Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

Background Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Methods Glucose-6-phosphate dehydrogenase normal patients with uncomplicated P. vivax malaria were randomized to receive either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine; given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Pre-dose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine and carboxyprimaquine were measured. Methemoglobin levels were measured on day 7. Results Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the primaquine mg/kg daily dose, day of sampling, partner drug, and fever clearance, there was a significant non-linear relationship between age and trough primaquine and carboxyprimaquine concentrations, and day methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations 0.53 (95% CI: 0.39- 0.73) fold lower, trough carboxyprimaquine concentrations 0.45 (95% CI: 0.35- 0.55) fold lower, and day 7 methemoglobin levels 0.87 (95% CI: 0.58-1.27) fold lower. Increasing concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence. Conclusion Young children have lower primaquine and carboxyprimaquine exposures, and lower levels of methemoglobinemia, than adults. Young children may need higher weight adjusted primaquine doses than adults.

Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

Background: Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Methods: Glucose-6-phosphate dehydrogenase normal patients with uncomplicated P. vivax malaria were randomized to receive either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine; plus either 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Pre-dose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine and carboxyprimaquine were measured. Methemoglobin levels were measured on days 1, 4, 7. Results: Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the primaquine mg/kg daily dose, day of sampling, partner drug, and fever clearance, there was a significant non-linear relationship between age and trough primaquine and carboxyprimaquine concentrations, and day methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations 0.55 (95% CI: 0.39- 0.78) fold lower, trough carboxyprimaquine concentrations 0.43 (95% CI: 0.34- 0.55) fold lower, and day 7 methemoglobin levels 0.87 (95% CI: 0.58-1.27) fold lower. Increasing concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were also associated with higher day 7 primaquine and carboxyprimaquine concentrations. Increased methemoglobin concentrations were associated with a lower risk of recurrence. Conclusion: Young children have lower primaquine and carboxyprimaquine exposures, and lower levels of methemoglobinemia, than adults. Young children may need higher weight adjusted primaquine doses than adults.

Review on Arakoda (Tafenoquine) and its approach as an Anti-Malarial Agent.

Tafenoquine is an analogue of primaquine with an improved therapeutic and safety profile. It has a long half-life and activity against liver-stage malaria parasites, so may be useful for chemoprophylaxis. Antimalarial agents are drugs used for the treatment or prophylaxis of malaria. Malaria is caused by four species of Plasmodium, such as Plasmodium falciparum, P. malariae, P. ovale, and P. vivax. Arakoda contains tafenoquine succinate, an antimalarial agent for oral administration. The molecular formula of tafenoquine succinate is C24H28F3N3O3∙C4H6O4 and its molecular weight is 581.6 as the succinate salt. It is given in prophylaxis of malaria patient aged 18 years older. Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species. G6PD test is performed before giving the drug. Analytical studies were on NMR, IR, MS, HPLC, Flourimetry analysis. In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0.436mcg against blood stages of seven strains of P. falciparum. The long‐acting 8‐aminoquinoline tafenoquine (TQ) co-administered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Volume of distribution. The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. Routes of elimination are through feces.

Prescription de tramadol chez les enfants : une bonne alternative à la codéine ?

La population pédiatrique est considérée comme vulnérable, et la prise en charge de la douleur nociceptive y est parfois complexe mais essentielle. Depuis 2013, la prescription de codéine est restreinte chez les enfants en raison du risque de dépression respiratoire parfois fatale lié à l’activité variable du cytochrome P450 (CYP) 2D6 qui bioactive la codéine en morphine. Les options thérapeutiques approuvées chez l’enfant sont limitées, et pour nombre de prescripteurs, le tramadol est devenu l’alternative de choix à la codéine. Le tramadol est cependant, comme la codéine, un promédicament opioïde qui doit être bioactivé par le CYP2D6. Il est donc également soumis à une importante variabilité de sa réponse et expose les enfants aux mêmes risques de complications respiratoires. La décision de traiter par tramadol doit prendre en compte les comédications, les comorbidités du patient, le type de douleur et les conditions de surveillance. Les soignants et les parents doivent être informés des risques liés à l’administration du tramadol, notamment la variabilité interindividuelle, les risques d’interactions médicamenteuses et les signes de surdosage. Dans les situations de douleurs récurrentes, une approche personnalisée, avec adaptation des doses et sélection du médicament antalgique en fonction de l’activité du CYP2D6, est certainement la méthode la plus sûre. Lorsque l’activité du CYP2D6 n’est pas connue, la prescription de tramadol reste envisageable si le traitement est initié à la dose minimale efficace, titré sous surveillance et administré sous une forme posologique adaptée à l’enfant. Chez l’enfant de moins de 12 ans et en présence de facteurs de risque de dépression respiratoire, la morphine reste une option prudente, puisque son métabolisme ne dépend pas du CYP2D6.

Quasi-Irreversible Inhibition of CYP2D6 by Berberine

In our previous study, Hwang-Ryun-Hae-Dok-Tang, which contains berberine (BBR) as a main active ingredient, inhibited cytochrome P450 (CYP) 2D6 in a quasi-irreversible manner. However, no information is available on the detailed mechanism of BBR-induced CYP2D6 inhibition. Thus, the present study aimed to characterize the inhibition mode and kinetics of BBR and its analogues against CYP2D6 using pooled human liver microsomes (HLM). BBR exhibited selective quasi-irreversible inhibition of CYP2D6 with inactivation rate constant (kinact) of 0.025 min−1, inhibition constant (KI) of 4.29 µM, and kinact/KI of 5.83 mL/min/µmol. In pooled HLM, BBR was metabolized to thalifendine (TFD), demethyleneberberine (DMB), M1 (proposed as demethylene-TFD), and to a lesser extent berberrubine (BRB), showing moderate metabolic stability with a half-life of 35.4 min and a microsomal intrinsic clearance of 7.82 µL/min/mg protein. However, unlike BBR, those metabolites (i.e., TFD, DMB, and BRB) were neither selective nor potent inhibitors of CYP2D6, based on comparison of half-maximal inhibitory concentration (IC50). Notably, TFD, but not DMB, exhibited metabolism-dependent CYP2D6 inhibition as in the case of BBR, which suggests that methylenedioxybenzene moiety of BBR may play a critical role in the quasi-irreversible inhibition. Moreover, the metabolic clearance of nebivolol (β-blocker; CYP2D6 substrate) was reduced in the presence of BBR. The present results warrant further evaluation of BBR–drug interactions in clinical situations.

β-Naphthoflavone and Ethanol Reverse Mitochondrial Dysfunction in A Parkinsonian Model of Neurodegeneration

The 1-methyl-4-phenylpyridinium (MPP+) is a parkinsonian-inducing toxin that promotes neurodegeneration of dopaminergic cells by directly targeting complex I of mitochondria. Recently, it was reported that some Cytochrome P450 (CYP) isoforms, such as CYP 2D6 or 2E1, may be involved in the development of this neurodegenerative disease. In order to study a possible role for CYP induction in neurorepair, we designed an in vitro model where undifferentiated neuroblastoma SH-SY5Y cells were treated with the CYP inducers β-naphthoflavone (βNF) and ethanol (EtOH) before and during exposure to the parkinsonian neurotoxin, MPP+. The toxic effect of MPP+ in cell viability was rescued with both βNF and EtOH treatments. We also report that this was due to a decrease in reactive oxygen species (ROS) production, restoration of mitochondrial fusion kinetics, and mitochondrial membrane potential. These treatments also protected complex I activity against the inhibitory effects caused by MPP+, suggesting a possible neuroprotective role for CYP inducers. These results bring new insights into the possible role of CYP isoenzymes in xenobiotic clearance and central nervous system homeostasis.