Role of clinical pharmacists to prevent drug interactions in cancer outpatients: a single-centre experience.

BACKGROUND: Cancer patients are especially vulnerable to drug interactions, which may alter the efficacy and toxicity of treatment, leading to severe clinical consequences. OBJECTIVE: Determine the incidence of such interactions in patients receiving chemotherapy, as well as to identify the drugs most frequently involved, investigate the influence of the pharmacist's interventions and verify the degree of acceptance of pharmacist's recommendations by the medical team. SETTING: The oncology department of a Spanish tertiary hospital. METHODS: During 3 months, all the drug interactions in the regular combined with treatment for cancer were analysed using two databases, and recommendations were made when clinically significant interactions (CSI) were identified. MAIN OUTCOME MEASURE: Incidence of CSI in oncology outpatients; drugs involved in CSI. RESULTS: Of the 75 patients included, 31 (41%) presented CSI. Most interactions were among drugs included in the patient's usual treatment. The principal drug groups involved in CSI were cytostatic agents, antiemetics and antidepressants. The hospital pharmacist intervened on 20 occasions (35% of the patients presenting drug interactions). These interventions mainly focused on recommendations to modify or discontinue drug prescriptions, and were followed in 94% of cases. CONCLUSION: The incidence of drug interactions in cancer patients is high, and they most often involve medications to treat comorbid conditions. The pharmacist, as a member of the multidisciplinary team, can contribute significantly by checking the treatment prescribed and detecting interactions, to reduce medication-related problems and to optimise drug therapy for these patients.

Sitamaquine overcomes ABC-mediated resistance to miltefosine and antimony in Leishmania.

Although oral miltefosine represented an important therapeutic advance in the treatment of leishmaniasis, the appearance of resistance remains a serious threat. LMDR1/LABCB4, a P-glycoprotein-like transporter included in the Leishmania ABC (ATP-binding cassette) family, was the first molecule shown to be involved in experimental miltefosine resistance. LMDR1 pumps drugs out of the parasite, thereby decreasing their intracellular accumulation. Sitamaquine, another promising oral drug for leishmaniasis, is currently in phase 2b clinical trials. The physicochemical features of this drug suggested to us that it could be considered for use as an LMDR1 inhibitor. Indeed, we report herein that nonleishmanicidal concentrations of sitamaquine reverse miltefosine resistance in a multidrug resistance Leishmania tropica line that overexpresses LMDR1. This reversal effect is due to modulation of the LMDR1-mediated efflux of miltefosine. In addition, sitamaquine is not a substrate of LMDR1, as this transporter does not affect sitamaquine accumulation or sensitivity in the parasite. Likewise, we show that ketoconazole, another oral leishmanicidal drug known to interact with ABC transporters, is also able to reverse LMDR1-mediated miltefosine resistance, although with a lower efficiency than sitamaquine. Molecular docking on a three-dimensional homology model of LMDR1 showed different preferential binding sites for each substrate-inhibitor pair, thus explaining this different behavior. Finally, we show that sitamaquine is also able to modulate the antimony resistance mediated by MRPA/LABCC3, another ABC transporter involved in experimental and clinical antimony resistance in this parasite. Taken together, these data suggest that the combination of sitamaquine with miltefosine or antimony could avoid the appearance of resistance mediated by these membrane transporters in Leishmania.

The 8-aminoquinoline analogue sitamaquine causes oxidative stress in Leishmania donovani promastigotes by targeting succinate dehydrogenase.

The 8-aminoquinoline analogue sitamaquine (SQ) is an oral antileishmanial drug currently undergoing phase 2b clinical trials for the treatment of visceral leishmaniasis. In the present study, we investigated the mechanism of action of this drug in Leishmania donovani promastigotes. SQ causes a dose-dependent inhibition of complex II (succinate dehydrogenase) of the respiratory chain in digitonin-permeabilized promastigotes, together with a drop in intracellular ATP levels and a decrease of the mitochondrial electrochemical potential. This is associated with increases of reactive oxygen species and intracellular Ca(2+) levels, a higher percentage of the population with sub-G(1) DNA content, and exposure of phosphatidylserine. Taken together, these results support a lethal mechanism for SQ that involves inhibition of the respiratory chain complex II, which in turn triggers oxidative stress and finally leads to an apoptosis-like death of Leishmania parasites.

Sitamaquine sensitivity in Leishmania species is not mediated by drug accumulation in acidocalcisomes.

Sitamaquine (WR6026), an 8-aminoquinoline derivative, is a new antileishmanial oral drug. As a lipophilic weak base, it rapidly accumulates in acidic compartments, represented mainly by acidocalcisomes. In this work, we show that the antileishmanial action of sitamaquine is unrelated to its level of accumulation in these acidic vesicles. We have observed significant differences in sitamaquine sensitivity and accumulation between Leishmania species and strains, and interestingly, there is no correlation between them. However, there is a relationship between the levels of accumulation of sitamaquine and acidotropic probes, acidocalcisomes size, and polyphosphate levels. The Leishmania major AP3delta-null mutant line, in which acidocalcisomes are devoid of their usual polyphosphate and proton content, is unable to accumulate sitamaquine; however, both the parental strain and the AP3delta-null mutants showed similar sensitivities to sitamaquine. Our findings provide clear evidence that the antileishmanial action of sitamaquine is unrelated to its accumulation in acidocalcisomes.