Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

Fascioliasis occurs on all inhabited continents. It is caused by Fasciola hepatica and Fasciola gigantica, trematode parasites with complex life cycles, and primarily affects domestic livestock. Humans become infected after ingestion of contaminated food (typically wild aquatic vegetables) or water. Fascioliasis may be difficult to diagnose as many symptoms are non-specific (e.g. fever, abdominal pain and anorexia). Treatment options are limited, with older effective therapies such as emetine and bithionol no longer used due to safety issues and unavailability, and most common anthelminthics having poor efficacy. Clinical trials conducted over a 25-year period, together with numerous case reports, demonstrated that triclabendazole has high efficacy in the treatment of human fascioliasis in adults and children and in all stages and forms of infection. Triclabendazole was approved for human use in Egypt in 1997 and in France in 2002 and a donation program for the treatment of fascioliasis in endemic countries was subsequently established by the manufacturer and administered by the World Health Organization. Here the published data on triclabendazole in the treatment of human fascioliasis are reviewed, with a focus on more recent data, in light of the 2019 US Food and Drug Administration approval of the drug for use in human infections.

In Southeast Asia, mutations in the Plasmodium falciparum k13 gene have led to delayed parasite clearance and treatment failures in malaria patients receiving artemisinin combination therapies. Until recently, relevant k13 mutations had been mostly absent from Africa. Between 2018 and 2019 a phase 2 clinical study with 186 patients was conducted in Mali, Gabon, Ghana, Uganda and Rwanda. Patients with malaria were randomized and treated with artemether-lumefantrine or cipargamin. Here we report an allele frequency of 22% for R561H in Rwanda and associated delayed parasite clearance. Notwithstanding, efficacy of artemether-lumefantrine remained high in Rwanda with a 94.4% PCR-corrected cure rate.

Background Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). Methods This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)–corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. Results All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. Conclusions Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. Clinical Trials Registration ClinicalTrials.gov (NCT03334747).

The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum. Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma cipargamin concentrations. Parasite regrowth was treated with piperaquine monotherapy to clear asexual parasites, while allowing gametocyte transmissibility to mosquitoes to be investigated. An initial rapid decrease in parasitemia occurred in all participants following cipargamin dosing, with a parasite clearance half-life of 3.99 h. As anticipated from the dose selected, parasite regrowth occurred in all 8 subjects 3-8 days after dosing, and allowed the pharmacokinetic/pharmacodynamic relationship to be determined. Based on the limited data from the single sub-therapeutic dose cohort, a minimum inhibitory concentration of 11.6 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 23.5 ng/mL was estimated, and a single 95 mg dose (95% CI: 50-270) was predicted to clear 109 parasites/mL. Low gametocyte densities were detected in all subjects following piperaquine treatment, which did not transmit to mosquitoes. Serious adverse liver function changes were observed in three subjects which led to premature study termination. The antimalarial activity characterized in this study supports the further clinical development of cipargamin as a new treatment for P. falciparum malaria, although the hepatic safety profile of the compound warrants further evaluation.