Mefloquine

Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial

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Abstract

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate–mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6–14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg−1 single dose; n = 364) or to artesunate–mefloquine (antimalarial dosage: artesunate 4 mg kg−1 and mefloquine 8 mg kg−1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate–mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings.

Discussion

In this proof-of-concept, pragmatic, open-label, randomized, noninferiority trial, we demonstrated that a 3-day course of artesunate–mefloquine at antimalarial dosage was noninferior to a standard single-dose of praziquantel, for the treatment of schistosomiasis in African schoolchildren. This observation was mainly driven by the effect on S. haematobium infection. The mean arithmetic egg reduction rates were, however, above the recommended threshold of 90% (ref. 9) for both S. hematobium and S. mansoni species. Drug-related AEs were more frequent in the artesunate–mefloquine arm compared with the praziquantel arm, but they were all mild or moderate. An additional second and third courses of artesunate–mefloquine substantially increased the cure rate compared with a single course, with only a marginal increment of AEs. The frequency of schistosomiasis symptoms and abnormal morbidity markers 24 weeks after initial treatment decreased in similar proportions in both study arms.

This is an adequately powered trial that evaluated the parasitological and clinical efficacy of the antimalarial combination artesunate–mefloquine as an alternative to praziquantel for the treatment of schistosomiasis. This study also explored the incremental benefit, as well as cumulative toxicity, of repeated courses of artesunate–mefloquine. Apart from its large sample size, other strengths of this trial included its pragmatic school-based design, which is similar to the MDA reality, the rigorous parasitological evaluation by experienced microscopists blinded to treatment, the careful follow-up of potential mefloquine toxicity up to 1 month after each drug administration, and the molecular monitoring of malaria infection on dried blood spots in both study arms. There were also some limitations. For the efficacy outcome, cure rates were assessed by conventional microscopy, which is still the WHO established standard for diagnosis of schistosomiasis and assessment of treatment response9. However, microscopy is considered an insensitive method that tends to overestimate treatment efficacy. Concurrently with microscopic examinations, we therefore evaluated a set of highly sensitive antigen-based (that is, circulating cathodic and anodic antigens) and DNA-based detection assays as alternative tests of cure22; due to space limitations, comparative results on the performance of those diagnostics will be published elsewhere. The use of the egg reduction rate as measure for the efficacy outcome would have substantially inflated the required sample size, beyond the scope of a proof-of-concept trial. In addition, the study design did not allow to investigate the parasitic efficacy of a single course of artesunate–mefloquine beyond the week 4 assessment, although activity of mefloquine on juvenile worms may provide longer protection than praziquantel. For the safety analysis, the absence of praziquantel placebo comparison at weeks 6 and 12 might have overestimated the difference in occurrence of AEs between the two treatment arms. Also, this proof-of-concept trial, deliberately conducted in an area with low malaria endemicity to focus on schistosomiasis endpoints, did not provide insights on the potential benefits and risks of single and repeated artesunate–mefloquine administrations on malaria infection or on the potential emergence of resistance. Finally, the ultrasound assessments scheduled at the interim (week 24) and final (week 48) assessments could not take place because of the COVID-19 pandemic, during which schools were closed and large gatherings forbidden. The frequency of ultrasound abnormalities was, however, rather low at the initial assessment. The sampling of urine, stool and blood was able to be kept on schedule through door-to-door visits throughout the study period.

The clinical efficacy of artemisinin derivatives on schistosomiasis has been found inferior to that of praziquantel18,27, as their activity is mainly restricted to the juvenile worms. In addition, the use of artemisinin derivatives in monotherapy as antischistosomal agents cannot be envisaged in the large areas of sub-Saharan Africa where P. falciparum is co-endemic, given the risk of malaria resistance to this key compound. Mefloquine is an antimalarial drug with activity against both juvenile and adult Schistosoma worms, but the clinical evidence of efficacy is very limited16,19,20. The evaluation of the artesunate–mefloquine combination has provided equivocal results in two small exploratory trials, so far16,20. The current trial demonstrates substantial antiparasitic activity of artesunate–mefloquine, with clinical benefit on schistosomiasis-related symptoms and morbidity, and the incremental effect of successive treatment courses. Additionally, its safety profile is confirmed, even in repeated administration, at least in the pediatric population21,28,29. Therefore, the important potential of artesunate–mefloquine as repurposed antischistosomal drug is highlighted, with the key advantage that it is a cheap and immediately available treatment. The slightly lower tolerance and need of 3-day administration would, however, position it as second-line treatment, in case of intolerance or decreased susceptibility to praziquantel, pending future feasibility and acceptability studies. Acute schistosomiasis in nonimmune travelers could be another clinical scenario where the artesunate–mefloquine combination, with its activity on juvenile worms, would be worth being evaluated against praziquantel.

Moreover, the concomitant antimalarial and antischistosomal activity of artesunate–mefloquine opens exciting research perspectives in coinfected patients and in co-endemic areas30. The dual benefit for coinfected patients appears quite obvious, but the simultaneous diagnosis of both infections is probably infrequent in first-line health facilities. However, artesunate–mefloquine could be studied as the preferred ACT in any child presenting with clinical malaria in regions moderately or highly prevalent for schistosomiasis. In a larger perspective, as transmission of both malaria and schistosomiasis peaks during the rainy season in Africa, it would also be interesting to explore the dual protective effect of seasonal administration of artesunate–mefloquine at the community level, by analogy with the seasonal preventive chemotherapies recommended by the WHO for malaria control31,32,33,34. Since repeated courses are acceptably safe and provide cumulative efficacy on schistosomiasis, it would be worth evaluating different schedules and timing of artesunate–mefloquine as seasonal chemoprevention against both malaria31 and schistosomiasis in school-aged children. In a next step, research into artesunate–mefloquine as an alternative seasonal (malaria) chemoprevention in children <5 years could also be considered, as this age group is also particularly affected by both conditions.

Perennial or seasonal intermittent preventive treatment in school-aged children is conditionally recommended by the WHO in malaria-endemic settings with moderate to high transmission, preferably with regimens not used locally as first or second-line malaria treatment31. Artesunate–mefloquine could be a good investigational candidate for seasonal intermittent preventive treatment in children of different age groups, in settings where prevalence of both malaria and schistosomiasis is moderate or high. However, the emergence of artemisinin resistance in the past few years in East Africa35 has increased legitimate concerns about the use of ACT-based preventive chemotherapies. Although there is no evidence that such interventions promote clinical resistance36, adequate molecular monitoring should be integrated into each new trial and routinely established wherever implementation of such strategy is being considered. Next-generation sequencing tools such as deep amplicon sequencing, capable of targeting multiple markers in a single assay, are gradually being deployed to support the surveillance activities of malaria control programs37.

In conclusion, the combination artesunate–mefloquine at antimalarial dosage is safe and its efficacy against schistosomiasis is noninferior to that of standard-care praziquantel, at least for S. haematobium infection. If similar results are reproduced in other epidemiological settings, especially where S. mansoni is more prevalent, or in other demographics, such as malaria-coinfected patients, more advanced schistosomiasis cases or pre-school-aged children, it could become one of the much-needed alternative drugs for individualized treatments.

Malaria drug causes brain damage that mimics PTSD: case study

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The case of a service member diagnosed with post-traumatic stress disorder but found instead to have brain damage caused by a malaria drug raises questions about the origin of similar symptoms in other post-9/11 veterans.

According to the case study published online in Drug Safety Case Reports in June, a U.S. military member sought treatment at Walter Reed National Military Medical Center in Bethesda, Maryland, for uncontrolled anger, insomnia, nightmares and memory loss.

The once-active sailor, who ran marathons and deployed in 2009 to East Africa, reported stumbling frequently, arguing with his family and needing significant support from his staff while on the job due to cognitive issues.

Physicians diagnosed the service member with anxiety, PTSD and a thiamine deficiency. But after months of treatment, including medication, behavioral therapy and daily doses of vitamins, little changed.

The patient continued to be hobbled by his symptoms, eventually leaving the military on a medical discharge and questioning his abilities to function or take care of his children.

It wasn’t until physicians took a hard look at his medical history, which included vertigo that began two months after his Africa deployment, that they suspected mefloquine poisoning: The medication once used widely by the U.S. armed forces to prevent and treat malaria has been linked to brain stem lesions and psychiatric symptoms.

While no test is available to prove the sailor suffered what is called “mefloquine toxicity,” he scored high enough on an adverse drug reaction probability survey to tie his symptoms to the drug, also known as Lariam.

The sailor told his Walter Reed doctors that he began experiencing vivid dreams and disequilibrium within two months of starting the required deployment protocol.

Symptoms can last years

Case reports of mefloquine side effects have been published before, but the authors of “Prolonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine” say their example is unusual because it shows that symptoms can last years after a person stops taking the drug.

And since the symptoms are so similar to PTSD, the researchers add, they serve to “confound the diagnosis” of either condition.

“It demonstrates the difficulty in distinguishing from possible mefloquine-induced toxicity versus PTSD and raises some questions regarding possible linkages between the two diagnoses,” wrote Army Maj. Jeffrey Livezey, chief of clinical pharmacology at the Walter Reed Army Institute of Research, Silver Spring, Maryland.

Once the U.S. military’s malaria prophylactic of choice, favored for its once-a-week dosage regimen, mefloquine was designated the drug of last resort in 2013 by the Defense Department after the Food and Drug Administration slapped a boxed warning on its label, noting it can cause permanent psychiatric and neurological side effects,

50,000 prescriptions in 2003

At the peak of mefloquine’s use in 2003, nearly 50,000 prescriptions were written by military doctors.

That figure dropped to 216 prescriptions in 2015, according to data provided by the Defense Department. According to DoD policy, mefloquine is prescribed only to personnel who can’t tolerate other preventives.

But Dr. Remington Nevin, a former Army epidemiologist and researcher at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said any distribution of the drug, which was developed by the Army in the late 1970s, is too much.

“This new finding should motivate the U.S. military to consider further revising its mefloquine policy to ban use of the drug altogether,” Nevin told Military Times.

While a case study is a snapshot of one patient’s experience and not an indication that everyone who took or takes mefloquine has similar issues, one randomized study conducted in 2001 — more than a decade after the medication was adopted by the military for malaria prevention — showed that 67 percent of study participants reported more than one adverse side effect, such as nightmares and hallucinations, and 6 percent needed medical treatment after taking the drug.

Yet mefloquine remains on the market while Walter Reed Army Institute of Research conducts research on medications in the same family as mefloquine, including tafenoquine, hoping to find a malarial preventive that is less toxic but as effective.

Mefloquine was developed under the Army’s malaria drug discovery program and approved for use as a malaria prophylactic in 1989. Shortly after commercial production began, stories surfaced about side effects, including hallucinations, delirium and psychoses.

Once considered ‘well-tolerated’

Military researchers maintained, however, that it was a “well-tolerated drug,” with one WRAIR scientist attributing reports of mefloquine-associated psychoses to a “herd mentality.”

“Growing controversies over neurological side effects, though, are appearing in the literature, from journal articles to traveler’s magazines and resulting legal ramifications threaten global availability,” wrote researcher Army Col. Wilbur Milhous in 2001. “As the ‘herd mentality’ of mefloquine associated psychoses continues to gain momentum, it will certainly affect operational compliance and readiness. … The need for a replacement drug for weekly prophylaxis will continue to escalate.”

Mefloquine was implicated in a series of murder-suicides at Fort Bragg, North Carolina, in 2002, and media reports also tied it to an uptick in military suicides in 2003.

A 2004 Veterans Affairs Department memo urged doctors to refrain from prescribing mefloquine, citing individual cases of hallucinations, paranoia, suicidal thoughts, psychoses and more.

The FDA black box warning nine years later led to a sharp decline in demand for the medication. But while the drug is no longer widely used, it has left damage in its wake, with an unknown number of troops and veterans affected, according to retired Navy Cmdr. Bill Manofsky, who was discharged from the military in 2004 for PTSD and later documented to have mefloquine toxicity.

He said the Defense Department and VA should do more to understand the scope of the problem and reach out to those who have been affected.

New concerns rising over antimalaria drug

“I’m kind of the patient zero for this and I now spend my life trying to help other veterans who have health problems that may have been caused by mefloquine. More needs to be done,” Manofsky said.

He said while there is no cure for the vertigo and vestibular damage or the psychiatric symptoms caused by mefloquine, treatments for such symptoms, such as behavior and vestibular therapy help.

And, he added, simply having a diagnosis is comforting.

Veterans can seek help

“Veterans need to come forward,” he said. “The VA’s War Related Illness and Injury Study Center can help.”

The patient in the case study written by Livezey continues to see a behavioral therapist weekly but takes no medications besides vitamins and fish oil.

He sleeps just three to four hours a night, has vivid dreams and nightmares and vertigo that causes him to fall frequently, and continues to report depression, restlessness and a lack of motivation.

The sailor’s experience with mefloquine has been “severely life debilitating” and Livezey notes that the case should alert physicians to the challenges of diagnosing patients with similar symptoms.

“This case documents the potential long-term and varied mefloquine-induced neuropsychiatric side effects,” he wrote.

Source:www.militarytimes.com

Anti-malarial drug linked to Afghan massacre.

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Soldier was taking mefloquine when he killed 16 civilians, report indicates.

bilde

in less than a month, Army Staff Sgt. Robert Bales will be sentenced for the massacre of 16 Afghan civilians in March 2012.

His attorney, John Henry Browne, has not publicly disclosed whether he will use a mental health defense to fight for a parole-eligible sentence.

But an argument could be made that Bales, 40, was out of his mind:

■ He was treated for a traumatic brain injury resulting from a rollover accident in 2010 and possibly had post-traumatic stress disorder.

■ He admitted to using steroids, which can cause aggression and violence.

■ And new evidence suggests he was prescribed an anti-malaria drug known to cause hallucinations, aggression and psychotic behavior in some patients.

The Food and Drug Administration received notification in April 2012 from the maker of the anti-malarial drug Lariam, also manufactured under the generic name mefloquine, that a patient taking the medication “developed homicidal behavior and led to homicide killing 17 [sic] Afghans.”

The report, obtained July 5 by Military Times through a Freedom of Information Act request, states:

“It was reported that this patient was administered mefloquine in direct contradiction to U.S. military rules that mefloquine should not be given to soldiers who had suffered traumatic brain injury due to its propensity to cross blood-brain barriers inciting psychotic, homicidal or suicidal behavior.”

A spokesman for the manufacturer, Roche, said the company received an initial report March 29 from a pharmacist in the U.S. and was obligated to notify drug monitoring agencies worldwide by law.

An FDA adverse event report does not mean the medication caused any health problems; it indicates only that patients developed symptoms while using the product.

But the medically confirmed report does imply either that the source was someone involved with the patient’s medical care or that Roche received documentation verifying the information, said Dr. Remington Nevin, a leading researcher on mefloquine toxicity, who also filed a FOIA request for the information.

In 2009, the assistant secretary of defense for health affairs issued a policy listing mefloquine as a third-choice malaria preventative, behind doxycycline and chloroquine.

The memo stated that in cases where a service member had a history of neurological or mental health disorder, mefloquine should be used with caution only in areas where the malaria strain is resistant to other medications.

In January 2012, just months before the Kandahar massacre, Dr. Jonathan Woodson, assistant secretary of defense for health affairs, directed the Army, Navy and Air Force and the commander of the Joint Task Force National Capital Region Medical Command to provide his office with all data and policies related to mefloquine.

From 2010 to 2011, the military health system wrote 14,420 prescriptions for mefloquine, down from 55,766 from 2007 to 2009.

The drug remains popular for distribution among special operations forces because it is taken weekly rather than daily.

The FDA launched a review earlier this year to determine whether the drug needs a stronger warning label or more prescribing restrictions. That investigation is ongoing.

From 1996 to 2012, the FDA received 438 reports of adverse symptoms from 37 patients who took mefloquine or Lariam, according to a review of records conducted by Military Times.

Symptoms ranged from homicidal and suicidal ideation and psychosis to vomiting, nausea and dizziness.

Other factors that may play into Bales’ defense include discussion that he may have suffered from post-traumatic stress disorder. But while research shows that PTSD often causes anxiety, irritability and impulsive aggression, it is not associated with premeditated aggression and violence.

A medication Bales has admitted to taking is stanazolol or Winstrol, an anabolic steroid used for building muscles. Steroids can cause violence and aggression in “a certain percentage of people,” according to Dr. Harrison Pope, director of the biological psychiatry laboratory at McLean Hospital, Belmont, Mass.

All steroids “are capable of producing these reactions in a small minority of people,” Pope said. But steroids are not associated with memory loss during a violent incident, Pope added.

Bales told the judge in his case, Col. Jeffery Nance, that he does not remember setting fire to several bodies during his rampage.

Bales’ sentencing hearing is set for Aug. 19. Browne, his attorney, was to notify the court by July 1 if he planned to call on mental health experts as part of Bales’ defense. Neither Browne nor the Army returned requests regarding whether that motion has been filed.

If Bales receives a sentence that includes the possibility of parole, he would be eligible after 10 years.