excel spreadsheet (Microsoft, WA, USA) was used for data collection and management. Qualitative data are presented as numbers and percentages, and where appropriate, mean + SD or median (range) or range values. RESULTS: Twenty-eight articles fulfilled the eligibility criteria, 19 in children, 7 in pregnant women, and 2 in elderly (14 and 7 articles in complicated and uncomplicated malaria, respectively). Severity of infection, routes of administration, and nutritional status were shown to be the key factors impacting quinine pharmacokinetics in these vulnerable groups. CONCLUSIONS: The recommended dosages for both uncomplicated and complicated malaria are, in general, adequate for elderly and children with uncomplicated malaria. Dose adjustment may be required in pregnant women with both uncomplicated and complicated malaria, and in children with complicated malaria. Pharmacokinetics studies relevant to clinical efficacy in these vulnerable groups of patients with large sample size and reassessment of MIC (minimum inhibitory concentration) should be considered.

Need for optimized dosages in the design of comparative clinical trials of anti-malarial drugs.

We read with interest the publication on malaria treatment by Obonyo et al. (Malaria J 21:30, 2022). This commentary questions the methodology, especially the chosen time points of treatment outcome measures.

Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria.

BACKGROUND: In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM. METHODS: From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up. RESULTS: 346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07-0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine. CONCLUSIONS: Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.

Drug treatment and prevention of malaria in pregnancy: a critical review of the guidelines.

BACKGROUND: Malaria caused by Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae. This review evaluated the adherence of the national guidelines drawn from World Health Organization (WHO) regions, Africa, Eastern Mediterranean, Southeast Asia, and Western Pacific, to the WHO recommendations on drug treatment and prevention of chloroquine-resistant falciparum malaria in pregnant women. METHODS: Thirty-five updated national guidelines and the President's Malaria Initiative (PMI), available in English language, were reviewed. The primary outcome measures were the first-line anti-malarial treatment protocols adopted by national guidelines for uncomplicated and complicated falciparum malaria infections in early (first) and late (second and third) trimesters of pregnancy. The strategy of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) was also addressed. RESULTS: This review evaluated the treatment and prevention of falciparum malaria in pregnancy in 35 national guidelines/PMI-Malaria Operational Plans (MOP) reports out of 95 malaria-endemic countries. Of the 35 national guidelines, 10 (28.6%) recommend oral quinine plus clindamycin as first-line treatment for uncomplicated malaria in the first trimester. As the first-line option, artemether-lumefantrine, an artemisinin-based combination therapy, is adopted by 26 (74.3%) of the guidelines for treating uncomplicated or complicated malaria in the second and third trimesters. Intravenous artesunate is approved by 18 (51.4%) and 31 (88.6%) guidelines for treating complicated malaria during early and late pregnancy, respectively. Of the 23 national guidelines that recommend IPTp-SP strategy, 8 (34.8%) are not explicit about directly observed therapy requirements, and three-quarters, 17 (73.9%), do not specify contra-indication of SP in human immunodeficiency virus (HIV)-infected pregnant women receiving cotrimoxazole prophylaxis. Most of the guidelines (18/23; 78.3%) state the recommended folic acid dose. CONCLUSION: Several national guidelines and PMI reports require update revisions to harmonize with international guidelines and emergent trends in managing falciparum malaria in pregnancy. National guidelines and those of donor agencies should comply with those of WHO guideline recommendations although local conditions and delayed guideline updates may call for deviations from WHO evidence-based guidelines.

A randomized, control and comparative study of polyherbal formulation use for Malaria (Plasmodium falciparum).

Plasmodium falciparum is the most well-known reason for extreme and life-debilitating malaria. Falciparum malaria causes more than 1 million deaths annually. Malaria remains a noteworthy reason for major morbidity and mortality in the tropics, with Plasmodium falciparum accountable for the mainstream of the disease weight and Plasmodium vivax being the geologically greatest broadly dispersed cause of malaria. The controlling of severe malaria comprises quick direction of suitable parenteral anti-malarial agents and initial acknowledgement and treatment of the complications. This clinical trial was piloted in 100 patients, in which 50 received the test drug (Malarina) and 50 received the control drug (Quinine Bisulphate). The age range of patients was 12 years to above 50 years. The sample paired t-test was applied to evaluate the significant level. Malarina was very effective in treating malaria sign and symptoms. The new treatment Malarina was safe and well tolerated in all patients.

Quinine, Malaria, and the Cinchona Bureau: Marketing Practices and Knowledge Circulation in a Dutch Transoceanic Cinchona-Quinine Enterprise (1920s-30s).

In this study, we will show how a Dutch pharmaceutical consortium of cinchona producers and quinine manufacturers was able to capitalize on one of the first international public health campaigns to fight malaria, thereby promoting the sale of quinine, an antimalarial medicine. During the 1920s and 1930s, the international markets for quinine were controlled by this Dutch consortium, which was a transoceanic cinchona-quinine enterprise centered in the Cinchona Bureau in the Netherlands. We will argue that during the interwar period, the Cinchona Bureau became the decision-making center of this Dutch cinchona-quinine pharmaceutical enterprise and monopolized the production and trade of an essential medicine. In addition, we will argue that capitalizing on the international public health campaign in the fight against malaria by the Dutch cinchona-quinine enterprise via the Cinchona Bureau can be regarded as an early example of corporate colonization of public health by a private pharmaceutical consortium. Furthermore, we will show how commercial interests prevailed over scientific interests within the Dutch cinchona-quinine consortium, thus interfering with and ultimately curtailing the transoceanic circulation of knowledge in the Dutch empire.

Successful use of quinine in the treatment of electrical storm in a child with Brugada syndrome.

A 10-year-old girl developed life-threatening recurrent polymorphic ventricular tachycardia following surgical closure of a simple secundum atrial septal defect. Post hoc analysis of a Holter recording suggested Brugada syndrome. After managing the acute phase, a dual chamber defibrillator was implanted. One week later she experienced VF storm, needing 96 appropriate shocks within a few hours. Quinidine, by virtue of its I(to) blocking property, is the only drug reported to be useful in managing VF storm in Brugada syndrome. Nonavailability of quinidine led us to try its diastereomer, intravenous quinine, which succeeded in controlling the ventricular tachycardia. Arrhythmia storm in the setting of ion channelopathy can be difficult to manage, and sometimes requires innovative therapies.

Symmetrical peripheral gangrene and neurological manifestations in Plasmodium falciparum malaria.

A case of Falciparum malaria complicated with symmetrical peripheral gangrene has been discussed. This association is not very common as reported in the literature. The special feature of this case is that the patient had bilateral hypoglossal nerve palsy and the signs of pyramidal tract involvement which improved after conservative management.

Reversible splenial lesion syndrome in cerebral malaria.

A 71-year-old Caucasian man living in Congo was investigated by serial magnetic resonance imaging (MRI) after having presented cerebral malaria due to Plasmodium falciparum. The clinical picture was characterized initially by coma and seizures. The patient developed multiple organ failure. There was, at 4 months follow-up only, a minimal neurological improvement consistent with minimally conscious state. The first cerebral MRI on day 17 showed a lesion of the splenium of corpus callosum with high signal intensity on DWI and FLAIR sequence and reduced ADC, and small cortical infarcts in the internal occipital regions. Follow-up MRI obtained 36 days later showed a complete resolution of splenial lesion, though without clinical improvement. Cerebral malaria should be added to the list of possible causes of reversible lesion of the splenium of corpus callosum.

Cost-effectiveness of artesunate for the treatment of severe malaria.

OBJECTIVE: To explore the cost-effectiveness of artesunate against quinine based principally on the findings of a large multi-centre trial carried out in Southeast Asia. METHODS: Trial data were used to compare mortality of patients with severe malaria, treated with either artesunate or quinine. This was combined with retrospectively collected cost data to estimate the incremental cost per death averted with the use of artesunate instead of quinine. RESULTS: The incremental cost per death averted using artesunate was approximately 140 USD. Artesunate maintained this high level of cost-effectiveness also when allowing for the uncertainty surrounding the cost and effectiveness assessments. CONCLUSION: This analysis confirms the vast superiority of artesunate for treatment of severe malaria from an economic as well as a clinical perspective.

The Sergent brothers and the antimalarial campaigns in Algeria (1902-1948).

Edmond and Etienne Sergent, "the Sergent brothers", were both born in Algeria. They both studied medicine at the Algiers Medical School and then followed the Course of Microbiology of Emile Roux at the Institut Pasteur in Paris (1899-1900). From 1900, they were put in charge of a permanent mission aimed at antimalarial control in Algeria, which was supervised by the Institut Pasteur. The first campaign was carried out during the summer of 1902 at a station of the East Algerian Railway Company. The success of this mission lead to the creation of the Antimalaric Department of Algeria in 1904, which was directed by Etienne Sergent for the duration his life. This antimalarial programme was progressively extended to many other locations. The programme was optimized between 1927 and 1947, in the experimental field study of the Ouled Mendil Marsh, where global environmental measures and drainage lead to settlement of farms, the families of which did not suffered from malaria. At a time when neither insecticides nor synthetic antimalarial drug existed, antimalarial control measures that were developed tended to target human reservoirs and the mosquito vectors. The extension of the programme across the Algerian territory lead to a decrease of both malaria endemicity and extension of affected areas.

[Intramuscular injections of quinine and tetanus at the Centre Hospitalier Universitaire of Brazzaville, Congo]. / Injections de quinine et tétanos au CHU de Brazzaville, congo.

Intramuscular injections are known for their iatrogenic complications. IM quinine is a routine procedure in Congo for drug resistant malaria management. In this short note, the authors evaluate tetanus relative to intramuscular injection of quinine among the cases of tetanus treated in the infectious diseases unit of "Centre Hospitalier Universitaire of Brazzaville". This study was conducted from January to December 2005 regarding 18 cases of tetanus among which 5 infected after intramuscular injection of quinine. Their level of severity was significantly higher with a high mortality rate (post intramuscular: 4 deaths out of 5; other cases: 3 deaths out of 13). Tetanus was generalized in 17 cases. A significant difference between the intramuscular and the non-intramuscular injection was observed regarding the pulse (p < 0.05), the level of severity (p < 0.005) and deaths (p < 0.005). Awareness-raising campaigns with populations and medical staff about the risks of intramuscular injections as well as vaccination schedule should be regularly implemented.

Severe Babesia microti infection presenting as multiorgan failure in an immunocompetent host.

A previously healthy 67-year-old farmer presented to an outside hospital after a 2-week history of non-specific respiratory symptoms. A certain diagnosis was not initially apparent, and the patient was discharged home on a regimen for presumed chronic obstructive pulmonary disease exacerbation. He re-presented to the emergency department with shock and hypoxaemic respiratory failure requiring prompt intubation and fluid resuscitation. He was then transferred to our institution due to multiorgan failure. On arrival, the patient demonstrated refractory shock and worsening acute kidney injury, severe anaemia and thrombocytopaenia. The peripheral smear revealed absence of microangiopathic haemolytic anaemia. A closer review of the smear displayed red blood cell inclusion bodies consistent with babesiosis. The patient was started on clindamycin and loaded with intravenous quinidine, and subsequently transitioned to oral quinine. A red cell exchange transfusion was pursued with improvement of the parasite load. The patient was discharged home on clindamycin/quinine and scheduled for outpatient intermittent haemodialysis.

Splenic rupture from babesiosis, an emerging concern? A systematic review of current literature.

Babesiosis is a relatively common tick-borne parasitic infection of erythrocytes primarily affecting the northeastern United States. Babesiosis' prevalence and presentation have earned it the monikers "malaria of the northeast" and "Nantucket fever". Clinical presentation ranges from asymptomatic infection to severe infection including acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulopathy (DIC) or death. Since 2008, there have been a number of reports of splenic rupture in patients with the disease. We seek to provide a further understanding of this process, with the report of a case of splenic rupture followed by a systematic review of the current literature. We found that 87% of splenic rupture secondary to babesiosis occurred in male patients who are otherwise healthy, with an average of 56 years. Computed tomography is a reliable mode of diagnosis, and hemoperitoneum is the most common imaging finding. Patients with splenic rupture due to human babesiosis were successfully treated by various management strategies, such as conservative non-operative approach, splenic artery embolization, and splenectomy. The modality of treatment depends on patient's clinical course and hemodynamic stability, although spleen conserving strategy should be considered first whenever possible.

[One hundred years later, recalling how BMJ and JAMA reported the 1918-1919 influenza pandemic]. / Cien años después, recordando cómo BMJ y JAMA comunicaron la pandemia de gripe de 1918-1919.

The influenza pandemic that ravaged the planet in 1918-1919 is, undoubtedly, the most virulent and lethal infectious disease that the human species has ever overcome. This essay was to evaluate the medical interpretation of this phenomenon and the response given by doctors in terms of diagnostic and therapeutic technology based on the data published in the medical literature of two of the most important journals of the time, BMJ (The British Medical Journal) and JAMA (The Journal of the American Medical Association). It was found that the arsenal of knowledge, diagnosis and therapeutics of the time offered very few tools to address clinical management and curb contagion and mortality. However, the difficulties that clinicians and health authorities had to overcome were a solid incentive to make significant progress in the understanding and management of infectious diseases, particularly of viral etiology, in a short period of time.

La pandemia de gripa que en 1918-1919 asoló el planeta, es sin duda el evento de enfermedad masivo de mayor virulencia y letalidad que la especie humana ha sorteado a lo largo de la historia. Este ensayo se centró en evaluar, a partir de lo publicado en la literatura médica de dos de las más importantes revistas de la época, (BMJ) The British Medical Journal y (JAMA)The Journal of the American Medical Association, la interpretación que desde la medicina se hizo de este fenómeno y de la respuesta que en términos de tecnología diagnóstica y terapéutica se dio por parte de los médicos. Se encontró que el arsenal de conocimientos, diagnóstico y terapéutica de la época ofrecía muy pocas herramientas para abordar el manejo clínico y frenar los contagios y mortalidad. No obstante, las dificultades que debieron sortear los clínicos y autoridades sanitarias de la época se constituyeron en un sólido aliciente para que en poco tiempo se avanzara significativamente en la comprensión y manejo de las enfermedades infecciosas, particularmente de etiología viral.

Cinchonism in a patient taking Quinine for leg cramps.

Quinine is often used as a treatment for benign nocturnal cramps. The use of Quinine remains controversial with conflicting studies regarding its efficacy. Quinine has a side effect profile that cannot be ignored. Cinchonism, or quinine toxicity, includes nausea, vomiting, and tinnitus. Many other side effects have been reported in the literature. A case report demonstrating the side effects of quinine is presented. We briefly review the literature on quinine and alternative medications.

Nicobrevin for smoking cessation.

BACKGROUND: Nicobrevin is a proprietary product marketed as an aid to smoking cessation. It contains quinine, menthyl valerate, camphor and eucalyptus oil. OBJECTIVES: The objective of this review was to assess the effects of Nicobrevin on long term smoking cessation SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register. SELECTION CRITERIA: Randomized trials comparing Nicobrevin to placebo or an alternative therapeutic control, which reported smoking cessation with at least six months follow up. DATA COLLECTION AND ANALYSIS: Data were sought on the outcome, method of randomization, and completeness of follow up. MAIN RESULTS: We identified no trials meeting the full inclusion criteria including long-term follow up. AUTHORS' CONCLUSIONS: There is no evidence available from long-term trials that Nicobrevin can aid smoking cessation.

[Atypical course of falciparum malaria in an asplenic patient]. / Paludisme à Plasmodium falciparum d'évolution atypique chez un patient splénectomisé

INTRODUCTION: The aim of treatment for falciparum malaria therapy is to achieve adequate clinical and parasitologic response within 7 days of starting treatment, with no subsequent relapse. We report and discuss the atypical course of a falciparum malaria attack observed in an asplenic patient returning from Burkina-Faso. CASE: This 34-year-old man was hospitalized for severe malaria and treated for 7 days with quinine, as an inpatient. Adequate early clinical response was observed. Twenty days after the end of the quinine course, he was readmitted for uncomplicated falciparum malaria. Inpatient treatment used mefloquine this time. Clinical response was adequate, but the blood smear was still positive 10 days later. It was decided not to administer further treatment at that time. Subsequent clinical and parasitologic assessments 1 month and 3 months later showed the patient was cured. CONCLUSION: This report illustrates the critical role played by the spleen in parasite clearance. Clinical and parasitologic assessments are essential after treatment of asplenic patients for falciparum malaria.

Steroid Pulse Therapy May Mitigate Prolonged Neurological Manifestations after Eradication of Severe Plasmodium falciparum Parasitemia.

A 58-year-old Japanese man with a high parasitemia of Plasmodium falciparum, returning from Uganda, was admitted to our hospital since his consciousness level rapidly deteriorated after the initial dose of mefloquine. Despite the parasitemia was cleared by quinine by day 7, the coma remained unchanged and diffuse leukoencephalopathy was detected on magnetic resonance image. Steroid pulse therapy was initiated on day 8. Subsequently, the neurological manifestations improved and he was discharged on day 73 without any sequelae. Pathogenesis of P. falciparum causing cerebral malaria is diverse and complex. If neurological symptoms unusually prolong, steroid may be an effective treatment option.

Historical Review: Problematic Malaria Prophylaxis with Quinine.

Quinine, a bitter-tasting, short-acting alkaloid drug extracted from cinchona bark, was the first drug used widely for malaria chemoprophylaxis from the 19th century. Compliance was difficult to enforce even in organized groups such as the military, and its prophylaxis potential was often questioned. Severe adverse events such as blackwater fever occurred rarely, but its relationship to quinine remains uncertain. Quinine prophylaxis was often counterproductive from a public health viewpoint as it left large numbers of persons with suppressed infections producing gametocytes infective for mosquitoes. Quinine was supplied by the first global pharmaceutical cartel which discouraged competition resulting in a near monopoly of cinchona plantations on the island of Java which were closed to Allied use when the Japanese Imperial Army captured Indonesia in 1942. The problems with quinine as a chemoprophylactic drug illustrate the difficulties with medications used for prevention and the acute need for improved compounds.